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Enzalutamide (MDV3100) CONFIDENTIAL Cancer Investigator’s Brochure Edition 10

Investigator’s Brochure Enzalutamide (MDV3100)

For the Treatment of Cancer

Astellas Including Astellas Pharma Global Development, Inc (APGD), Astellas Pharma Europe BV, Astellas Pharma Inc and Affiliates. Medivation, Inc., a wholly owned subsidiary of Inc.

Edition Number Edition 10 Edition Date: 18 Jun 2018 Release Date Considered to be date of the last signature

Replaces Previous Edition 9, dated 01 Jun 2016

The information contained in this brochure is supplied as a background for clinical investigations. This document contains confidential information which is the intellectual property of Astellas and Medivation, Inc. By reviewing this document, you agree to hold this information in confidence and not copy or disclose it to others or use it for unauthorized purposes except (1) as otherwise agreed to in writing; (2) where required by applicable law; (3) where disclosure is directly related to the care and safety of the research participant; and (4) where disclosure of such information is made to a member of the investigator’s team who agrees to hold this information in confidence.

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Table of Contents 1 SUMMARY·························································································10 2 INTRODUCTION·················································································19 2.1 Cancer ················································································19 2.2 ··················································································20 2.3 HCC·····························································································21 3 PHYSICAL, CHEMICAL AND PHARMACEUTICAL PROPERTIES AND FORMULATION ·················································································24 3.1 Drug Substance················································································24 3.2 Drug Product···················································································24 3.2.1 Capsule ···················································································24 3.2.2 Tablet ·····················································································25 4 NONCLINICAL STUDIES······································································26 4.1 Nonclinical Pharmacology ···································································26 4.1.1 Primary Pharmacodynamics ···························································26 4.1.1.1 Primary Pharmacodynamics············································26 4.1.1.2 In Vivo Primary Pharmacodynamics············································27 4.1.1.3 Primary Pharmacodynamics in HCC············································28 4.1.2 Secondary Pharmacodynamics ························································28 4.1.3 Safety Pharmacology ···································································29 4.1.3.1 Safety Pharmacology Studies·······················29 4.1.3.2 Respiratory Safety Pharmacology Study········································29 4.1.3.3 Cardiovascular Safety Pharmacology Studies··································29 4.1.4 Pharmacodynamic Drug Interactions ·················································30 4.1.5 Other Pharmacology Studies···························································30 4.2 and Product ················································30 4.2.1 Absorption················································································30 4.2.2 Distribution···············································································30 4.2.3 Metabolism···············································································30 4.2.4 ·················································································31 4.2.5 Pharmacokinetic Drug Interactions ···················································31 4.3 Toxicology ·····················································································32 4.3.1 Single-dose Toxicity ····································································32 4.3.2 Repeat-dose Toxicity ···································································32

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4.3.3 Genotoxicity ·············································································33 4.3.4 Carcinogenicity ··········································································34 4.3.5 Reproductive and Developmental Toxicity ··········································35 4.3.6 Local Tolerance··········································································35 4.3.7 Other Toxicity Studies ··································································35 4.3.7.1 Phototoxicity ·······································································35 4.4 Integrated Nonclinical Overview and Conclusion: Potential Clinical Relevance ·····35 5 EFFECTS IN HUMANS ·········································································39 5.1 Pharmacokinetics and Product Metabolism in Humans ··································49 5.1.1 Pharmacokinetics········································································49 5.1.1.1 Absorption··········································································49 5.1.1.2 Distribution·········································································49 5.1.1.3 Metabolism ·········································································50 5.1.1.4 Elimination ·········································································50 5.1.1.5 Food Effects ········································································51 5.1.2 Pharmacokinetics in Special Populations·············································51 5.1.3 DDIs ······················································································52 5.1.3.1 Potential for Enzalutamide to Affect Exposures to Other Drugs·············52 5.1.3.2 Potential for Other Drugs to Affect Exposure to Enzalutamide··············54 5.1.3.3 Potential for Interactions with Transporters ····································55 5.1.4 Pharmacodynamics······································································55 5.2 Safety and Efficacy ···········································································56 5.2.1 Overview of Efficacy ···································································56 5.2.1.1 Efficacy in Metastatic CRPC Population ·······································57 5.2.1.2 Summary of Efficacy in Metastatic CRPC ·····································69 5.2.1.3 Efficacy in Nonmetastatic CRPC ················································70 5.2.1.4 Efficacy in -naïve ···································73 5.2.1.5 Efficacy in Breast Cancer·························································75 5.2.1.6 Efficacy in HCC ···································································82 5.2.2 Safety ·····················································································83 5.2.2.1 Exposure ············································································83 5.2.2.2 Summary of Safety in CRPC Studies ···········································84 5.2.2.3 Safety in Female Patients With Breast Cancer ······························· 105 5.2.2.4 Summary of Safety in Patients With HCC···································· 112 5.2.2.5 Safety in Special Populations ·················································· 113

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5.2.2.6 Overdose, Dependence, Rebound and Abuse ································ 114 5.2.2.7 Effects on Ability to Drive or Operate Machinery or Impairment of Mental Ability···································································· 114 5.2.2.8 Safety Data From Individual Completed and Ongoing Studies ············ 115 5.2.2.9 Safety Data From Postmarketing Experience ································ 115 5.2.3 Expected Serious Adverse Reactions (Reference Safety Information for Assessment of Expectedness of Serious Adverse Reactions) ···················· 115 5.3 Marketing Experience ······································································ 117 6 SUMMARY OF DATA AND GUIDANCE FOR THE INVESTIGATOR··········· 119 6.1 General (Including Indications and Usage) ·············································· 119 6.1.1 Contraindications······································································ 119 6.1.2 Drug and Food Interactions ·························································· 119 6.1.3 Use in Special Populations ··························································· 121 6.1.4 Carcinogenesis, Mutagenesis, Teratogenicity and Impairment of Fertility····· 122 6.1.5 Use During and Lactation ··············································· 123 6.1.6 Warning and Precautions ····························································· 123 6.1.6.1 Overdose·········································································· 123 6.1.6.2 Hypersensitivity·································································· 124 6.1.6.3 Ischemic Heart Disease ························································· 124 6.1.6.4 Potential AEs Based on Those Reported for Drugs With Similar Pharmacological Activity······················································· 124 6.1.6.5 Potential AEs Based on the Results of Toxicology Studies in Animals··· 124 6.1.7 Expected Nonserious Adverse Reactions From Clinical Studies ················ 125

List of Attachments Attachment 1 Review and Approval

Appendices Appendix Individual Study Summaries

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List of In-Text Tables Table 1 Exposure Multiples of Enzalutamide and Its Metabolites in Rats of the Exposure in Humans··········································································35 Table 2 Summary of Completed and Ongoing Clinical Studies in the Enzalutamide Program ························································································41 Table 3 MDV3100-03 Summary of Efficacy Results (ITT Population) ·························61 Table 4 CRPC2 Summary of Efficacy Results (ITT Population) ·································64 Table 5 MDV3100-14 Summary of Primary and Secondary Efficacy Results (ITT Population)·····················································································71 Table 6 MDV3100-11 Summary of Efficacy Results for the ITT Population and by Diagnostic Status··············································································77 Table 7 Demographic and Baseline Characteristics in the Combined Phase 3 Studies (Male Prostate Cancer Patients) ·····························································86 Table 8 TEAEs Reported in at Least 5% of Patients in Either Treatment Group by System Organ Class in the Combined Phase 3 Studies···································87 Table 9 Grade 3 or Higher TEAEs Experienced by at Least 1% of Patients in the Combined Phase 3 Studies ···································································89 Table 10 TEAEs Resulting in Death by Preferred Term in at Least 2 Patients and Fatal TEAEs Within the SOC of Cardiac Disorders in the Combined Phase 3 Studies ·····90 Table 11 Treatment-emergent SAEs Experienced by at Least 1% of Patients in the Combined Phase 3 Studies ···································································91 Table 12 TEAEs Reported as the Primary Reason for Study Drug Discontinuation in More Than 2 Patients in Either Treatment Group of the Combined Phase 3 Studies··························································································92 Table 13 Overall Summary of TEAEs of Interest in the Combined Phase 3 Studies ············93 Table 14 Summary of Clinical Studies of Enzalutamide in Breast Cancer······················ 105 Table 15 Summary of Common TEAEs in 3 Open-label Studies of Enzalutamide in Female Patients With Advanced Breast Cancer (MDV3100-08, MDV3100-11 and 9785-CL-1121) ········································································· 107 Table 16 Summary of TEAEs in at Least 5% of Patients in the Cohort 1 or Cohort 2 Safety Populations, Double-blind Treatment Period, Study MDV3100-12·········· 109 Table 17 SARs for Enzalutamide Considered Expected for Regulatory Reporting Purposes ······················································································ 116 Table 18 Postmarketing SARs for Enzalutamide Considered Expected for Regulatory Reporting Purposes ········································································· 117 Table 19 Postmarketing Nonserious Adverse Reactions for Enzalutamide Considered Expected for Regulatory Reporting Purposes············································ 118 Table 20 Nonserious Adverse Reactions for Enzalutamide Considered Expected for Regulatory Reporting Purposes ··························································· 125

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List of In-Text Figures Figure 1 Chemical Structure of Enzalutamide ·······················································24 Figure 2 Enzalutamide Induces Tumor Regression in an LNCaP/ Receptor Mouse Xenograft Model of -resistant Prostate Cancer ·······················28 Figure 3 Effect of Enzalutamide on Other Drugs ····················································53 Figure 4 Effects of Other Drugs and Intrinsic/Extrinsic Factors on Enzalutamide ··············54 Figure 5 MDV3100-03 Forest Plot for Duration of Overall Survival: Subgroup Analysis (ITT Population) ··············································································59 Figure 6 MDV3100-03 Forest Plot for Duration of Radiographic Progression-Free Survival Based on Independent Central Review and Data Analysis Cutoff Date for the Interim Analysis - Subgroup Analysis (ITT Population) ························60 Figure 7 CRPC2 Forest Plot for Duration of Overall Survival - Subgroup Analysis (ITT Population)·····················································································63 Figure 8 Kaplan-Meier Curves for Progression-free Survival (Weeks) (A) and Overall Survival (Weeks) (B) by Diagnostic Subgroup in MDV3100-11 ·······················78 Figure 9 Kaplan-Meier Curves for Duration of Progression-free Survival (Cohort 1, ITT Population) (A) and Duration of Progression-free Survival (Cohort 2, ITT Population) (B) in MDV3100-12····························································81 Figure 10 Time to Onset of Second Primary Malignancy (Excluding Nonmelanoma Skin Cancer) ······················································································· 102

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List of Abbreviations ADT androgen deprivation therapy AE adverse event ALP alkaline phosphatase ALT alanine aminotransferase AR AR+ androgen receptor-positive AST aspartate aminotransferase AUC area under the plasma concentration-time curve

AUC24h area under the plasma concentration-time curve from time 0 to 24 hours after dosing

AUCinf area under the plasma concentration-time curve from time 0 to infinity after dosing

AUCtau area under the plasma concentration-time curve for the dosing interval BCRP breast cancer resistance BICR blinded independent central review BPI Brief Pain Inventory Short Form CBR clinical benefit rate CBR16 clinical benefit rate at 16 weeks CBR24 clinical benefit rate at 24 weeks CI confidence interval

CLCR creatinine clearance

Cmax maximum plasma concentration

Cmin minimum plasma concentration CNS central nervous system CR complete response CRPC castration-resistant prostate cancer CYP DDI drug- DHT DMC Data Monitoring Committee DOR duration of response Dx- diagnostic-negative Dx+ diagnostic-positive ECG electrocardiogram ECOG Eastern Cooperative Oncology Group EORTC European Organisation for Research and Treatment of Cancer EQ-5D European Quality of Life-Five Domain Scale ER receptor ER- estrogen receptor-negative ER+ estrogen receptor-positive FACT-P Functional Assessment of Cancer Therapy - Prostate FAS full analysis set GABA γ-aminobutyric acid HBV hepatitis B virus

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HCC hepatocellular carcinoma hCES human recombinant carboxylesterases HER2 human epidermal growth factor receptor 2 HER2- human epidermal growth factor receptor 2–negative HER2+ human epidermal growth factor receptor 2–positive hERG human ether-à-go-go related gene HR hazard ratio IB investigator’s brochure

IC50 half maximal inhibitory concentration ICR independent central review IGF insulin-like growth factor IHC immunohistochemistry INR international normalized ratio ITT intent-to-treat

Ki inhibition constant LDH lactate dehydrogenase LHRH -releasing hormone MFS -free survival MRP multidrug resistance-associated protein MTD maximum tolerated dose NR not reached NYR not yet reached OAT organic anion transporter OATP organic anion transporting polypeptide OCT organic cation transporter ORR overall response rate OS overall survival PCWG2 Prostate Cancer Clinical Trials Working Group 2 PD progressive disease PFS progression-free survival P-gp P-glycoprotein PgR progesterone receptor PgR+ progesterone receptor-positive PR partial response PRES posterior reversible encephalopathy syndrome PSA prostate-specific antigen QLQ Quality of Life Questionnaire QoL quality of life QTcF QT interval corrected using Fridericia’s formula RECIST Response Evaluation Criteria in Solid Tumors rPFS radiographic progression-free survival SAE serious adverse event SAR serious adverse reaction SEER Surveillance, Epidemiology and End Results Cancer Statistics Review

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SMQ Standardized MedDRA Query t1/2 half-life of elimination. The amount of time required for serum concentration to fall by 50%. TEAE treatment-emergent adverse event Tg transgenic TNBC triple-negative breast cancer TTP time to progression TTR time to response UGT uridine 5'-diphospho-glucuronosyltransferase VEGF vascular endothelial growth factor V/F apparent volume of distribution WH Wistar Hannover

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1 SUMMARY Enzalutamide (MDV3100) is an androgen receptor (AR) inhibitor that targets the AR signaling pathway. Enzalutamide competitively inhibits binding of to the AR, has a higher affinity for the receptor than and is a pure , whereas bicalutamide has partial activity. Consequently, enzalutamide inhibits nuclear translocation of the AR, while bicalutamide enhances this effect, and enzalutamide inhibits binding of the AR to DNA better than bicalutamide, even in prostate cancer cells resistant to and with AR overexpression. Astellas Pharma Global Development, Inc. (Astellas) and Medivation, Inc., a wholly owned subsidiary of Pfizer, Inc. (Medivation), are developing enzalutamide for the treatment of cancer. Enzalutamide was approved in the United States on 31 Aug 2012 under the trade name XTANDI® for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC) who have previously received docetaxel. XTANDI has subsequently been approved for the treatment of adult men with metastatic CRPC who are asymptomatic or mildly symptomatic after failure of androgen deprivation therapy (ADT) in whom chemotherapy is not yet clinically indicated. To date, XTANDI has been approved in 94 countries. Clinical development is ongoing for other prostate cancer indications. The breast cancer and hepatocellular carcinoma development programs have been discontinued, though some patients continue in ongoing studies. Enzalutamide, which is formulated with Labrasol® (caprylocaproyl macrogolglycerides) and filled into soft gelatin capsules containing 40 mg of the active pharmaceutical ingredient, is provided as an orally available immediate-release dosage form. In addition, in order to reduce the number and size of daily dosage units, enzalutamide is provided as an immediate- release tablet dosage form containing 80 mg and 40 mg of the active pharmaceutical ingredient. Ongoing and completed company-sponsored studies assessing enzalutamide are presented in this investigator’s brochure (IB). The data cutoff date for the clinical studies presented is 30 Aug 2017, unless otherwise noted. Pharmacology The primary pharmacodynamic effect of enzalutamide is inhibition of the AR signaling pathway. Enzalutamide inhibits androgen binding to the AR and thereby inhibits AR nuclear translocation in the presence of androgen and AR:chromatin association. In multiple prostate cancer cell lines that specifically model CRPC (LNCaP/AR, VCaP, W741C LNCaP), the consequences of enzalutamide treatment include inhibition of AR-induced gene transcription, reduced cell proliferation, increased cell death by and tumor regression. In a mouse xenograft model of CRPC using prostate cancer cells that overexpress the AR (LNCaP/AR), enzalutamide inhibits tumor growth and reduces tumor size. One of the 2 major human metabolites of enzalutamide, N-desmethyl enzalutamide, demonstrates key primary pharmacodynamics of similar potency to the parent molecule, while the second major human metabolite, a carboxylic acid metabolite, has no known pharmacodynamic

Jun 2018 Astellas/Medivation Page 10 of 126 Enzalutamide (MDV3100) CONFIDENTIAL Cancer Investigator’s Brochure Edition 10 effect. In humans, N-desmethyl enzalutamide circulates at approximately the same steady-state plasma concentrations as enzalutamide and is assumed to contribute to clinical effects. Nonclinical studies have shown that enzalutamide suppresses the growth of AR-expressing breast cancer cells that also express the estrogen receptor (ER), as well as cells that do not express the ER. Nonclinical studies have been conducted with hepatocellular carcinoma (HCC) cell lines; however, the importance of AR signaling inhibition has not yet been determined. Enzalutamide and N-desmethyl enzalutamide bind to and antagonize the γ-aminobutyric acid (GABA)-gated chloride channel. Enzalutamide given at high doses to mice induced dose-dependent , an observation that parallels the clinical safety data showing that dose appears to be an important predictor of the risk of in patients. As some molecules that antagonize the GABA-gated chloride channel are associated with convulsions, enzalutamide and N-desmethyl enzalutamide may both contribute to the convulsions that were observed in nonclinical studies. Safety pharmacology studies evaluating the central nervous, respiratory and cardiovascular systems did not identify any additional acute effects of enzalutamide at exposures relevant to the approved human clinical dose of 160 mg/day. Pharmacokinetics Nonclinical studies with in vitro test systems have contributed to the understanding of enzalutamide pharmacokinetics and the potential for drug-drug interactions (DDIs). Enzalutamide has high permeability across Caco-2 monolayers. Both enzalutamide and N-desmethyl enzalutamide are inducers and inhibitors of P-glycoprotein (P-gp). Data from a study with human cytochrome P450 (CYP) showed that CYP2C8 and CYP3A4/5 are both responsible for the metabolism of enzalutamide and a clinical study showed that it is primarily CYP2C8 that is responsible for the metabolism of enzalutamide and the subsequent formation of the active metabolite (N-desmethyl enzalutamide). Inhibition studies with CYP enzymes showed that enzalutamide, N-desmethyl enzalutamide and the inactive carboxylic acid metabolite caused direct inhibition of CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4/5 and time-dependent inhibition of CYP1A2. Induction studies with CYP enzymes showed that enzalutamide caused induction of CYP2B6, CYP3A4 and uridine 5'-diphospho-glucuronosyltransferase (UGT) and that enzalutamide is not expected to induce CYP1A2 at therapeutically relevant concentrations. Subsequent clinical studies showed that enzalutamide is an inducer of CYP2C9, CYP2C19, CYP3A4 and possibly UGT1A1, while enzalutamide has no clinically meaningful effect on CYP1A2, CYP2C8 or CYP2D6. Enzalutamide is 97% to 98% bound to plasma , primarily albumin and there is no in vitro protein binding displacement between enzalutamide and other highly bound drugs (warfarin, ibuprofen and salicylic acid). N-desmethyl enzalutamide is 95% bound to plasma proteins.

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Toxicology Macroscopic and microscopic findings, as well as organ weight changes related to enzalutamide administration, were observed in the prostate gland, seminal vesicles, testes and epididymides after repeat dosing in mice, rats and dogs. These changes are consistent with the primary pharmacological properties of enzalutamide and have been previously observed with compounds, such as bicalutamide. Mild and reversible hypertrophy or hyperplasia of Leydig cells in the testes was found in repeat-dose studies of enzalutamide and/or N-desmethyl enzalutamide in mice and dogs. Leydig cell hypertrophy/hyperplasia is a common finding in toxicity studies for antiandrogen compounds such as bicalutamide, and and is related to the occurrence of Leydig cell tumors in carcinogenicity studies for these agents. The extensive clinical experience with antiandrogens has shown that Leydig cell tumors in animals do not translate to a risk for humans. Mammary gland changes were not observed in male and female dogs treated with enzalutamide for 39 weeks. In embryo-fetal toxicity studies in mice, enzalutamide induced premature deliveries in dams and embryo-fetal deaths. Decreased fetal body weights and high incidence of external and skeletal abnormalities, such as decreased anogenital distance and cleft palate associated with absent palatine bone were also observed. Such effects are likely to be attributed to AR inhibition, as similar effects in rodents have also been found for other AR antagonists. No effects on dams or on embryo-fetal development were found in rabbits. In a 26-week carcinogenicity study in transgenic (Tg) rasH2 mice, there were no enzalutamide-related neoplastic findings and enzalutamide did not show carcinogenic potential in the tumor-prone Tg rasH2 mice at doses up to 20 mg/kg per day. The enzalutamide plasma exposure (Cmax and AUC24h) at 20 mg/kg per day was similar to the steady-state plasma exposure in patients with metastatic CRPC receiving 160 mg daily. In a 104-week carcinogenicity study in Wistar Hannover (WH) rats, findings in male rats included increased incidence of Leydig cell tumor in the testis, benign thymoma in the thymus, urothelial papilloma/carcinoma in the urinary bladder, adenoma of pars distalis in the pituitary and fibroadenoma in the mammary gland. In female rats, adenoma of pars distalis in the pituitary and benign granulosa cell tumor in the ovary were noted. At 10, 30 and 100 mg/kg per day, the exposure multiples of enzalutamide in male rats were 0.28-, 0.76- and 1.4-fold, respectively, of the exposure in humans taking enzalutamide 160 mg/day, while those of the inactive carboxylic acid metabolite were 0.17-, 0.44- and 1.7-fold, respectively. At all dose levels, the exposure multiple of the active metabolite, N-desmethyl enzalutamide, in male rats was less than 0.12-fold. The nonclinical toxicology studies demonstrate an acceptable safety profile at relevant clinical exposures and support the use of enzalutamide in all patients with CRPC at a clinical dose of 160 mg/day.

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Clinical Studies Pharmacokinetics The pharmacokinetics and metabolism of enzalutamide have been evaluated in more than 2500 patients with prostate cancer and in more than 200 volunteers, including healthy male volunteers and subjects with mild, moderate or severe hepatic impairment. Individual daily doses have ranged from 30 to 600 mg. In studies MDV3100-08, MDV3100-12 and 9785-CL-1121, the pharmacokinetics of single- and multiple-dose enzalutamide in more than 400 women with breast cancer was found to be similar to the pharmacokinetics of enzalutamide in men with prostate cancer. In study 9785-CL-3021 in patients with HCC, the pharmacokinetics of enzalutamide and its metabolites was found to be similar to those in men with prostate cancer and women with breast cancer. After oral administration to patients with CRPC, the median time to reach maximum enzalutamide plasma concentrations was 1 hour and the mean terminal half‑life was 5.8 days. Enzalutamide steady state was achieved by day 28 and the accumulation ratio was 8.3-fold. At steady state, enzalutamide showed approximately dose proportional pharmacokinetics over the range of 30 to 360 mg/day. A mass balance and biotransformation study in healthy male volunteers showed that enzalutamide is primarily eliminated by hepatic metabolism. A food-effect study showed that food does not have a clinically relevant effect on the AUC of enzalutamide or N-desmethyl enzalutamide; therefore, enzalutamide can be taken with or without food. Hepatic impairment studies showed that the composite AUC of enzalutamide plus N-desmethyl enzalutamide after single-dose enzalutamide was similar in subjects with baseline mild, moderate or severe hepatic impairment (Child-Pugh Class A, B and C, respectively) relative to subjects with normal hepatic function and no starting dose adjustment is needed in subjects with hepatic impairment. A 2.2-fold increase in drug half-life was observed in subjects with severe hepatic impairment, possibly related to increased tissue distribution. The clinical relevance of this observation is unknown; however, prolonged time to reach steady-state concentrations is anticipated. Based on population pharmacokinetics modeling, age, weight and renal function (creatinine clearance [CLCR] ≥ 30 mL/min) do not have clinically meaningful effects on enzalutamide exposures; therefore, no dose adjustments are indicated for these covariates. Based on pharmacokinetic data from a study in Japanese patients with prostate cancer, there were no clinically relevant differences in exposure between Japanese and white patients. Clinical data are insufficient to assess the potential effect of severe renal impairment (CLCR < 30 mL/min) and end-stage renal disease on enzalutamide pharmacokinetics. DDI studies in prostate cancer patients showed that enzalutamide can affect exposures to certain co-medications. At steady state, enzalutamide reduced the AUC of oral midazolam (CYP3A4 substrate), S-warfarin (CYP2C9 substrate) and omeprazole (CYP2C19 substrate). Therefore, enzalutamide is a strong CYP3A4 inducer and a moderate CYP2C9 and

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CYP2C19 inducer. Substrates of CYP3A4, CYP2C9 and CYP2C19 with a narrow therapeutic index are to be avoided, as enzalutamide may decrease plasma exposure of these drugs. If enzalutamide is coadministered with warfarin (CYP2C9 substrate), additional international normalized ratio (INR) monitoring is to be conducted. Enzalutamide (160 mg/day) did not have a clinically relevant effect on exposure to intravenous docetaxel (CYP3A4 substrate), oral caffeine (CYP1A2 substrate), dextromethorphan (CYP2D6 substrate) or pioglitazone (CYP2C8 substrate). DDI studies in healthy male subjects showed that concomitant medications can affect exposure to enzalutamide. Coadministration of gemfibrozil (a strong CYP2C8 inhibitor) increased the composite AUC of enzalutamide plus N-desmethyl enzalutamide by 2.2-fold; therefore, strong CYP2C8 inhibitors are to be avoided. If coadministration with a strong CYP2C8 inhibitor is necessary, the dose of enzalutamide is to be reduced to 80 mg once daily. Coadministration of itraconazole (strong CYP3A4 inhibitor) or rifampin (moderate CYP2C8 inducer and strong CYP3A4 inducer) did not have a clinically relevant effect on the composite AUC of enzalutamide plus N-desmethyl enzalutamide. Efficacy Prostate Cancer The efficacy of enzalutamide in patients with metastatic CRPC is being assessed in 13 clinical studies including 3 phase 4 open-label studies, MDV3100-10 (PLATO), 9785-CL-0410 and 9785-MA-1008; 4 phase 3, randomized, placebo-controlled studies: MDV3100-03 (PREVAIL), CRPC2 (AFFIRM), 9785-CL-0232 (Asian PREVAIL) and 9785-MA-1001; 2 phase 2 head-to-head studies against bicalutamide: 9785-CL-0222 (TERRAIN) and MDV3100-09 (STRIVE); 2 additional phase 2 studies: CRPC-MDA-1 and MDV3100-07; a phase 1/2 study (9785-CL-0111) and phase 1 study (S-3100-1-01). Data from 9785-MA-1001 have not been analyzed as of the data cutoff date for this IB. Efficacy has been assessed in a phase 2 study (9785-CL-0321) in patients with hormone-naïve prostate cancer. Efficacy is being assessed in a phase 3, randomized, placebo-controlled study in patients with metastatic hormone sensitive prostate cancer (9785-CL-0335 [ARCHES]) (data not yet analyzed as of the data cutoff date for this IB). Efficacy is also being assessed in patients with nonmetastatic prostate cancer in 2 phase 3, randomized, placebo-controlled studies: MDV3100-13 (EMBARK) in patients with high-risk, nonmetastatic hormone sensitive prostate cancer progressing after definitive therapy (data not yet analyzed as of the data cutoff date for this IB); and MDV3100-14 (PROSPER) in patients with nonmetastatic CRPC at high risk of disease progression. In the 2 pivotal, randomized, placebo-controlled phase 3 studies (MDV3100-03 and CRPC2) in men with metastatic CRPC, enzalutamide treatment showed a statistically significant advantage over placebo across multiple clinically relevant endpoints such as overall survival (OS), radiographic progression-free survival (rPFS), time to first skeletal-related event, time to prostate-specific antigen (PSA) progression, PSA response rate, best overall soft tissue response and quality of life as measured by the Functional Assessment of Cancer Therapy –

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Prostate (FACT-P). Notably, in MDV3100-03, a study of enzalutamide versus placebo in men with metastatic CRPC who were chemotherapy-naïve, enzalutamide delayed time to initiation of cytotoxic chemotherapy compared with placebo. In both phase 3 studies of patients with metastatic CRPC (MDV3100-03 and CRPC2), the benefit of enzalutamide treatment on OS as measured by the estimated hazard ratio (HR) was observed across all prespecified subgroups. A significant benefit on OS was observed despite substantially higher and earlier use in the placebo groups of subsequent therapies that are known to have a survival benefit in patients with prostate cancer. In addition, data from studies 9785-CL-0222 and MDV3100-09 show a clinically meaningful and statistically significant increase in progression-free survival (PFS) for enzalutamide compared with bicalutamide. Likewise, treatment with enzalutamide resulted in clinically meaningful and statistically significant improvements in the secondary efficacy endpoints evaluating investigator-assessed rPFS, PSA response and time to PSA progression. Further data from the open-label studies S-3100-1-01, CRPC-MDA-1, 9785-CL-0111, 9785-CL-0410 and 9785-MA-1008 in patients with metastatic CRPC and open-label 9785-CL-0321 in patients with hormone-naïve prostate cancer provide supportive efficacy information. In a phase 3, randomized, placebo-controlled study (MDV3100-14 [PROSPER]) in patients with nonmetastatic CRPC at high risk of disease progression, treatment with enzalutamide has demonstrated a consistent and clinically meaningful improvement in the primary MFS endpoint, as well as a delay in the time to onset of new antineoplastic therapies, including cytotoxic chemotherapy. Although OS data from MDV3100-14 are not yet mature as of the data cutoff date for this IB, the observed trend suggested an OS benefit with enzalutamide treatment in the nonmetastatic disease setting and is further supported by the consistent correlation between improvement in rPFS and OS established with enzalutamide in patients with metastatic CRPC. The overall efficacy observed with enzalutamide in MDV3100-14 represents a clinically meaningful benefit to patients with nonmetastatic CRPC. Overall, enzalutamide has consistently and robustly demonstrated substantial clinical benefits to patients across the CRPC disease continuum. Breast Cancer The clinical efficacy of enzalutamide in women with breast cancers have been evaluated in 4 clinical studies (MDV3100-08, MDV3100-11, MDV3100-12 and 9785-CL-1121). The efficacy endpoints in the phase 1 safety, tolerability and pharmacokinetics study MDV3100-08 were exploratory. No patient had an objective response (complete response [CR] or partial response [PR]). Clinical benefit rate at 16 weeks (CBR16, the proportion of evaluable patients with a best response of CR, PR or stable disease at ≥ 16 weeks) was 6.9% for the enzalutamide monotherapy group and 20.0% for the combination therapy group (enzalutamide with , or fulvestrant). CBR16 was highest for patients who received enzalutamide plus fulvestrant (45.5%). Clinical benefit rate at 24 weeks (CBR24) was 3.4% for the monotherapy group and 8.6% for the combination therapy group; CBR24 was highest for patients who received enzalutamide plus fulvestrant (18.2%).

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MDV3100-11 was an open-label phase 2 study in locally advanced or metastatic triple-negative breast cancer (TNBC). The study met its primary endpoint (CBR16). CBR16 was 33% (26 of 78 patients) in the evaluable population (i.e., patients with AR+ total nuclear staining ≥ 10% and a postbaseline tumor assessment) and 25% (29 of 118) in the intent-to- treat (ITT) population; CBR24 was 28% (22 of 78) in the evaluable population and 20% (24 of 118) in the ITT population. Median PFS was 14.3 weeks and median OS was 75.6 weeks in the evaluable population. Patients with diagnostic-positive (Dx+) TNBC (by gene expression profiling) had more favorable outcomes than patients with diagnostic-negative (Dx-) TNBC. MDV3100-12 was a phase 2 double-blind, placebo controlled study of enzalutamide plus exemestane versus placebo plus exemestane in patients with advanced breast cancer that is estrogen receptor-positive (ER+)/progesterone receptor-positive (PgR+) and human epidermal growth factor receptor 2 (HER2) normal. The primary objective was to determine the benefit of exemestane plus enzalutamide vs exemestane plus placebo as assessed by PFS. The incidence of PFS events was lower in the enzalutamide group than in the placebo group (66.7% vs 75.0% in Cohort 1 [patients who had not previously received hormone treatment for advanced breast cancer] and 73.3% vs 83.% in Cohort 2 [patients who previously progressed following 1 hormone treatment for advanced breast cancer]); the difference between the treatment groups was not statistically significant. 9785-CL-1121 was a phase 2 open-label, single-arm, 2-stage, study evaluating enzalutamide with trastuzumab in patients with human epidermal growth factor receptor 2-positive (HER2+) and AR+ metastatic or locally advanced breast cancer who progressed on at least 1 prior line of anti-HER2 therapy in the metastatic or advanced setting. Overall, the study met its primary endpoint: the clinical benefit rate (CBR) for patients with confirmation was 23.6% , (95% confidence interval [CI]: 15.2, 33.8) with 4 (4.5%) patients achieving PR and 17 (19.1%) patients achieving durable stable disease at week 24. The best confirmed overall response rate (ORR) was 4.5%. The median PFS was 105 days. Based on the data from the abovementioned enzalutamide breast cancer studies, the breast cancer development program has been discontinued. Hepatocellular Carcinoma HCC has been studied in 1 phase 2 clinical study (9785-CL-3021). The efficacy results showed that enzalutamide was not significantly different from placebo for OS and PFS and did not meet the primary endpoint of OS in the treatment of patients with HCC of any etiology who had progressed on or were intolerant to sorafenib or other antivascular endothelial growth factor (anti-VEGF) therapy in the advanced setting. Based on the results from the phase 2 study, the HCC development program has been discontinued. Overall Safety Profile The safety data cutoff date for this IB is 30 Aug 2017, unless otherwise specified.

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Prostate Cancer The safety profile of enzalutamide is summarized for 4 randomized, placebo-controlled phase 3 studies, comprising 4697 unique patients with either nonmetastatic or metastatic CRPC, as follows (hereafter defined as the combined phase 3 studies): ● One study in patients with nonmetastatic CRPC (MDV3100-14 [PROSPER]) ● Two studies in chemotherapy-naïve patients with metastatic CRPC (MDV3100-03 [PREVAIL] and 9785-CL-0232 [Asian PREVAIL]) ● One study in patients with metastatic CRPC previously treated with docetaxel-based chemotherapy (CRPC2 [AFFIRM]) Several other studies in patients with prostate cancer and healthy volunteers provide additional safety data. In the combined phase 3 studies, the median duration of exposure to enzalutamide was 13.7 months and the median duration of exposure to placebo was 4.8 months. Approximately 55% of patients treated with enzalutamide remained on study drug for at least 1 year compared with 21% of patients treated with placebo; approximately 19% of patients treated with enzalutamide remained on study drug for at least 2 years compared with approximately 5% of patients treated with placebo. Overall, enzalutamide treatment was generally well tolerated across the combined phase 3 studies. As expected for this patient population with prostate cancer, nearly all enzalutamide-treated and placebo-treated patients experienced at least 1 adverse event (AE) during each study. The proportion of treatment-emergent adverse events (TEAEs) in the enzalutamide group of the combined phase 3 studies was higher than in the placebo group (93.2% vs 89.1%). Since the median duration of treatment for the enzalutamide group was longer compared with placebo, the analyses of TEAEs included an adjustment for the duration of treatment with the determination of event rates per 100 patient-years of treatment and the incidence of TEAEs by time of onset. When TEAEs occurring in at least 5% of patients in the enzalutamide group and with a ≥ 2% higher incidence than the placebo group were adjusted for treatment duration, the differences between the enzalutamide group and the placebo group were reduced (event rate per 100 patient-years of treatment): hot flush (13.1 enzalutamide vs 11.3 placebo), (9.4 vs 5.7), (9.5 vs 9.1) and fall (9.1 vs 5.6). No new safety signals were identified in review of treatment-emergent serious adverse events (SAEs) in the enzalutamide group of the combined phase 3 studies. Overall, study drug-related treatment-emergent SAEs were reported infrequently with no meaningful difference between treatment groups (3.3% of enzalutamide treated patients and 3.2% of placebo treated patients). In the combined phase 3 studies, the proportion of patients who discontinued treatment primarily as a result of a TEAE and the proportion of patients with fatal TEAEs were comparable between treatment groups.

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An adverse reaction is a noxious and unintended response to a medicinal product. The following adverse reactions for enzalutamide were identified in patients with nonmetastatic or metastatic CRPC (either primarily in chemotherapy-naïve patients with earlier stage disease, or patients with more advanced stage disease after docetaxel): , asthenia, , fracture, fall, , grand mal convulsion, partial , status epilepticus, complex partial seizures, cognitive disorder, headache, , , , hypertension, accelerated hypertension, , neutrophil count decreased, blood pressure increased, memory impairment, disturbance in attention, restless legs syndrome, , epistaxis, dry skin , pruritus, hot flush, blood pressure inadequately controlled, essential hypertension and systolic hypertension. Breast Cancer Data from phase 1 and phase 2 breast cancer studies (MDV3100-08, MDV3100-11, MDV3100-12 and 9785-CL-1121) support enzalutamide monotherapy as generally well tolerated, as reflected by the low rates of grade 3 or higher TEAEs, treatment-emergent SAEs and treatment discontinuations due to TEAEs. The safety of enzalutamide was also favorable in combination with aromatase inhibitors (exemestane, anastrazole), a selective ER modulator (fulvestrant) and a monoclonal antibody (trastuzumab). The safety profile of enzalutamide in women with breast cancer is consistent with the safety data generated in studies of enzalutamide in men with prostate cancer. Data from these studies further suggest that the pharmacokinetics of enzalutamide in women with breast cancer is similar to that in men with prostate cancer. Hepatocellular Carcinoma The phase 2 clinical study of HCC (9785-CL-3021) showed that the safety profile of enzalutamide monotherapy in patients with HCC is consistent with the safety data generated in studies of enzalutamide in men with prostate cancer.

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2 INTRODUCTION The AR is a well-known target in prostate cancer, as prostate cancer growth is dependent on androgens. Depleting or blocking androgen action has been a mainstay of treatment for over 6 decades in the setting of metastatic disease or when prostate cancer recurs following resection and/or radiation. In addition, AR expression has been noted in a variety of breast cancers and an emerging body of data suggests that growth of breast cancer tumors may be promoted through the AR. Enzalutamide (MDV3100) is a selective AR signaling inhibitor. Enzalutamide exerts more substantial beneficial effects than bicalutamide in nonclinical models of CRPC [Tran et al, 2009]. Enzalutamide has also shown activity in nonclinical models of breast cancer. Enzalutamide slows tumor growth and induces apoptosis. Enzalutamide competitively inhibits binding of androgens to the AR, has a higher affinity for the receptor than bicalutamide and is a pure receptor antagonist, whereas bicalutamide has partial agonist activity. Consequently, enzalutamide inhibits nuclear translocation of the AR, while bicalutamide enhances this effect, and enzalutamide inhibits binding of the AR to DNA better than bicalutamide, even in prostate cancer cells resistant to antiandrogens and with AR overexpression. The unique AR antagonist activity of enzalutamide imparts a more complete blockade of the AR signaling pathway in the setting of AR overexpression. 2.1 Prostate Cancer The American Cancer Society estimates that 164690 new cases will be diagnosed and 29430 men will die of prostate cancer in the US during 2018 [Siegel et al, 2018]. Prostate cancer is the second cause of male cancer mortality in the US (after lung). Prostate cancer death rates have been decreasing since the early 1990s, attributed to improvements in detection and treatment, although rates appear to have stabilized from 2013 to 2015 [American Cancer Society, 2018; Siegel et al, 2018]. In the EU, it is estimated that approximately 417000 new cases were diagnosed and approximately 92000 men died of prostate cancer during 2012 [Ferlay et al, 2013]. While prostate cancer remains the third cause of male cancer mortality in the EU (after lung and colorectal), the death rate has decreased in the EU by 8.5% since 2012; in 2018, an estimated 77000 deaths due to prostate cancer are predicted [Malvezzi et al, 2018]. Although tumors are often initially sensitive to medical or surgical therapies aiming to decrease levels of (ADT), disease progression ultimately occurs even in the setting of castrate levels of testosterone. This step generally represents a transition to the more lethal variant of the illness (CRPC) [Pienta & Bradley, 2006; Petrylak et al, 2004]. Despite low or even undetectable levels of androgen in these patients, evidence suggests that the AR signaling remains active and that their tumors continue to respond to therapies directed at the AR signaling axis. The treatment of patients with metastatic CRPC has evolved rapidly over the past 5 years. Despite recent advances, additional treatment options are still needed to continue to improve clinical outcomes in patients with progressive metastatic prostate cancer. The goals of

Jun 2018 Astellas/Medivation Page 19 of 126 Enzalutamide (MDV3100) CONFIDENTIAL Cancer Investigator’s Brochure Edition 10 treatment in this patient population include prolonging OS, minimizing disease-related and treatment-related complications and maintaining quality of life (QoL). 2.2 Breast Cancer Breast cancer is one of the most frequently diagnosed malignancies and the second most common cause of cancer deaths in women, despite improvements in screening and treatment regimens. According to the International Agency for Research on Cancer, 1.7 million women were diagnosed with breast cancer and over 522000 women died of breast cancer in 2012 [GLOBOCAN, 2012]. Breast cancer is genetically heterogeneous and biologically diverse. The long recognized clinical and phenotypic differences have been shown to correlate with differences at the gene expression level [Sørlie, 2004; Perou et al, 2000]. Expression of the AR has been observed in the majority of breast cancer specimens. In studies evaluating over 3000 breast tumor specimens, AR expression was observed in 77% of invasive breast tumors and its expression was observed across all molecular phenotypes [Collins et al, 2011; Goldhirsch et al, 2011; Niemeier et al, 2010]. Triple-negative Breast Cancer TNBC has the worst prognosis of all breast cancer subtypes, characterized by an aggressive clinical course with a high rate of early visceral relapse following adjuvant or neoadjuvant therapy, resistance to chemotherapy and shorter OS compared to the other subtypes [Gerratana et al, 2015; Kast et al, 2015; von Minckwitz et al, 2014; Chácon and Costanzo, 2010; Thomas et al, 2007]. No therapies are specifically approved for patients with TNBC, limiting the standard of care to nonselective cytotoxic chemotherapy. In vitro experiments have shown that cell viability and survival of the TNBC subtype luminal AR are dependent on signaling through the AR [Lehmann et al, 2011]. HER2-positive Breast Cancer Approximately 20% of all breast cancers have gene amplification or overexpression (or both) of HER2, a tyrosine kinase transmembrane receptor, resulting in a more aggressive phenotype and a poor prognosis. Most patients with HER2+ metastatic breast cancer experience disease progression [Baselga et al, 2012]. An evaluation of published microarray data from 3 patient sets demonstrated that AR gene expression levels correlated with HER2 amplification/ overexpression [Ni et al, 2011] and immunohistochemistry (IHC) has shown AR expression correlates with HER2 overexpression [Niemeier et al, 2010; Park et al, 2010; Agoff et al, 2003]. Hormone Receptor-positive Breast Cancer Two molecular subtypes of breast cancer are considered hormone receptor-positive in that they express ER, progesterone receptor (PgR) or both. Endocrine therapies that target ER signaling pathways play a critical role in the treatment of patients with ER+/PgR+ disease, even in the advanced setting. However, all patients with advanced disease treated with will develop treatment resistance. The AR is most prevalent in patients with

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ER+/PgR+ breast cancer and has been implicated in resistance to hormone-based therapies. In nonclinical studies, cell lines expressing both AR and ER can be growth-stimulated with dihydrotestosterone (DHT) and this growth can be blocked by enzalutamide [D’Amato et al, 2013]. Based on the data from the abovementioned enzalutamide breast cancer studies, the breast cancer development program has been discontinued. 2.3 HCC HCC represents more than 90% of primary cancers and remains a major global health problem [GLOBOCAN, 2012]. The literature suggests AR signaling may play an important role in HCC. High serum testosterone levels and active AR gene alleles in males infected with hepatitis B virus (HBV) have been shown to be associated with the development of HCC [Liu and Liu, 2014; Yu et al, 2001; Wang et al, 2009]. In addition to high androgen levels, AR overexpression is observed in 60% to 80% of human HCCs [Nagasue et al, 1989]. AR overexpression is correlated with cell cycle-related kinase, an AR signaling mediator that drives hepatocarcinogenesis via a signaling pathway dependent on β-catenin and T-cell factor [Feng et al, 2011]. Liver-specific knockout of AR significantly reduced tumorigenicity in carcinogen- and HBV-induced HCC mouse models [Ma et al, 2008; Wu et al, 2010]. Jiang et al [2014] reported that apoptosis in HepG2 cells, a human HCC cell line, was induced via inhibition of AR signaling. Based on the results from the phase 2 study, the HCC development program has been discontinued. List of References Agoff SN, Swanson PE, Linden H, Hawes SE, Lawton TJ. Androgen receptor expression in estrogen receptor-negative breast cancer. Immunohistochemical, clinical and prognostic associations. Am J Clin Pathol. 2003;120:725-31.

American Cancer Society, Cancer facts & figures [Internet]. Atlanta: American Cancer Society; 2018 [cited 14 Apr 2018]. Available from: https://www.cancer.org/content/dam/cancer- org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2018/cancer-facts-and- figures-2018.pdf

Baselga J, Cortes J, Kim S-B, Im S-A, Hegg R, Im Y-H, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012;366:109-19.

Chácon RD, Costanzo MV. Triple-negative breast cancer. Breast Cancer Res. 2010;12(Suppl 2):S3.

Collins LC, Cole KS, Marotti JD, Hu R, Schnitt SJ, Tamimi RM. Androgen receptor expression in breast cancer in relation to molecular phenotype: results from the Nurses' Health Study. Mod Pathol. 2011;24:924-31.

D’Amato NC, Gu H, Cochrane DR, Bernales S, Jacobsen BM, Jedlicka P, et al. Elucidating the role of AR in breast cancer. Abstract presented at: American Association for Cancer Research (AACR) annual meeting; 2013; Washington, DC. (abstract 4756).

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Feng H, Cheng ASL, Tsang DP, Li MS, Go MY, Cheung YS, et al. Cell cycle-related kinase is a direct androgen receptor-regulated gene that drives β-catenin/T call factor-dependent hepatocarcinogenesis. J Clin Invest. 2011;121:3159-75.

Ferlay J, Steliarova-Foucher E, Lortet-Tieulent J, Rosso S, Coebergh JWW, Comber H, et al. Cancer incidence and mortality patterns in Europe: estimates for 40 countries in 2012. Eur J Cancer. 2013;49:1374-403.

Gerratana L, Fanotto V, Bonotto M, Bolzonello S, Minisini AM, Fasola G, et al. Pattern of metastasis and outcome in patients with breast cancer. Clin Exp Metastasis. 2015;32:125-33.

Goldhirsch A, Wood WC, Coates AS, Gelber RD, Thürlimann B, Senn HJ. Strategies for subtypes— dealing with the diversity of breast cancer: highlights of the St. Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2011. Ann Oncol. 2011;22:1736-47.

International Agency for Research on Cancer (World Health Organization). GLOBOCAN 2012: Estimated cancer incidence, mortality and prevalence worldwide in 2012 [Internet]. Cited 15 April 2016. Available from: http://globocan.iarc.fr/Default.aspx

Jiang X, Kanda T, Nakamoto S, Miyamura T, Wu S, Yokosuka O. Involvement of androgen receptor and glucose-regulated protein 78 kDa in human hepatocarcinogenesis. Exp Cell Res. 2014;323:326-36.

Kast K, Link T, Friedrich K, Petzold A, Niedostatek A, Schoffer O, et al. Impact of breast cancer subtypes and patterns of metastasis on outcome. Breast Cancer Res Treat. 2015;150:621-9.

Lehmann BD, Bauer JA, Chen X, Sanders ME, Chakravarthy AB, Shyr Y, et al. Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Invest. 2011;121:2750-67.

Liu WC, Liu QY. Molecular mechanisms of gender disparity in hepatitis B virus-associated hepatocellular carcinoma. World J Gastroenterol. 2014;20:6252-61.

Ma WL, Hsu CL, Wu MH, Wu CT, Wu CC, Lai JJ, et al. Androgen receptor is a new potential therapeutic target for the treatment of hepatocellular carcinoma. Gastroenterology. 2008;135:947–55.

Malvezzi M, Carioli G, Bertuccio P, Boffetta P, Levi F, La Vecchia C et al. European cancer mortality predictions for the year 2018 with focus on colorectal cancer. Ann Oncol. 2018;0:1-7.

Nagasue N, Chang YC, Hayashi T, Galizia G, Kohno H, Nakamura T, et al. Androgen receptor in hepatocellular carcinoma as a prognostic factor after hepatic resection. Ann Surg. 1989;209:424-7.

Ni M, Chen Y, Lim E, Wimberly H, Bailey ST, Imai Y, et al. Targeting androgen receptor in estrogen receptor-negative breast cancer. Cancer Cell. 2011;20:119-31.

Niemeier LA, Dabbs DJ, Beriwal S, Striebel JM, Bhargava R. Androgen receptor in breast cancer: expression in estrogen receptor-positive tumors and in estrogen receptor-negative tumors with apocrine differentiation. Mod Pathol. 2010;23:205-12.

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Park S, Koo J, Park HS, Kim JH, Cho SY, Lee JH, et al. Expression of androgen receptors in primary breast cancer. Ann Oncol 2010;21:488-92.

Perou CM, Sørlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, et al. Molecular portraits of human breast tumours. Nature. 2000;406:747-52.

Petrylak DP, Tangen CM, Hussain MHA, Lara PN, Jones JA, Taplin ME, et al. Docetaxel and compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med. 2004;351:1513-20.

Pienta KJ, Bradley D. Mechanisms underlying the development of androgen-independent prostate cancer. Clin Cancer Res. 2006;12:1665-71.

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Tran C, Ouk S, Clegg NJ, Chen Y, Watson PA, Arora V, et al. Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science. 2009;324:787-90. von Minckwitz G, Puglisi F, Cortes J, Vrdoljak E, Marschner N, Zielinski C, et al. Bevacizumab plus chemotherapy versus chemotherapy alone as second-line treatment for patients with HER2-negative locally recurrent or metastatic breast cancer after first-line treatment with bevacizumab plus chemotherapy (TANIA): an open-label, randomised phase 3 trial. Lancet Oncol. 2014;15:1269-78.

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3 PHYSICAL, CHEMICAL AND PHARMACEUTICAL PROPERTIES AND FORMULATION 3.1 Drug Substance Compound Number: MDV3100, ASP9785 International Nonproprietary Name: enzalutamide

Molecular Formula: C21H16F4N4O2S Chemical Name: 4-{3-[4-Cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2- sulfanylideneimidazolidin-1-yl}-2-fluoro-N-methylbenzamide Figure 1 Chemical Structure of Enzalutamide CF F 3 O S NC NHMe N N

O

Molecular Weight: 464.44 Appearance: White crystals Solubility: Practically insoluble in water Hygroscopicity: Not hygroscopic

3.2 Drug Product 3.2.1 Capsule Ingredients: Enzalutamide is provided as liquid-filled soft gelatin capsule for oral administration. Each capsule contains 40 mg of enzalutamide. The inactive ingredients are caprylocaproyl polyoxylglycerides (caprylocaproyl macrogolglycerides), butylated hydroxyanisole (butylhydroxyanisole), butylated hydroxytoluene (butylhydroxytoluene), gelatin, sorbitol sorbitan solution, glycerin, purified water, titanium dioxide and black iron oxide. Placebo capsules contain all inactive ingredients listed above. Appearance: Opaque white to off-white oblong liquid-filled soft gelatin capsule Packaging: Capsules are packaged as a 1-month supply in bottles with child-resistant caps or 4-week supply in blister packs. Storage and Handling: Store at room temperature. For more information please follow the storage instructions provided on the drug product label.

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3.2.2 Tablet Ingredients: Enzalutamide is provided as immediate-release tablets for oral administration. Each tablet contains either 80 mg or 40 mg of enzalutamide. The inactive ingredients are hypromellose acetate succinate, microcrystalline cellulose (cellulose, microcrystalline), colloidal silicon dioxide (silica, colloidal anhydrous), croscarmellose sodium and stearate. Placebo tablets contain lactose monohydrate, microcrystalline cellulose, hydroxypropyl cellulose and magnesium stearate. The tablet film coating is comprised of hypromellose, talc, polyethylene glycol (macrogol), titanium dioxide and ferric oxide (iron oxide yellow). Appearance: The 80-mg enzalutamide tablets are oval, yellow film-coated tablets and the 40-mg enzalutamide tablets are round, yellow film-coated tablets. The appearance of placebo tablets matches the corresponding enzalutamide tablet strength. Packaging: Both enzalutamide 80-mg and 40-mg tablets are packaged as 1-month supplies either in bottles with child-resistant caps or in blister packs. Storage and Handling: Store at room temperature. For more information, please follow the storage instructions provided on the drug product label.

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4 NONCLINICAL STUDIES 4.1 Nonclinical Pharmacology Enzalutamide is an AR signaling inhibitor, which was rationally designed to block the AR signaling pathway and to be devoid of agonist activity. 4.1.1 Primary Pharmacodynamics Primary pharmacodynamics have been defined in experiments that demonstrated inhibition of AR binding, inhibition of AR nuclear translocation, inhibition of AR chromatin association, inhibition of AR-dependent transcription and cancer cell proliferation, induction of cell death and tumor regression and a lack of agonist activity. On the whole, nonclinical data on the primary pharmacodynamics of enzalutamide show that it is a potent AR inhibitor that targets the AR signaling pathway without showing agonist activity. 4.1.1.1 In Vitro Primary Pharmacodynamics Effects on AR Signaling and Prostate Cancer In vitro data showed that enzalutamide does the following: ● Competes for binding to the wild-type AR and mutated AR (LNCaP) with half maximal inhibitory concentration (IC50) values of 0.021 µM (0.0098 µg/mL) and 0.060 µM (0.028 µg/mL), respectively ([Tran et al, 2009]; studies PRO3100NC44, PRO3100NC66, PRO3100NC132 and PRO3100NC134) ● Competes for binding to the -binding domain of the AR (study PRO3100NC81) and prevented a conformational change in the AR that would enable it to associate with proteins necessary for optimal signaling [Tran et al, 2009] ● Inhibits nuclear translocation of AR induced by DHT (study PRO3100NC155) or an AR agonist (studies PRO3100NC43, PRO3100NC57, PRO3100NC78) ● Inhibits the association of AR with chromatin of AR-regulated genes, including PSA and transmembrane protease, serine 2 (study 9785-PH-0005, [Tran et al, 2009]) ● Inhibits AR signaling independently of nuclear translocation [Tran et al, 2009] Enzalutamide lacked AR agonist activity in cell-based assays that evaluated nuclear translocation, association with co-activator proteins, AR association with chromatin and AR-dependent gene expression. These effects contrasted with the agonist activity seen with bicalutamide (studies PRO3100NC43, PRO3100NC127, PRO3100NC138, 9785-PH-0005 and [Tran et al, 2009]). Enzalutamide consistently reduced cell growth and increased cell death by apoptosis in castration-resistant cell lines (LNCaP/AR, VCaP and W741C LNCaP) (studies 9785-PH-0003, 9785-PH-0004 and PRO3100NC155 [Tran et al, 2009]). To evaluate whether metabolites of enzalutamide have the potential to contribute to primary pharmacodynamics, metabolites were tested in AR binding and nuclear translocation assays. The majority of the studies focused on the 2 major metabolites in human plasma, N-desmethyl enzalutamide and the carboxylic acid metabolite. N-desmethyl enzalutamide

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was shown to have high affinity for the AR (IC50 = 0.12 µM) with a potency similar to that of the parent drug (study PRO3100NC73). Furthermore, N-desmethyl enzalutamide inhibited AR nuclear translocation in response to an agonist (IC50 = 3.2 µM; 1.44 µg/mL) (study PRO3100NC70) with a potency similar to parent (study PRO3100NC78). These results indicate that N-desmethyl enzalutamide may potentially contribute to the mode of action of enzalutamide. Indeed, in the exposure-response analysis of plasma concentration data from the phase 3 study (study CRPC2), enzalutamide, N-desmethyl enzalutamide, as well as enzalutamide plus N-desmethyl enzalutamide correlated with OS (study ICON 2147016). In vitro assays of the carboxylic acid metabolite showed no detectable AR binding at the highest concentration that was tested, 10 μM; therefore, the carboxylic acid metabolite is not considered to contribute to the efficacy of enzalutamide. Based on these results, the major human metabolites, the carboxylic acid metabolite and N-desmethyl enzalutamide, are referred to as inactive and active metabolites, respectively. In Vitro Primary Pharmacodynamics in Breast Cancer Two androgen receptor-positive (AR+) and ER+ breast cancer cell lines, MCF7 and BCK4, were shown to proliferate in response to AR stimulation with DHT. Enzalutamide inhibited DHT-mediated cell growth in both cell lines. Enzalutamide also inhibited -mediated cell growth of MCF7 and BCK4 cells [Cochrane et al, 2014]. In contrast, bicalutamide did not inhibit estradiol-enhanced growth of MCF7 cells. Consistent with the inhibitory effect of enzalutamide on estradiol-induced cell growth, enzalutamide also blocked estradiol-stimulated expression of 3 genes: Stromal Cell-Derived Factor 1, the PgR and the AR. As enzalutamide does not block binding of estradiol to the ER, these data suggest that AR and ER crosstalk and AR signaling inhibition with enzalutamide has a dominant negative role on ER signaling. In AR+, estrogen receptor-negative (ER-) breast cancer cells (MDA- kb2), enzalutamide inhibits DHT-induced viability at 10 μM. 4.1.1.2 In Vivo Primary Pharmacodynamics Tumor growth was evaluated in an in vivo xenograft mouse model of CRPC (study PRO3100NC48). Severe combined immunodeficiency mice bearing human LNCaP/AR tumor xenografts were treated with enzalutamide or bicalutamide by once-daily oral dosing for 28 days. The effect of enzalutamide on tumor size was dose dependent, with tumor volume decreases of up to 82% relative to vehicle on day 28. In contrast, bicalutamide inhibited tumor growth until day 16, after which tumor growth increased [Figure 2].

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Figure 2 Enzalutamide Induces Tumor Regression in an LNCaP/Androgen Receptor Mouse Xenograft Model of Castration-resistant Prostate Cancer

Nonparametric analysis of variance with Kruskal Wallis Post Test were conducted (*P < 0.05; **P < 0.01). Error bars were not included in this figure to reduce complexity. MDV3100: enzalutamide Source: PRO3100NC48 In addition, enzalutamide blocked DHT-induced growth of AR+, ER- breast cancer cells (MDA-MB-453) in mouse xenografts [Cochrane et al, 2014]. 4.1.1.3 Primary Pharmacodynamics in HCC

The antiproliferative effect of enzalutamide on 10 HCC cell lines was determined. The IC50 values were ≥ 75 µM in all cell lines tested (study MDV3100NC038). Antitumor activity of enzalutamide was investigated in 4 HCC patient-derived xenograft mouse models. Enzalutamide at a dose of 20 or 75 mg/kg per day showed marginal effect on tumor size in all models tested (study 9785-PH-9001). 4.1.2 Secondary Pharmacodynamics To assess whether enzalutamide affected other cell proteins besides the AR, the compound was tested for activity in a broad binding panel including receptors, channels, transporters and enzymes (including a large panel of kinases) (study PRO3100NC49). Enzalutamide was tested at 10 μM (4.6 μg/mL). At doses of 160 mg/day, mean plasma concentrations in patients treated are expected to fluctuate between 12.00 μg/mL (Cmin) and 16.59 μg/mL (Cmax) (9785-CL-0007). Assuming 97% protein binding (PRO3100NC32), this would correspond to a free concentration at Cmax of 0.46 μg/mL, which is reasonably less than the 4.6 μg/mL screening concentration used in the binding assays. In addition to binding to the human AR, measurable binding was detected for only 2 targets: the rat GABA-gated chloride channel (inhibition constant [Ki] = 2.1 μM) (study PRO3100NC50) and the human PgR (Ki = 6.08 μM) (study PRO3100NC130). N-desmethyl enzalutamide showed comparable binding to the GABA-gated chloride channel. Using a cell-based activity assay, enzalutamide was shown to inhibit the α1β3 GABA-A

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complex in a concentration dependent manner with an IC50 of 3.0 ± 0.8 μM (study PRO3100NC72). Enzalutamide did not activate the GABA-gated chloride channel. As some compounds that block the GABA-gated chloride channel are associated with seizures, nonclinical studies were performed to assess this and are described in Section 4.1.3.1. Enzalutamide inhibited the progesterone β receptor in a cell-based activity assay (IC50 = 13.5 μM) but had only trace inhibitory activity against the progesterone α receptor (study PRO3100NC145). No agonist activity was observed in a progesterone β receptor cell-based activity assay (study PRO3100NC131). 4.1.3 Safety Pharmacology 4.1.3.1 Central Nervous System Safety Pharmacology Studies Enzalutamide did not have acute neurobehavioral effects as assessed by functional observational battery endpoints in rats (study PRO3100NC96). In addition, besides the GABA-A receptor, enzalutamide did not interact with central nervous system (CNS)-related receptors or enzymes and was not associated with clinical signs suggesting psychoactive effects, such as sedation, hyperactivity or decreased food consumption, during the dosing or recovery periods in the repeat-dose oral toxicity studies in rats (studies PRO3100NC39 and PRO3100NC17) [Section 4.3.2]. The nonclinical data therefore suggest that enzalutamide is unlikely to have abuse liability. As enzalutamide showed binding to and inhibition of the GABA-gated chloride channel, an in vivo study in mice to investigate convulsion potential was conducted (study 9785-PT-0005). Convulsions occurred in mice given 400 mg/kg enzalutamide as a single dose or 200 mg/kg per day enzalutamide for 7 days. Based on the totality of the data, enzalutamide is associated with dose-dependent convulsions in mice. 4.1.3.2 Respiratory Safety Pharmacology Study The acute respiratory effects of enzalutamide were evaluated in male rats after single oral doses up to 200 mg/kg (study PRO3100NC95). Enzalutamide had no effect on any clinical observations or respiratory function assessments at doses up to and including 200 mg/kg. 4.1.3.3 Cardiovascular Safety Pharmacology Studies Cardiovascular safety was evaluated in vitro in patch clamped mammalian cells expressing the human ether-à-go-go related gene (hERG) channel. For both enzalutamide and N-desmethyl enzalutamide, the predicted free fraction in patient plasma is well below the hERG IC50 value. Cardiovascular safety was also evaluated in conscious, unrestrained male dogs that were instrumented for telemetry. Single oral doses of enzalutamide were administered at 5, 15 and 30 mg/kg (study PRO3100NC94). No test article-related changes in hemodynamic parameters were observed at any dose level. No abnormal electrocardiogram (ECG) results or arrhythmias were attributable to the administration of enzalutamide in the male dogs.

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In addition, based on the intensive ECG monitoring that was embedded in the phase 3 study CRPC2, treatment with enzalutamide was not associated with any clinically relevant effect on cardiac repolarization or other ECG parameter. Additionally, review of TEAEs falling under the Torsades de Pointes/QT prolongation Standardized MedDRA Query (SMQ) in the enzalutamide and placebo groups did not reveal a safety signal. (An SMQ is a validated, predetermined set of MedDRA terms grouped together after extensive review, testing, analysis and expert discussion.) More information is presented in Section 5.2.2.2.9. Taken together, the nonclinical and clinical data suggest that enzalutamide is not associated with an increased risk of QT prolongation, ischemic heart disease, heart failure or arrhythmias. 4.1.4 Pharmacodynamic Drug Interactions No nonclinical pharmacodynamic drug interaction studies have been performed. 4.1.5 Other Pharmacology Studies No other nonclinical pharmacology studies have been completed. 4.2 Pharmacokinetics and Product Metabolism 4.2.1 Absorption Enzalutamide is well absorbed after oral administration in animals. In vitro experiments with Caco-2 cell monolayers showed that permeability of enzalutamide is consistently high. There is no significant transport asymmetry between absorptive and secretory processes, indicating that transport is passive. Enzalutamide is not a substrate of the efflux transporters P-gp or breast cancer resistance protein (BCRP). 4.2.2 Distribution Tissue distribution data in rats after oral administration of 14C-enzalutamide showed rapid and extensive distribution to all tissues. Data in rodents suggest that enzalutamide and N-desmethyl enzalutamide readily partition into the brain. In vitro protein binding of enzalutamide in human plasma is 97% to 98% and is comparable across species. The extent of is constant over a wide range of concentrations (0.05 to 25 μg/mL). Albumin is the major binding protein for enzalutamide in human plasma; other human plasma proteins to which enzalutamide binds (in order of decreasing importance) are high density lipoprotein, low density lipoprotein, α1-glycoprotein and γ-globulin. In vitro protein binding of N-desmethyl enzalutamide in human plasma was 95%, comparable across species and constant over a wide range of concentrations (0.5 to 25 μg/mL). 4.2.3 Metabolism The 2 major human metabolites (N-desmethyl enzalutamide and an inactive carboxylic acid metabolite) are also produced in animals. In vitro studies show that enzalutamide is metabolized by human recombinant isoenzymes CYP2C8 and CYP3A4/5, both of which play a role in the formation of N-desmethyl enzalutamide. In addition, an in vitro study with human recombinant

Jun 2018 Astellas/Medivation Page 30 of 126 Enzalutamide (MDV3100) CONFIDENTIAL Cancer Investigator’s Brochure Edition 10 carboxylesterases (hCES) showed that hCES1 is capable of catalyzing the formation of the carboxylic acid metabolite from enzalutamide and N-desmethyl enzalutamide, while hCES2 does not appear to play a role in the metabolism of either enzalutamide or N-desmethyl enzalutamide. Enzalutamide does not appear to be metabolized by the CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C18, CYP2C19, CYP2D6 or CYP2E1 isoenzymes. In addition, N-desmethyl enzalutamide does not appear to be metabolized by CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP3A4 or CYP3A5. 4.2.4 Excretion

Enzalutamide is eliminated slowly from plasma with a long t1/2 across species; plasma clearance is low and corresponds to ≤ 5% of liver blood flow in rats and dogs. After an oral dose of 14C‑enzalutamide, urinary, fecal and biliary excretion play important roles in eliminating drug-derived radioactivity from the body. In rats, urinary and fecal excretion are equally important routes of excretion of radioactivity (primarily as metabolites), with evidence of enterohepatic recirculation. In dogs, urinary excretion is the major route of excretion of radioactivity (primarily as metabolites). Excretion in milk has not been assessed. 4.2.5 Pharmacokinetic Drug Interactions The potential for enzalutamide and its major human metabolites to affect the pharmacokinetics of other drugs via effects on CYP enzymes was assessed through a series of in vitro experiments. In vitro, enzalutamide and its metabolites caused direct inhibition of multiple CYP enzymes, including CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4/5; however, subsequent clinical data showed that enzalutamide is an inducer of CYP2C9, CYP2C19 and CYP3A4/5 and has no clinically meaningful effect on CYP2C8 or CYP2D6 (studies PRO3100NC24, 9785-ME-0009 and 9785-ME-0010) [Section 5.1.3]. In vitro, enzalutamide caused time-dependent inhibition of CYP1A2 (study PRO3100NC24); however, clinical data showed that enzalutamide does not have a clinically meaningful effect on exposure to a sensitive CYP1A2 substrate (caffeine). An in vitro study in human hepatocytes (study 9785-ME-0036) evaluated the potential for enzalutamide, N-desmethyl enzalutamide and the carboxylic acid metabolite to act as inducers of CYP and UGT isoforms and P-gp. The results suggest that enzalutamide and N-desmethyl enzalutamide, but not the carboxylic acid metabolite, may induce CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP3A4, UGT1A1 and P-gp through activation of the pregnane X receptor and constitutive receptor. These results corroborate in vivo results in patients (study 9785-CL-0007), which suggested that enzalutamide is an inducer that acts through pregnane X receptor activation. In vitro data indicate that enzalutamide may be an inhibitor of the efflux transporter P-gp (study 9785-ME-0026). In addition, based on in vitro data, it cannot be excluded that enzalutamide may be an inhibitor of BCRP, multidrug resistance-associated protein (MRP)2 and organic anion transporter (OAT)3 at clinically relevant systemic concentrations or in the gastrointestinal wall during absorption (studies 9785-ME-0027 and 9785-ME-0029). In vitro

Jun 2018 Astellas/Medivation Page 31 of 126 Enzalutamide (MDV3100) CONFIDENTIAL Cancer Investigator’s Brochure Edition 10 data indicate that enzalutamide and its major metabolites do not inhibit the following transporters at clinically relevant concentrations: organic anion transporting polypeptide (OATP)1B1, OATP1B3, organic cation transporter (OCT)1, OCT2, or OAT1 (study 9785-ME-0029). In vitro data show that enzalutamide does not displace warfarin, ibuprofen or salicylic acid from protein binding sites in human plasma (study 9785-ME-0017). 4.3 Toxicology Single-dose toxicity studies were conducted in mice and cynomolgus monkeys and repeat-dose studies were performed in mice, rats and beagle dogs. The rat and dog were selected as the main species for the toxicology program because of extensive data and literature on reproductive tissues for both species. 4.3.1 Single-dose Toxicity Treatment-related mortality occurred in mice given ≥ 400 mg/kg as a single dose (study 9785-TX-0002). CNS effects, including decreased motor activity, ataxia, clonic convulsions and/or tremors occurred in a single-dose oral toxicokinetics study in which mice received 50, 100, 200, 400, 800 or 1600 mg/kg. No mortality occurred in a study in cynomolgus monkeys given enzalutamide as a single dose of 30 mg/kg and 100 mg/kg and two 30 mg/kg doses 4 hours apart (i.e., total dose of 60 mg/kg) (study 9785-TX-0003). Treatment-related clinical signs were limited to muddy stools and vomiting at all dose levels. 4.3.2 Repeat-dose Toxicity Repeat-dose studies in mice, rats and dogs showed no important changes in clinical pathology or histopathology other than changes that were attributable to the intended pharmacology of enzalutamide as an inhibitor of androgen signaling. Consistent with this pharmacology, the main findings were in reproductive (study PRO3100NC17) and hormone-sensitive tissues (study PRO3100NC39). Changes in the reproductive organs in rats and dogs most commonly involved atrophy of the prostate and epididymides with decreased organ weight. Atrophy of seminal vesicles with decreased organ weight was observed in mice and rats. Leydig cell hyperplasia and hypertrophy were observed in dogs after 39 weeks of treatment (study 9785-TX-0010) and all animals completely recovered after 13 weeks of withdrawal. Leydig cell hypertrophy was also observed in mice after a 4-week treatment (study 9785-TX-0019). Leydig cell hypertrophy/hyperplasia is a common nonclinical finding for antiandrogens, such as bicalutamide, flutamide and nilutamide and is a result of elevated luteinizing hormone production due to deregulated androgen feedback on the pituitary. Although this finding is related to the occurrence of Leydig cell tumors in carcinogenicity studies, the extensive clinical experience with antiandrogens has shown that Leydig cell tumors in animals do not translate to a risk for humans [Cook et al, 1999]. Other effects on reproductive and hormone-sensitive tissues appeared species-specific.

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Hypertrophy/hyperplasia of the pituitary gland and atrophy in seminal vesicles occurred in rats and testicular hypospermia and seminiferous tubule degeneration were found in dogs. Similar effects in rats and dogs have been reported with nonsteroidal antiandrogen compounds, such as bicalutamide [Iswaran et al, 1997]. Partial or full reversibility was noted after treatment-free periods ranging from 4 to 13 weeks. Given the relationship to the intended pharmacology, the changes in reproductive and hormone-sensitive tissues were not considered AEs. Clinical pathology changes were consistent with the intended pharmacology and/or changes reported for other antiandrogens and were not considered adverse because of their small magnitude. These included decreases in hematology parameters (red blood cell counts, hemoglobin and hematocrit) and increases in , alkaline phosphatase (ALP) and plasma protein. The mild decreases in hematology parameters were similar to changes that have been reported in rats treated with the AR inhibitors nilutamide and flutamide and the effect of androgens on erythropoiesis is well documented [Shahidi, 1973]. Increase in serum cholesterol is a well-known clinical effect of androgen deprivation therapies [Saylor & Smith, 2013]. As cholesterol levels were not measured in the clinical program, the effect of enzalutamide on cholesterol in castrate men remains unknown. Mild increases in ALP in male rats and dogs treated with enzalutamide may be secondary to atrophy of the male reproductive tissues, as ALP is present in male reproductive tissues in both species. Testicular ALP in the atrophying testes has been shown to be elevated in rat studies [Dixit et al, 1976]. Hepatocellular toxicity is commonly associated with other antiandrogen compounds, such as flutamide and nilutamide and both compounds are associated with liver injury in humans [Brahm et al, 2011; Gomez et al, 1992]. In contrast to other antiandrogens, enzalutamide showed no evidence of in animals or in the clinical program. In mice dosed with enzalutamide, increased alanine aminotransferase (ALT) was observed at 60 mg/kg per day and increased ALP was observed at ≥ 30 mg/kg/day (studies 9785-TX-0008 and 9785-TX-0019). Histopathologically, there was no finding that indicated liver injury; however, hepatocellular hypertrophy was observed (studies 9785-TX-0008 and 9785-TX-0019). Similar findings were observed in mice dosed with N-desmethyl enzalutamide. In rats, mild increases in total protein, albumin and globulin were observed across studies. An additional study (study 9785-TX-0014) suggested these increases are related to the mild hepatocellular hypertrophy. Enzalutamide showed in vitro evidence of hepatic enzyme induction and such responses are typically associated with hepatocellular hypertrophy in rodents [Maronpot et al, 2010]. In repeat-dose toxicity studies, convulsions were observed in 1 rat and 1 dog and occurred dose-dependently in mice. 4.3.3 Genotoxicity Enzalutamide did not induce mutations in the microbial mutagenesis (Ames) assay and was not clastogenic in either the in vitro cytogenetic assay with mouse lymphoma cells or the in vivo mouse micronucleus assay (studies PRO3100NC34 and 9785-TX-0005).

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Based on in silico evaluations for genotoxicity, as well as in vitro data, the current weight of evidence does not indicate a genotoxicity risk for enzalutamide metabolites, impurities or degradants (studies PRO3100NC020, PROC3100NC021, PRO3100NC022, MDV3100NC034, MDV3100NC035, PRO3100NC88, PRO3100NC123, PRO3100NC124 and PRO3100NC157). 4.3.4 Carcinogenicity A carcinogenicity program was initiated to support the approval of enzalutamide at an earlier stage in the prostate cancer disease process. The carcinogenicity program included a completed 26-week carcinogenicity study in Tg rasH2 mice (study 9785-TX-0020) and a 2-year carcinogenicity study in Wistar Han rats (study 9785-TX-0017); an in vitro plasma protein binding study in these species was also conducted to support free exposures (study 9785-ME-0045). In study 9785-TX-0020, there were no enzalutamide-related neoplastic findings and enzalutamide did not show carcinogenic potential in the tumor-prone Tg rasH2 mice at doses up to 20 mg/kg per day. The enzalutamide plasma exposure (Cmax and AUC24h) at 20 mg/kg per day was similar to the steady state plasma exposure in patients with metastatic CRPC receiving 160 mg daily. In study 9785-TX-0017 (dose levels: 0, 10, 30 and 100 mg/kg per day), increased incidences of the following tumors were considered treatment-related in male WH rats: Leydig cell tumor in the testis (≥ 10 mg/kg per day); benign thymoma in the thymus (≥ 10 mg/kg per day); and urothelial papilloma/carcinoma in the urinary bladder, adenoma of pars distalis in the pituitary and fibroadenoma in the mammary gland (100 mg/kg per day). In female WH rats, treatment-related increase in adenoma of pars distalis in the pituitary (≥ 30 mg/kg per day) and benign granulosa cell tumor in the ovary (100 mg/kg per day) were noted. Except for the urinary bladder, these tumors were observed in organs that are regulated via the hypothalamic-pituitary-gonadal hormone axis and considered to be related to the pharmacological activity of enzalutamide. Leydig cell tumors in rats are generally accepted as not relevant to humans [Cook et al, 1999]. The human relevance of thymoma, pituitary adenoma and fibroadenoma in rats is not well known. Urothelial papilloma/carcinoma in the urinary bladder is thought to be induced by continuous local irritation of the epithelium by crystals or calculi that consist of excreted carboxylic acid metabolite. To date, crystals or calculi have not been reported in humans treated with enzalutamide 160 mg/day. At 10, 30 and 100 mg/kg per day, the exposure multiples of enzalutamide in male rats were 0.28-, 0.76- and 1.4-fold, respectively, of the exposure in humans taking enzalutamide 160 mg/day, while those of the inactive carboxylic acid metabolite were 0.17-, 0.44- and 1.7-fold, respectively [Table 1]. At all dose levels, the exposure multiple of the active metabolite, N-desmethyl enzalutamide, in male rats was less than 0.12-fold.

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Table 1 Exposure Multiples of Enzalutamide and Its Metabolites in Rats of the Exposure in Humans Exposure Multiples -Fold human AUC 10 mg/kg 30 mg/kg 100 mg/kg Analyte (µg∙h/mL)† Male Female Male Female Male Female Enzalutamide 322 0.28 0.34 0.76 0.89 1.4 1.9 Carboxylic acid metabolite 193 0.17 0.19 0.44 0.54 1.7 1.5 N-desmethyl enzalutamide 278 0.017 0.0044 0.062 0.013 0.12 0.037 † Day 178 after daily administration of enzalutamide 160 mg (study 9785-CL-0007) 4.3.5 Reproductive and Developmental Toxicity No effects on dams or on embryo-fetal development were found in rabbits at doses up to 10 mg/kg per day (study 9785-TX-0012). An embryo-fetal toxicity study in mice (study 9785-TX-0009) showed that enzalutamide induced premature deliveries in dams and dose-dependent increases in the incidence of decreased anogenital distance and skeletal abnormalities, such as cleft palate associated with absent palatine bone. These effects are assumed to be related to the pharmacology of enzalutamide because they were previously reported in rats treated with bicalutamide [Iswaran et al, 1997], as well as mice and rabbits treated with [Takano et al, 1966]. Based on the embryo-fetal toxicity study and the known reproductive and developmental toxicity of other antiandrogens, it is assumed that enzalutamide may cause fetal harm and is thus contraindicated in pregnant women. An abbreviated, 3-day repeat-dose toxicity study was conducted in male dogs to evaluate the potential toxic effects of enzalutamide on the male reproductive system and their reversibility (study PRO3100NC101). The results suggest that short-term oral treatment of male dogs with enzalutamide (30 mg/kg/day) was associated with completely reversible effects on male reproductive organs. 4.3.6 Local Tolerance No studies were performed to evaluate local tolerance. 4.3.7 Other Toxicity Studies 4.3.7.1 Phototoxicity Enzalutamide did not induce phototoxicity in cultured mammalian cells (study 9785-TX-0001). 4.4 Integrated Nonclinical Overview and Conclusion: Potential Clinical Relevance Nonclinical pharmacology data demonstrate that enzalutamide is an AR signaling inhibitor that blocks the AR signaling pathway. Enzalutamide competitively inhibits binding of androgens to the AR and thereby inhibits nuclear translocation of AR and the association of the AR with chromatin. These inhibitory effects occur even in the setting of AR

Jun 2018 Astellas/Medivation Page 35 of 126 Enzalutamide (MDV3100) CONFIDENTIAL Cancer Investigator’s Brochure Edition 10 overexpression and in prostate cancer cells that are resistant to antiandrogens. By inhibiting AR signaling, enzalutamide elicits several downstream effects, which include reduced expression of AR-dependent genes, decreased growth of prostate cancer cells, induction of cancer cell death and tumor regression. Enzalutamide lacks agonist activities such as those that may limit the sustained efficacy of current antiandrogens. Enzalutamide is well absorbed after oral administration to mice, rats, rabbits, monkeys and dogs. Tissue distribution data in rats after oral administration of 14C-enzalutamide showed rapid and extensive distribution to all tissues. Enzalutamide is eliminated slowly from plasma with a long t1/2 across species; plasma clearance is low and corresponds to ≤ 5% of liver plasma flow in rats and dogs. The major metabolites in human plasma, the carboxylic acid metabolite and N-desmethyl enzalutamide, have been found in mouse, rat, rabbit, dog and monkey plasma. The carboxylic acid metabolite is considered an inactive metabolite based on primary pharmacodynamic studies. In addition, the carboxylic acid metabolite did not bind to the GABA-gated chloride channel in vitro and had low penetration into rat and mouse brains. In contrast, the primary and secondary pharmacodynamics profiles of N-desmethyl enzalutamide are essentially the same as those of enzalutamide. Like enzalutamide, N-desmethyl enzalutamide is thought to contribute to the safety and efficacy profiles of enzalutamide in patients. Like enzalutamide, N-desmethyl enzalutamide inhibits the GABA-gated chloride channel and also partitions readily to the brain; therefore, it is possible that N-desmethyl enzalutamide may also be associated with convulsions. Quantitative structure activity relationship analysis of the carboxylic acid metabolite and N-desmethyl enzalutamide using DEREK software did not show any structural alerts that are different from enzalutamide. N-desmethyl enzalutamide is structurally similar to enzalutamide and the toxicological profile of N-desmethyl enzalutamide appears to be very similar to enzalutamide based on the dose-range-finding studies with N-desmethyl enzalutamide in mice. The main findings in repeat-dose oral studies in mice, rats and dogs were histopathological and organ weight changes in reproductive and hormone-sensitive tissues, consistent with the pharmacological activity of enzalutamide and similar to those reported for other antiandrogen compounds. In addition, Leydig cell hypertrophy/hyperplasia was observed, a common nonclinical finding for antiandrogens, but is generally considered to be of little relevance for humans [Cook et al, 1999]. Enzalutamide and N-desmethyl enzalutamide were found to inhibit the GABA-gated chloride channel and literature suggests that compounds that inhibit this channel are associated with convulsions [Treiman, 2001]. Convulsions were rarely observed in repeat-dose studies in rats and dogs, but dose-dependent convulsions occurred in mice given 400 mg/kg as a single dose or 200 mg/kg per day for 7 days. Based on convulsions in animals, as well as the results from the CRPC2 clinical study, enzalutamide should be used with caution with compounds that inhibit the GABA-gated chloride channel.

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In a 26-week carcinogenicity study in Tg rasH2 mice, there were no enzalutamide-related neoplastic findings and enzalutamide did not show carcinogenic potential in this tumor prone species. In a 104-week carcinogenicity study in WH rats, findings in male rats included increased incidence of Leydig cell tumor in the testis, benign thymoma in the thymus, urothelial papilloma/carcinoma in the urinary bladder, adenoma of pars distalis in the pituitary and fibroadenoma in the mammary gland. In female rats, adenoma of pars distalis in the pituitary and benign granulosa cell tumor in the ovary were noted. Tumors in the testis, mammary gland and ovary have also been reported in rats treated with other antiandrogens such as bicalutamide [Iswaran et al, 1997] or flutamide [Eulexin, 2000]. These tumors and the tumors in the thymus and pituitary in enzalutamide-treated rats are considered related to the pharmacological properties of an antiandrogen drug. Therefore, the impact on the overall risk and benefit balance for patients with advanced cancer is unknown. Tumors in the urinary bladder of rats are thought to be induced by urinary crystals or calculi consisting of the excreted carboxylic acid metabolite of enzalutamide. Because urinary crystals or calculi are not expected in humans taking enzalutamide 160 mg daily, tumors in the urinary bladder are considered not relevant to humans. In conclusion, enzalutamide is an AR signaling inhibitor that inhibits the AR signaling pathway, thus representing a new approach for treating various cancers. The safety pharmacology and toxicology studies show an acceptable safety profile and support the use of enzalutamide in cancer patients at a clinical dose of 160 mg/day. List of References Brahm J, Brahm M, Segovia R, Latorre R, Zapata R, Poniachik J, et al. Acute and fulminant hepatitis induced by flutamide: case series report and review of the literature. Ann Hepatol. 2011;10:93-8.

Cochrane DR, Bernales S, Jacobsen BM, Cittelly DM, Howe EN, D’Amato NC, et al. Role of the androgen receptor in breast cancer and preclinical analysis of enzalutamide. Breast Cancer Res. 2014 Jan 22;16:R7.

Cook JC, Klinefelter GR, Hardisty JF, Sharpe RM, Foster PMD. Rodent Leydig cell tumorigenesis: a review of the physiology, pathology, mechanisms and relevance to humans. Crit Rev Toxicol. 1999;29:169-261.

Dixit VP, Agrawal M, Lohiya NK. Effects of a single ethanol injection into the vas deferens on the testicular function of rats. Endokrinologie. 1976;67:8-13.

Eulexin (United States Package insert). Kenilworth, NJ; Schering Corporation, Dec 2000.

Gomez JL, Dupont A, Cusan L, Tremblay M, Suburu R, Lemay M, et al. Incidence of liver toxicity associated with the use of flutamide in prostate cancer patients. Am J Med. 1992;92:465-70.

Iswaran TJ, Imai M, Betton GR, Siddall RA. An overview of animal toxicology studies with bicalutamide (ICI 176,334). J Toxicol Sci. 1997;22:75-88.

Maronpot RR, Yoshizawa K, Nyska A, Harada T, Flake G, Mueller G, et al. Hepatic enzyme induction: histopathology. Toxicol. Pathol. 2010; 38:776-95.

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Saylor PJ, Smith MR. Metabolic complications of androgen deprivation therapy for prostate cancer. J Urol. 2013;189(1 Suppl):S34-42.

Shahidi NT. Androgens and erythropoiesis. N Engl J Med. 1973;289:72-80.

Takano K, Yamamura H, Suzuki M, Nishimura H. Teratogenic effect of chlormadinone acetate in mice and rabbits. Proc Soc Exp Biol Med. 1966;121:455-7.

Tran C, Ouk S, Clegg NJ, Chen Y, Watson PA, Arora V, et al. Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science. 2009;324:787-90.

Treiman DM. GABAergic mechanisms in . Epilepsia. 2001;42 Suppl 3:8-12.

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5 EFFECTS IN HUMANS Enzalutamide, an AR inhibitor, was initially approved on 31 Aug 2012 in the United States for the treatment of patients with metastatic CRPC who have previously received docetaxel and was subsequently expanded for use in men with metastatic CRPC. Enzalutamide has been approved in 94 countries. Clinical development is ongoing for other prostate cancer indications; the breast cancer and hepatocellular carcinoma development programs have been discontinued, though some patients continue in ongoing studies. As of the data cutoff date for this IB (30 Aug 2017), more than 4800 male patients with prostate cancer, over 400 female patients with breast cancer, over 100 patients with HCC and over 300 subjects with no known cancer including healthy male subjects and subjects with hepatic impairment have received at least 1 dose of enzalutamide in 20 completed and 23 ongoing clinical studies (i.e., not including the expanded access or compassionate use programs). Studies completed to date include the following: ● 9 phase 1 studies in healthy male volunteers, of which 1 included subjects with mild to moderate liver impairment and 1 included subjects with severe liver impairment ● 4 phase 1 studies in patients with prostate cancer ● 5 phase 2 studies in patients with prostate cancer ● 2 phase 4 studies in patients with prostate cancer (including 1 terminated phase 4 study) The 23 ongoing studies include the following: ● A phase 1 dose escalation study in patients with CPRC (S-3100-1-01) ● A phase 1 study in patients with advanced prostate cancer eligible for docetaxel as first chemotherapy for advanced disease (MDV3100-06) ● 2 phase 2 head-to-head studies against bicalutamide in patients with metastatic CRPC (9785-CL-0222 [TERRAIN] and MDV3100-09 [STRIVE]) ● 1 phase 2 study evaluating enzalutamide in combination with and prednisone in bone metastatic CRPC patients (9785-CL-0011) ● 1 phase 2 extension study in CRPC patients (9785-CL-0123) (actively enrolling) ● 1 phase 2 bone-imaging study in chemotherapy-naïve bone metastatic CRPC patients (MDV3100-18) (actively enrolling) ● 1 phase 2 study in patients with localized prostate cancer undergoing active surveillance (9785-MA-1010 [ENACT]) (actively enrolling) ● 7 phase 3 randomized controlled studies in patients with prostate cancer as follows: ● with metastatic CRPC who were chemotherapy-naïve (MDV3100-03 [PREVAIL]) ● with metastatic CPRC progressing after docetaxel therapy (CRPC2 [AFFIRM]) ● with high-risk, nonmetastatic hormone sensitive prostate cancer progressing after definitive therapy (MDV3100-13 [EMBARK]) (actively enrolling) ● with nonmetastatic CRPC at high risk of disease progression based on rising PSA levels and sufficiently short (≤ 10-month) PSA doubling time (MDV3100-14 [PROSPER]) ● chemotherapy-naïve progressive metastatic prostate cancer patients who failed ADT (9785-CL-0232 [Asian PREVAIL])

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● with metastatic hormone sensitive prostate cancer (9785-CL-0335 [ARCHES]) (data not yet analyzed as of the data cutoff date for this IB) ● chemotherapy-naïve progressive metastatic CRPC patients who have failed ADT (9785-MA-1001) (actively enrolling) ● 1 phase 4 study in patients with metastatic CRPC who are chemotherapy-naïve (MDV3100-10 [PLATO]) ● 1 phase 4 study in patients with metastatic CRPC who are at a potential increased risk of seizure (9785-CL-0403 [UPWARD]) (actively enrolling) ● 1 phase 4 study in patients with CRPC that relapsed during complete androgen blockade therapy with bicalutamide (9785-MA-3051) (actively enrolling) ● 1 phase 1 and 3 phase 2 studies in patients with breast cancer (MDV3100-08, MDV3100-11, MDV3100-12 and 9785-CL-1121) ● 1 phase 2 study in patients with HCC (9785-CL-3021) All of these ongoing and completed studies are summarized in Table 2. All enzalutamide program studies that evaluate patients with prostate cancer continue to offer open-label access to enzalutamide following completion of the original study. Transition to commercially available enzalutamide was offered to patients participating in the compassionate use program.

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Table 2 Summary of Completed and Ongoing Clinical Studies in the Enzalutamide Program Enzalutamide No. of Comparator Total No. of Clinical Enzalutamide Subjects No. of Subjects Subjects Study Study Design and Type of Control Status Doses Evaluated Treated Treated Treated Phase 1 Studies in Healthy Volunteers and Special Populations 9785-CL-0001 Single dose (Mass balance in healthy male volunteers) Phase 1, single-dose, open-label Completed 6 0 6 160 mg [Appendix 7.1.1] MDV3100-05 Phase 1, single-dose, open-label, 2-period Single dose (BE and food effect in healthy male volunteers) Completed 60 0 60 crossover 160 mg [Appendix 7.1.2] 9785-CL-0006 Single dose (DDI in healthy male volunteers) Phase 1, single-dose, open-label Completed 41 0 41 160 mg [Appendix 7.1.3] 9785-CL-0009 (Hepatic impairment; subjects with mild or Single dose moderate hepatic impairment and with normal Phase 1, single-dose, open-label Completed 33 0 33 160 mg hepatic function) [Appendix 7.1.4] 9785-CL-0010 Phase 1, single-center, open-label, Single dose (BA in healthy male volunteers) randomized, parallel, relative Completed 55 0 55 160 mg [Appendix 7.1.5] 9785-CL-0404 (Hepatic impairment; male subjects with severe Phase 1, nonrandomized, open-label, Single dose hepatic impairment and normal hepatic single-dose to investigate Completed 16 0 16 160 mg function) pharmacokinetics, safety and tolerability [Appendix 7.1.6] Phase 1, randomized, open-label, 2-arm 9785-CL-0405 parallel-design to explore the effect of Single dose (DDI in healthy male volunteers) Completed 28 0 28 rifampin on the pharmacokinetics, safety 160 mg [Appendix 7.1.7] and tolerability MDV3100-19 Phase 1, single-center, open-label, Single dose (Healthy male volunteers) randomized, parallel-design, relative Completed 45 0 45 160 mg [Appendix 7.1.8] bioavailability Table continued on next page

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Enzalutamide No. of Comparator Total No. of Clinical Enzalutamide Subjects No. of Subjects Subjects Study Study Design and Type of Control Status Doses Evaluated Treated Treated Treated Phase 1 Studies in Healthy Volunteers and Special Populations (continued) Phase 1, randomized, 2-period, crossover 9785-CL-0014 bioequivalence of a capsule and tablet Single dose (Healthy male volunteers) Completed 59 0 59 formulation under fasted and fed 160 mg [Appendix 7.1.9] conditions Subtotal 343 0 343 Phase 1 Studies in Prostate Cancer Patients S-3100-1-01 Ongoing 30, 60, 150, 240, Phase 1, first-in-man, open-label, dose (First-in-man dose escalation in CRPC patients) (enrollment 360, 480, 140 0 140 escalation [Appendix 7.2.1] complete) 600 mg/day 9785-CL-0007 Phase 1, open-label, nonrandomized, (DDI in CRPC patients) Completed 160 mg/day 14 0 14 single sequence crossover DDI study [Appendix 7.2.2] 9785-CL-0003 (Patients with progressive prostate cancer with Phase 1, open-label, randomized, parallel, Completed 160 mg/day 27 0 27 no more than 2 rounds of prior chemotherapy) relative bioavailability [Appendix 7.2.3] 9785-CL-0111 80, 160, (Japanese men with CRPC) Phase 1-2, open-label, dose escalation Completed 47 0 47 240 mg/day [Appendix 7.2.4] 9785-CL-0406 Phase 1 open-label, fixed-sequence, (DDI in prostate cancer patients) Completed 160 mg/day 14 0 14 crossover DDI study [Appendix 7.2.5] MDV3100-06 (Patients with advanced prostate cancer eligible Ongoing Phase 1b, open-label, combination with for docetaxel as first chemotherapy for (enrollment 160 mg/day 21† 0 21† docetaxel advanced disease) complete) [Appendix 7.2.6] Subtotal 263 0 263 Table continued on next page

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Enzalutamide No. of Comparator Total No. of Clinical Enzalutamide Subjects No. of Subjects Subjects Study Study Design and Type of Control Status Doses Evaluated Treated Treated Treated Phase 2 Studies in Prostate Cancer Patients CRPC-MDA-1 (Bone marrow biopsy study to evaluate the Phase 2, open-label, single arm Completed 160 mg/day 60 0 60 tumor microenvironment) [Appendix 7.3.1] 9785-CL-0011 Ongoing Phase 2, open-label combination with (Patients with bone metastatic CRPC) (enrollment 160 mg/day 60 0 60 abiraterone acetate plus prednisone [Appendix 7.3.2] complete) 9785-CL-0121 (Open-label extension for CRPC patients who Phase 2, open-label, single arm Completed 160 mg/day 52 0 52 completed prior study) [Appendix 7.3.3] 9785-CL-0321 (Hormone-naïve monotherapy study) Phase 2, open-label, single arm Completed 160 mg/day 67 0 67 [Appendix 7.3.4] MDV3100-07 (Patients undergoing prostatectomy for Phase 2, randomized, open-label, Completed 160 mg/day 52 25‡ 52‡ localized prostate cancer) neoadjuvant pre-prostatectomy [Appendix 7.3.5] 9785-CL-0222 (TERRAIN) Phase 2, randomized, double-blind, Ongoing (Castrate patients with metastatic prostate efficacy and safety of enzalutamide vs (enrollment 160 mg/day 183 189 372 cancer) bicalutamide complete) [Appendix 7.3.6] MDV3100-09 (STRIVE) Phase 2, randomized double-blind, Ongoing (Prostate cancer patients post-primary ADT) efficacy and safety of enzalutamide vs (enrollment 160 mg/day 197 198 395 [Appendix 7.3.7] bicalutamide complete) 9785-CL-0122 (CRPC patients previously treated with Phase 2, single-arm, open-label monitor Completed 160 mg/day 30 0 30 docetaxel-based chemo) safety [Appendix 7.3.8] Table continued on next page

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Enzalutamide No. of Comparator Total No. of Clinical Enzalutamide Subjects No. of Subjects Subjects Study Study Design and Type of Control Status Doses Evaluated Treated Treated Treated Phase 2 Studies in Prostate Cancer Patients (continued) 9785-CL-0123 (Open-label extension for CRPC patients who Phase 2, single-arm, open-label monitor Ongoing 160 mg/day 0 0 0 completed prior study) safety (enrolling) [Appendix 7.3.9] MDV3100-18 Ongoing (18F-Sodium fluoride PET/CT bone imaging in Phase 2, open-label, single-arm (enrollment 160 mg/day 0 0 0 chemotherapy-naïve bone metastatic CRPC) complete) [Appendix 7.3.10] 9785-MA-1010 (ENACT) (Patients with low/intermediate risk localized Ongoing Phase 2, open-label, 2-arm 160 mg/day 0 0 0 prostate cancer undergoing active surveillance) (enrolling) [Appendix 7.3.11] Subtotal 701§ 412 1088§ Phase 3 Studies in Prostate Cancer Patients MDV3100-03 (PREVAIL)¶ Ongoing (Chemotherapy-naïve patients with progressive Phase 3, randomized, double-blind, (enrollment 160 mg/day 871 844 1715 metastatic prostate cancer post-ADT) placebo-controlled, efficacy and safety complete) [Appendix 7.4.1] CRPC2 (AFFIRM) Ongoing Phase 3, double-blind, randomized, (CRPC progressing after docetaxel therapy) (enrollment 160 mg/day 800 399 1199 placebo-controlled [Appendix 7.4.2] complete) MDV3100-13 (EMBARK) Phase 3, randomized, double-blind, (Patients with high-risk nonmetastatic prostate placebo-controlled, efficacy and safety of Ongoing 160 mg/day 0 0 0 cancer progressing after definitive therapy enzalutamide + leuprolide, enzalutamide (enrolling) [Appendix 7.4.3] monotherapy and placebo + leuprolide MDV3100-14 (PROSPER) Ongoing Phase 3, randomized, double-blind, (Patients with nonmetastatic CRPC) (enrollment 160 mg/day 930 465 1395 placebo-controlled, efficacy and safety [Appendix 7.4.4] complete) 9785-CL-0232 (Asian PREVAIL)†† Asian multinational phase 3, randomized, Ongoing (Chemotherapy-naïve patients with progressive double-blind, placebo-controlled efficacy, (enrollment 160 mg/day 198 190 388 metastatic prostate cancer who failed ADT) pharmacokinetics and safety complete) [Appendix 7.4.5] Table continued on next page

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Enzalutamide No. of Comparator Total No. of Clinical Enzalutamide Subjects No. of Subjects Subjects Study Study Design and Type of Control Status Doses Evaluated Treated Treated Treated Phase 3 Studies in Prostate Cancer Patients (continued) A multinational, phase 3, randomized, 9785-CL-0335 (ARCHES) Ongoing double-blind, placebo-controlled efficacy (mHSPC patients) (enrollment 160 mg/day 0 0 0 and safety study of enzalutamide plus [Appendix 7.4.6] complete) ADT 9785-MA-1001 Phase 3b, randomized, double-blind, (Chemotherapy-naïve metastatic CRPC patients placebo-controlled study of efficacy and who have failed ADT) safety of continuing enzalutamide in Ongoing 160 mg/day 0 0 0 [Appendix 7.4.7] patients treated with docetaxel plus (enrolling) prednisolone who progressed on enzalutamide alone Subtotal 2799 1898 4697 Phase 4 Studies in Prostate Cancer Patients MDV3100-10 (PLATO) Phase 4, randomized, double-blind Ongoing (Patients with metastatic CRPC who are efficacy and safety of enzalutamide + (enrollment 160 mg/day 509‡‡ 124‡‡ 509 chemotherapy-naïve) abiraterone and prednisone compared to complete) [Appendix 7.5.1] placebo + abiraterone and prednisone 9785-CL-0403 (UPWARD) Ongoing (Patients with metastatic CRPC who are at Phase 4, multicenter, single-arm, open- (enrollment 160 mg/day 423 0 423 potential increased risk of seizure) label, postmarketing safety complete) [Appendix 7.5.2] 9785-CL-0410 (Progressive metastatic CRPC patients Phase 4, multicenter, open-label, single- Completed 160 mg/day 214 0 214 previously treated with abiraterone) arm [Appendix 7.5.3] 9785-MA-1008 (Patients with metastatic CRPC who had received enzalutamide in the prechemotherapy Phase 4, open-label, single arm study Terminated 160 mg/day 4 0 4 setting) [Appendix 7.5.4] Table continued on next page

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Enzalutamide No. of Comparator Total No. of Clinical Enzalutamide Subjects No. of Subjects Subjects Study Study Design and Type of Control Status Doses Evaluated Treated Treated Treated Phase 4 Studies in Prostate Cancer Patients (continued) 9785-MA-3051 (Patients with CRPC that relapsed during Ongoing complete androgen blockade therapy with Phase 4, open-label, 2-arm study 160 mg/day 0 0 0 (enrolling) bicalutamide) [Appendix 7.5.5] Subtotal 1150 124 1150 Compassionate Use and Expanded Access Programs in Prostate Cancer Patients 9785-CL-0401 (Patients with progressive CRPC previously Expanded access, multicenter, open-label, Completed 160 mg/day 507¶ 0 507¶ treated with docetaxel-based chemotherapy) single-arm (USA and Canada) [Appendix 7.6.1] Named Patient Program Compassionate use, multicenter, open- (Patients with progressive CRPC previously label, single-arm (Europe, Russia, Ongoing 160 mg/day 3115 0 3115 treated with docetaxel-based chemotherapy) Australia, Canada, South Africa, New [Appendix 7.6.2] Zealand) 9785-CL-0402 Cohort Authorisation Temporaire d’Utilisation (Patients with progressive metastatic CRPC Compassionate use, open-label, single- Completed 160 mg/day 600 0 600 previously treated with docetaxel-based arm (France) therapy) [Appendix 7.6.3] Subtotal 4213§§ 0 4213§§ Phase 1 Studies in Breast Cancer Patients MDV3100-08 Phase 1, open-label, dose escalation, Ongoing (Patients with incurable [Stage IV or locally parallel group, monotherapy or in (enrollment 80, 160 mg/day 99 0 99 advanced unresectable] breast cancer) combination with anastrazole, complete) [Appendix 7.7.1] exemestane or fulvestrant Subtotal 99 0 99 Table continued on next page

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Enzalutamide No. of Comparator Total No. of Clinical Enzalutamide Subjects No. of Subjects Subjects Study Study Design and Type of Control Status Doses Evaluated Treated Treated Treated Phase 2 Studies in Breast Cancer Patients MDV3100-11 Ongoing (Patients with advanced, AR+, triple-negative Phase 2, open-label, single arm, (enrollment 160 mg/day 118 0 118 breast cancer) multicenter clinical activity and safety complete) [Appendix 7.8.1] MDV3100-12 Ongoing Phase 2, randomized, double-blind, (Patients with advanced hormone (enrollment placebo-controlled, efficacy and safety in 160 mg/day 154 123 245 receptor+/HER2-normal breast cancer) complete) combination with exemestane [Appendix 7.8.2] 9785-CL-1121 Phase 2, multicenter, open-label study to Ongoing (Patients with HER2+ AR+ metastatic or assess the efficacy and safety of (enrollment 160 mg/day 103 0 103 locally advanced breast cancer) enzalutamide with trastuzumab complete) [Appendix 7.8.3] Subtotal 375 123 466 Phase 2 Studies in Hepatocellular Carcinoma 9785-CL-3021 Phase 2, randomized, double-blind, Ongoing (Patients with advanced HCC) placebo-controlled study to assess the (enrollment 160 mg/day 107 55 162 [Appendix 7.9.1] efficacy and safety of enzalutamide complete) Subtotal 107 55 162 Subtotal of Healthy Volunteers and Special Populations 343 0 343 Subtotal Patients with Prostate Cancer in Clinical Studies 4861¶¶ 2434 7146¶¶ Subtotal Patient with Prostate Cancer in Compassionate Use and Expanded Access Programs 4213 0 4213 Subtotal Patients with Breast Cancer 474 123 565 Subtotal Patients with HCC 107 55 162 OVERALL TOTAL 9998 2612 12429 Note: Comparator treatment could have included either a placebo or an active drug. For ongoing studies, the clinical status as of 30 Aug 2017 is listed. Data cutoff dates for ongoing studies are 01 Sep 2010 (S-3100-1-01), 25 Sep 2011 (CRPC2 [AFFIRM]),01 Jul 2013 (MDV3100-06), 16 Sep 2013 (MDV3100-03 [PREVAIL]), 09 Feb 2015 (MDV3100-09 [STRIVE]), 19 Oct 2014 (9785-CL-0222 [TERRAIN]), 30 Aug 2015 (9785-CL-0011), 15 Sep 2015 (MDV3100-11), 08 Jan 2016 (MDV3100-08), 01 Feb 2016 (9785-CL-0403 [UPWARD]), 23 Sep 2016 (MDV3100-12), 07 Oct 2016 (MDV3100-10 [PLATO]), 28 Feb 2017 (9785-CL-1121), 28 Jun 2017 (MDV3100-14 [PROSPER]) and 02 Oct 2017 (9785-CL-3021). For ongoing study 9785-CL-0232 (Asian PREVAIL), data cutoff dates were 20 Sep 2015 (efficacy and safety) and 20 Jan 2016 (pharmacokinetics). Data are not yet available for ongoing studies 9785-CL-0123, MDV3100-18, 9785-MA-1010 (ENACT), MDV3100-13 (EMBARK), 9785-CL-0335 (ARCHES), 9785-MA-1001 or 9785-MA-3051. Footnotes continued on next page

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ADT: androgen deprivation therapy; AR+: androgen receptor-positive; BA: bioavailability; BE: bioequivalence; CRPC: castration-resistant prostate cancer; DDI: drug-drug interaction; HCC: hepatocellular carcinoma; HER2: human epidermal growth factor receptor 2; HER2+: human epidermal growth factor receptor 2-positive; mHSPC: metastatic hormone sensitive prostate cancer; PET/CT: positron emission tomography–computed tomography; USA: United States of America † 22 patients were enrolled and treated in the study; however, 1 patient received docetaxel only. ‡ 27 patients were treated with enzalutamide alone and 25 patients were treated with enzalutamide, leuprolide and . § Patients who completed studies 9785-CL-0007, 9785-CL-0003 and 9785-CL-0406 continued in the extension study 9785-CL-0121. These patients are included in both the phase 1 and phase 2 subtotals but are counted only once in the subtotal of patients with prostate cancer in clinical studies and the overall total. ¶ Includes 1 patient who previously participated in study CRPC2 and 8 patients who previously participated in the Named Patient Program. †† Patients from Site 105 were excluded due to data quality concerns. ‡‡ Enzalutamide-treated patients include 509 exposed to open-label enzalutamide during period 1. Of the 509 patients, 249 received double-blind treatment during period 2: 125 patients received enzalutamide plus abiraterone and prednisone and 124 patients received placebo plus abiraterone and prednisone during period 2 (double-blind). §§ The 9 patients in study 9785-CL-0401 who previously participated in the Named Patient Program (n = 8) or study CRPC2 (n = 1) are counted only once. ¶¶ The 52 patients in study 9785-CL-0121 who participated in studies 9785-CL-0007, 9785-CL-0003 and 9785-CL-0406 are counted only once.

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5.1 Pharmacokinetics and Product Metabolism in Humans 5.1.1 Pharmacokinetics The pharmacokinetics and metabolism of enzalutamide have been evaluated in more than 2500 patients with prostate cancer and in more than 200 volunteers, including healthy male subjects and subjects with mild, moderate or severe hepatic impairment. Individual daily doses have ranged from 30 to 600 mg. In studies MDV3100-08, MDV3100-12 and 9785-CL-1121, the pharmacokinetics of single- and multiple-dose enzalutamide in more than 400 women with breast cancer was found to be similar to the pharmacokinetics of enzalutamide in men with prostate cancer. Multiple-dose administration of enzalutamide 160 mg/day in female patients with breast cancer resulted in pharmacokinetic profiles of enzalutamide and its active metabolite, N-desmethyl enzalutamide, that were similar to those in men with prostate cancer. In study 9785-CL-3021 in patients with HCC, the pharmacokinetics of enzalutamide and its metabolites was found to be similar to those in men with prostate cancer and women with breast cancer. 5.1.1.1 Absorption Oral absorption of enzalutamide, whether administered as single or multiple doses, is rapid and independent of dose. Peak concentrations of enzalutamide are generally achieved 1 to 2 hours postdose in both patients and healthy subjects. The rapid attainment of Cmax is consistent with rapid dissolution of the capsule and release of solubilized enzalutamide into the gut lumen. Enzalutamide is well absorbed (estimated bioavailability based on mass balance data ≥ 84.2%); an expected finding for a low extraction ratio drug [Section 5.1.1.4] that displays high permeability and that is not a substrate for P-gp or BCRP [Section 4.2.1]. A high-fat meal reduces the rate of enzalutamide absorption but the extent of absorption is unaffected [Section 5.1.1.5]. Enzalutamide has been administered without regard to meals in clinical studies in patients, including the pivotal phase 3 studies MDV3100-03 and CRPC2. 5.1.1.2 Distribution The mean apparent volume of distribution (V/F) of enzalutamide in patients is 110 L (S-3100-1-01), or approximately 2.6-fold greater than total body water (42 L) [Davies & Morris, 1993], which is indicative of extensive extravascular distribution. The mean V/F in healthy subjects ranged from 62.7 to 117 L. In vitro and in vivo protein binding data showed that enzalutamide is 97% to 98% bound to plasma proteins, primarily albumin (study PRO3100NC32). N-desmethyl enzalutamide is 95% to 97% bound to plasma proteins (study 9785-ME-0018). An in vitro study to assess the potential for DDIs with enzalutamide via displacement from protein binding sites in human plasma showed that enzalutamide is not displaced by other highly bound drugs (warfarin, ibuprofen and salicylic acid; study 9785-ME-0017). Red blood cell partitioning was indirectly measured using whole blood and plasma radioactivity from a mass balance study in healthy subjects (study 9785-CL-0001). Following oral administration of 14C-enzalutamide, the blood-to-plasma concentration ratio

Jun 2018 Astellas/Medivation Page 49 of 126 Enzalutamide (MDV3100) CONFIDENTIAL Cancer Investigator’s Brochure Edition 10 was 0.55, indicating that the radioactivity is preferentially retained in the plasma component of blood. No clinical studies have investigated penetration of enzalutamide and metabolites into brain or cerebrospinal fluid. Enzalutamide and N-desmethyl enzalutamide cross the blood-brain barrier in mice and rats, achieving tissue concentrations equivalent to those in plasma (studies 9785-ME-5016 and PRO3100NC84). 5.1.1.3 Metabolism A single dose of 160 mg (100 µCi) 14C-enzalutamide was administered orally to healthy subjects to assess mass balance and to obtain metabolic profiles (study 9785-CL-0001). A total of 7 phase I metabolites were identified in plasma, and by comparison with reference standards and liquid chromatography with multiple stage mass spectrometry methods (study 9785-ME-0020). These metabolites were formed via demethylation, oxidation and hydrolysis reactions. No phase II conjugation products were observed. The major metabolites in humans were an inactive carboxylic acid metabolite and an active N-desmethyl metabolite of enzalutamide (N-desmethyl enzalutamide). Biotransformation pathways in animals and humans were similar. As 14C recovery was generally 100% during sample extraction procedures, there do not appear to be reactive metabolites in humans. The carboxylic acid metabolite and N-desmethyl enzalutamide are formed slowly. After a single 160 mg dose of enzalutamide in healthy subjects, peak plasma concentrations of the carboxylic acid metabolite are typically achieved 4 to 6 days postdose and peak plasma concentrations of N-desmethyl enzalutamide are typically achieved 5.5 to 6 days postdose. At steady state, the active metabolite N-desmethyl enzalutamide circulates at approximately the same plasma concentration as enzalutamide; whereas, plasma concentrations of the inactive carboxylic acid metabolite are approximately 25% lower than enzalutamide (study 9785-CL-0001). In vitro studies show that enzalutamide is metabolized by CYP2C8 and CYP3A4/5, both of which play a role in the formation of N-desmethyl enzalutamide (study 9785-ME-0001). A clinical DDI study in healthy volunteers (study 9785-CL-0006) revealed that CYP2C8 plays an important role in the metabolism of enzalutamide and the formation of N-desmethyl enzalutamide [Section 5.1.3.2]. In addition, an in vitro study showed that hCES1 is capable of catalyzing the formation of the carboxylic acid metabolite from enzalutamide and N-desmethyl enzalutamide (study 9785-ME-0042). Enzalutamide is not metabolized in vitro by CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1 or hCES2. In addition, in vitro data show that N-desmethyl enzalutamide is not metabolized by CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP3A4, CYP3A5 or hCES2. 5.1.1.4 Elimination Following oral administration of 14C-enzalutamide to healthy male subjects, 84.6% of the dose was recovered through day 77 postdose: 71.0% was recovered in urine (primarily as the

Jun 2018 Astellas/Medivation Page 50 of 126 Enzalutamide (MDV3100) CONFIDENTIAL Cancer Investigator’s Brochure Edition 10 carboxylic acid metabolite, with trace amounts of enzalutamide and N-desmethyl enzalutamide) and 13.6% was recovered in feces (0.39% as enzalutamide). Based on this information, renal excretion is a minor elimination pathway for unchanged parent enzalutamide and N-desmethyl enzalutamide. The mean apparent total body clearance of enzalutamide ranges from 0.520 and 0.564 L/h in patients with CRPC and from 0.596 to 0.753 L/h in healthy male subjects or approximately 1% of the liver plasma flow rate (48.7 L/h) [Davies & Morris, 1993]; thus, enzalutamide is a low extraction ratio drug. The mean t1/2 of enzalutamide in patients with CRPC is 5.8 days, while the mean t1/2 of enzalutamide is shorter in healthy male subjects, averaging 2.9 to 4.8 days. The t1/2 does not appear to be affected by dose. With daily administration, it takes approximately 1 month to reach steady state. Information on the t1/2 of the carboxylic acid metabolite and N-desmethyl enzalutamide in patients is not available. The mean t1/2 for the carboxylic acid metabolite in healthy male subjects ranges from 7.8 to 9.3 days and the mean t1/2 for N-desmethyl enzalutamide in healthy male subjects ranges from 7.5 to 8.8 days, respectively. With daily oral administration to patients with CRPC, enzalutamide accumulates approximately 8.3-fold relative to a single dose (study S-3100-1-01). At steady state, Cmax values for enzalutamide, the carboxylic acid metabolite and N-desmethyl enzalutamide are 16.6 µg/mL, 8.87 µg/mL and 12.7 µg/mL, respectively (study 9785-CL-0007).

Due to the long t1/2, daily fluctuation in plasma concentrations are low (mean peak-to-trough ratio of 1.25), resembling a constant infusion (study S-3100-1-01). At steady-state, Cmin values for enzalutamide, the carboxylic acid metabolite and N-desmethyl enzalutamide are 11.4 µg/mL, 8.44 µg/mL and 13.0 µg/mL, respectively (CRPC2). The steady-state Cmin values for enzalutamide in individual patients remained constant during more than 1 year of chronic therapy, demonstrating time-linear pharmacokinetics once steady state is achieved (study CRPC2). No major deviations from dose proportionality or linearity are observed over the dose range 30 to 600 mg (study S-3100-1-01). 5.1.1.5 Food Effects A food-effect study (study MDV3100-05) involving administration of a single dose of enzalutamide to healthy male subjects under fasting conditions and with a high-fat, high-calorie meal indicated that food had no effect on the extent of absorption. The reduction in the rate of absorption following a single dose is not clinically relevant and enzalutamide can be taken with or without food. Enzalutamide has been administered without regard to meals in the pivotal randomized phase 3 studies (studies CRPC2 and MDV3100-03). 5.1.2 Pharmacokinetics in Special Populations Hepatic Impairment No dose adjustment is necessary for patients with mild, moderate or severe hepatic impairment (Child-Pugh Class A, B and C, respectively).

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Sex The effects of gender on the pharmacokinetics of enzalutamide has been evaluated in 3 studies in more than 400 women with breast cancer. The pharmacokinetics of single- and multiple-dose enzalutamide in more than 400 women with breast cancer was found to be similar to the pharmacokinetics of enzalutamide in men with prostate cancer. Multiple-dose administration of enzalutamide 160 mg/day in female patients with breast cancer resulted in pharmacokinetic profiles of enzalutamide and its active metabolite, N-desmethyl enzalutamide, that were similar to those in men with prostate cancer. Race The majority of patients in the randomized clinical studies were white (84.6%). Based on the pharmacokinetic data from a study in Japanese patients with prostate cancer (study 9785-CL-0111) there were no clinically relevant differences in exposure between Japanese and white patients (Report 9785-PK-0102). There are insufficient data to evaluate potential differences in the pharmacokinetics of enzalutamide in other races. Other Demographics In study MDV3100-03 (phase 3 study in patients with CRPC), selected demographic characteristics (age, weight) were summarized by exposure quartiles (Cmin) for enzalutamide, N-desmethyl enzalutamide and the sum of enzalutamide plus N-desmethyl enzalutamide. The summary statistics (mean and median) suggested a positive relationship with increasing exposure in all 3 groups (enzalutamide, N-desmethyl enzalutamide and the sum of enzalutamide plus N-desmethyl enzalutamide) with increasing age and a negative relationship with increasing exposure in the 3 groups with decreasing baseline weight. For both age and weight, the ranges (min, max) were overlapping among the quartiles. In addition, a population pharmacokinetic analysis was performed with data from patients with CRPC and healthy male subjects to assess the effects of age, weight and renal function (CLCR ≥ 30 mL/min) on exposure. Based on the population pharmacokinetic analysis, the overall impacts of these covariates on enzalutamide pharmacokinetic profiles and calculated parameters were minor and not clinically meaningful when compared to interindividual and residual variability; therefore, covariate-based dose adjustments are not indicated for enzalutamide. Severe renal impairment (CLCR < 30 mL/min) and end-stage renal disease have not been assessed. 5.1.3 DDIs 5.1.3.1 Potential for Enzalutamide to Affect Exposures to Other Drugs The potential for enzalutamide to affect the pharmacokinetics of other drugs was assessed through a series of in vitro experiments [Section 4.2.5]. Based on in vitro findings, in vivo phenotypic cocktail DDI studies were performed in patients with CRPC (studies 9785-CL-0007 and 9785-CL-0406). In these studies, a single oral dose of a CYP probe substrate cocktail (for CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and/or CYP3A4) was administered before and concomitantly with enzalutamide (following at least

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50 days of dosing at 160 mg daily). The results are summarized in Figure 3. At steady state, enzalutamide is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer. Enzalutamide did not cause clinically meaningful changes in exposure to the CYP1A2, CYP2C8, or CYP2D6 substrates. In a DDI study in patients with metastatic CRPC, intravenously administered docetaxel (CYP3A4 substrate) was given before and concomitantly with enzalutamide (after at least 21 days of dosing at 160 mg daily). The results showed that enzalutamide did not cause a clinically meaningful change in exposure to the intravenously administered CYP3A4 substrate. An in vitro study to assess the potential for DDIs with enzalutamide via displacement from protein binding sites in human plasma showed that enzalutamide does not displace the binding of other highly bound drugs (warfarin, ibuprofen and salicylic acid; study 9785-ME-0017). Figure 3 Effect of Enzalutamide on Other Drugs

CYP: cytochrome P450; PK: pharmacokinetics In women with metastatic breast cancer, the addition of enzalutamide to currently approved hormone therapies could overcome resistance and provide increased antitumor activity without significantly altering the toxicity profile. However, most hormone therapies are metabolized by CYP3A4; therefore, a phase 1 study was performed to evaluate the use of enzalutamide in combination with hormonal therapies. MDV3100-08 evaluated the use of enzalutamide in combination with anastrozole 1 mg, exemestane 25 mg, exemestane 50 mg and fulvestrant 500 mg. The exemestane 50 mg cohort was added to compensate for the CYP3A4 induction effect by enzalutamide.

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The geometric mean (90% CI) ratios of the AUCtau for anastrozole, exemestane 25 mg/day and exemestane 50 mg/day were 0.111 (0.067, 0.185), 0.575 (0.500, 0.661) and 0.434 (0.364, 0.519), respectively. Based on these results, concomitant use of enzalutamide caused mean AUCtau to decrease by 89% for anastrozole and 43% to 57% for exemestane. Comparisons based on Cmax produced similar results.

The AUCtau and Cmax for 50 mg/day exemestane combined with enzalutamide were similar to those for 25 mg/day exemestane alone and the geometric mean (90% CI) ratios for AUCtau and Cmax were 0.949 (0.650, 1.39) and 0.888 (0.602, 1.31), respectively.

The geometric mean (90% CI) ratio of Cmin was 0.920 (0.800, 1.08) for fulvestrant, representing a mean change in Cmin of 8% with a 90% CI that included 1.00. 5.1.3.2 Potential for Other Drugs to Affect Exposure to Enzalutamide In DDI studies in healthy male volunteers (9785-CL-0006 and 9785-CL-0405), a single 160 mg oral dose of enzalutamide was administered alone or after multiple oral doses of gemfibrozil (strong CYP2C8 inhibitor), itraconazole (strong CYP3A4 inhibitor) or rifampin (moderate CYP2C8 inducer and strong CYP3A4 inducer). Gemfibrozil increased the AUC of enzalutamide plus N-desmethyl enzalutamide by 2.2-fold with minimal effect on Cmax. Itraconazole and rifampin did not cause clinically meaningful changes in the sum of exposure to enzalutamide plus N-desmethyl enzalutamide. The results are summarized in Figure 4. Figure 4 Effects of Other Drugs and Intrinsic/Extrinsic Factors on Enzalutamide

CYP: cytochrome P450; PK: pharmacokinetics

# Pharmacokinetic parameters (Cmax and AUCinf) are for enzalutamide plus N-desmethyl enzalutamide, except in the food-effect study, where they are for enzalutamide alone.

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5.1.3.3 Potential for Interactions with Transporters The potential for enzalutamide to affect the pharmacokinetics of other drugs via effects on drug transporters was assessed through a series of in vitro experiments [Section 4.2.5]. Based on in vitro data, enzalutamide, N-desmethyl enzalutamide and/or the carboxylic acid metabolite may be inhibitors of BCRP, MRP2 and OAT3 at clinically relevant systemic concentrations or in the gastrointestinal wall during absorption. Thus, enzalutamide may increase the plasma concentrations of coadministered medicinal products that are BCRP, MRP2 or OAT3 substrates. In vitro experiments also suggest enzalutamide, N-desmethyl enzalutamide and the carboxylic acid metabolite do not inhibit OATP1B1, OAT1B3, OCT1, OCT2, OAT1 or OAT3-mediated transport at clinically relevant concentrations. Enzalutamide is not a substrate for OATP1B1, OATP1B3 or OCT1; and N-desmethyl enzalutamide is not a substrate for P-gp or BCRP. Based on in vitro data, enzalutamide is an inhibitor but not a substrate for P-gp; however, under conditions of clinical use, enzalutamide may be an inducer of P-gp via activation of pregnane X receptor. Thus, enzalutamide may alter the plasma concentrations of coadministered medicinal products that are P-gp substrates. 5.1.4 Pharmacodynamics Limited clinical data are available for a pharmacodynamic assessment and confined to an assessment of blood samples and bone marrow biopsies in a phase 2 study (CRPC-MDA-1) in 60 patients with CRPC. Sampling of blood and the bone marrow microenvironment with bone marrow biopsies in study CRPC-MDA-1 demonstrated that therapy with 160 mg daily of enzalutamide was associated with increases in testosterone concentrations in both plasma (mean change from baseline to week 9 of 0.09 ng/mL; P < 0.0010) and bone marrow (mean change from baseline to week 9 of 0.05 ng/mL; P < 0.0001). This increase in testosterone is proposed to be an adaptive biologic response to effective AR signaling inhibition. There was a larger increase (not statistically significant) in mean plasma testosterone (mean change from baseline to week 9 of 0.12 ng/mL in responders vs 0.07 ng/mL in nonresponders; P = 0.168) and DHT (mean change from baseline to week 9 of 0.02 ng/mL in responders vs 0.01 ng/mL in nonresponders; P = 0.2210) in the PSA responder group. There was an increase in bone marrow testosterone (nonsignificant) but not bone marrow DHT at week 9 compared to baseline. There was no change (week 9 compared to baseline) in bone marrow testosterone or DHT for PSA responders or non-PSA responders. The interpretation of bone marrow DHT was difficult because the majority of results were below the limit of quantitation. The observation of increased plasma and bone marrow androgens is consistent with a potential adaptation of prostate cancer to overcome enzalutamide AR axis blockade. Analysis of AR expression by IHC in prostate cancer cells in paired bone marrow tumor samples at baseline and week 9 suggests that enzalutamide therapy increased the localization of the AR to a cytoplasmic (not nuclear) subcellular localization. While the number of paired bone marrow samples with prostate cancer cells with adequate immunohistochemical staining of the AR was small and a statistical correlation was not assessed, these human data corroborate the nonclinical finding that enzalutamide inhibits nuclear translocation.

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The results from this study are consistent with the proposed of enzalutamide, that of a high affinity, competitive inhibitor of the AR that inhibits nuclear translocation of the receptor. 5.2 Safety and Efficacy This section contains safety (data cutoff date 30 Aug 2017, unless otherwise noted) and efficacy data for enzalutamide used as monotherapy or in combination. All completed and ongoing enzalutamide company-sponsored studies for the treatment of prostate cancer, breast cancer and HCC are included in Table 2, with study status as of 30 Aug 2017 for the ongoing studies. 5.2.1 Overview of Efficacy Pivotal efficacy data are provided from 2 phase 3 randomized studies: MDV3100-03 in chemotherapy-naïve metastatic CRPC patients and CRPC2 in patients with metastatic CRPC who previously received docetaxel [Section 5.2.1.2]. The efficacy of enzalutamide in patients with metastatic CRPC also is being assessed in 10 other clinical studies including patients who were chemotherapy-naïve as well as those who previously received docetaxel: 3 phase 4 open-label studies: MDV3100-10, 9785-CL-0410 and 9785-MA-1008; 2 additional phase 3, randomized, placebo-controlled studies: 9785-CL-0232 and 9785-MA-1001; 2 phase 2 head-to-head studies against bicalutamide: 9785-CL-0222 and MDV3100-09; 1 additional phase 2 study (CRPC-MDA-1), a phase 1/2 study (9785-CL-0111) and a phase 1 study (S-3100-1-01). Data from 9785-MA-1001 have not been analyzed as of the data cutoff date for this IB. Efficacy is also being assessed in patients with nonmetastatic prostate cancer in 2 phase 3, randomized, placebo-controlled studies (MDV3100-13 and MDV3100-14) and a phase 2 study (MDV3100-07). Data for study MDV3100-14 (in patients with nonmetastatic CRPC at high risk of disease progression) are summarized in Section 5.2.1.3. Data for study MDV3100-07 (in patients with localized prostate cancer) are summarized in [Appendix 7.3.5]. As of the data cutoff date for this IB, data for study MDV3100-13 (in patients with high-risk, nonmetastatic hormone sensitive prostate cancer progressing after definitive therapy) have not yet been analyzed. A brief summary of efficacy data is also provided for the phase 2 study (9785-CL-0321) in patients with hormone-naïve prostate cancer [Section 5.2.1.4]. Efficacy is being assessed in a phase 3, randomized, placebo-controlled study in patients with metastatic hormone sensitive prostate cancer (9785-CL-0335) (data not yet analyzed as of the data cutoff date for this IB). In addition, brief summaries of efficacy results are provided in Section 5.2.1.5 for studies MDV3100-08, MDV3100-11, MDV3100-12 and 9785-CL-1121 in patients with breast cancer and in Section 5.2.1.6 for study 9785-CL-3021 in patients with HCC; these development programs have been discontinued.

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5.2.1.1 Efficacy in Metastatic CRPC Population 5.2.1.1.1 Study MDV3100-03 (Chemotherapy-naïve Metastatic CRPC Patients) MDV3100-03 is a multinational, phase 3, randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of enzalutamide 160 mg/day administered orally in asymptomatic or mildly symptomatic patients with metastatic CRPC who progressed on ADT. The coprimary objectives were to determine the benefit of enzalutamide compared with placebo on OS and rPFS. Secondary objectives were to determine the benefit of enzalutamide compared with placebo on time to first skeletal related event, time to initiation of cytotoxic chemotherapy, time to PSA progression, PSA response rate ≥ 50% and best overall soft tissue response. Exploratory objectives were to determine the benefit of enzalutamide compared with placebo on PSA response rate ≥ 90%; time to initiation of any cytotoxic, hormonal, or investigational antineoplastic therapy; and quality of life measures such as the FACT-P, European Quality of Life-Five Domain Scale (EQ-5D) and Brief Pain Inventory Short Form (BPI) instruments. Between Sep 2010 and Sep 2012, 1717 patients were randomized across 207 study centers in 22 countries in North America, Europe, Australia and Asia. Based on the results of the prespecified interim analysis of OS and final rPFS analyses and considering the observed safety profile, the Data Monitoring Committee (DMC) recommended halting the blinded portion of the study and allowing patients randomized to placebo to receive open-label enzalutamide. Treatment with enzalutamide was associated with a statistically significant benefit on both coprimary endpoints and all secondary endpoints. Study MDV3100-03 demonstrated that treatment with enzalutamide decreased the risk of death by 29% (HR: 0.706; P < 0.0001) [Table 3]. As described through the Kaplan Meier curve of OS, the OS benefit was observed early, approximately 3 to 4 months after randomization and was maintained over the duration of the study. It is also noteworthy that the survival benefit was observed despite substantially higher and earlier use in the placebo group (70.3%) compared with the enzalutamide group (40.3%) of subsequent therapies with a demonstrated survival benefit in patients with prostate cancer. A consistent relative OS benefit was observed across all prespecified subgroups, including patients with Eastern Cooperative Oncology Group (ECOG) performance status 0 vs 1 at baseline; age; geographic region; Gleason score at diagnosis; type of progression at study entry; presence of visceral disease at study entry; and baseline laboratory prognostic markers such as PSA, hemoglobin and lactate dehydrogenase (LDH) [Figure 5]. Treatment with enzalutamide also conferred an important benefit on the coprimary endpoint, rPFS, as measured by blinded central review. Patients receiving enzalutamide had an 81% decreased risk of radiographic progression or death (HR: 0.186; P < 0.0001) [Figure 6]. The results of the rPFS analysis were robust as confirmed by all prespecified sensitivity analyses as well as consistent with the investigator-assessed rPFS analysis. The effect on rPFS was observed at the first postbaseline imaging time point as demonstrated by the early separation of the Kaplan-Meier curves and increased over time. The data integrity for the

Jun 2018 Astellas/Medivation Page 57 of 126 Enzalutamide (MDV3100) CONFIDENTIAL Cancer Investigator’s Brochure Edition 10 rPFS endpoint was high; more than 98% of imaging scans were received for central review and a high degree of concordance (87.6%) was observed between central and investigator assessments of radiographic progression using the same 06 May 2012 data cutoff date. Other clinically important findings in study MDV3100-03 include a 17.2-month delay in the median time to initiation of cytotoxic chemotherapy in the enzalutamide group vs placebo (28.0 vs 10.8 months), which also delayed chemotherapy treatment-associated morbidities. Additionally, the absolute difference in objective soft tissue response between the enzalutamide-treated patients and placebo-treated patients was 53.9% (95% CI: 48.5%, 59.2%; P < 0.0001). In patients with measurable soft tissue disease, CR was reported in 19.7% of enzalutamide-treated patients compared to 1.0% of placebo-treated patients and PR was reported in 39.1% of enzalutamide-treated patients vs 3.9% of placebo-treated patients. A decrease in risk of a skeletal-related event (HR: 0.718; 95% CI: 0.610, 0.844; P < 0.0001) and PSA progression (HR: 0.169; 95% CI: 0.147, 0.195; P < 0.0001) with substantial and statistically significant PSA response rates (78.0% had PSA response ≥ 50% and 46.8% had PSA response ≥ 90%, P < 0.0001 for both) in enzalutamide-treated patients provide additional evidence of clinical benefit. Furthermore, the benefit on time to degradation of FACT-P total scores (HR: 0.625; 95% CI: 0.542, 0.720; P < 0.0001) suggests that treatment with enzalutamide may prolong quality of life. In summary, treatment with enzalutamide in study MDV3100-03 resulted in clinically meaningful and statistically significant improvement over treatment with placebo on both coprimary endpoints and all secondary endpoints, as well as most exploratory endpoints. Enzalutamide treatment provided clinically important benefits over placebo treatment on OS, disease progression and QoL.

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Figure 5 MDV3100-03 Forest Plot for Duration of Overall Survival: Subgroup Analysis (ITT Population)

CI: confidence interval; ECOG: Eastern Cooperative Oncology Group; ITT: intent-to-treat; mo: months; NYR: not yet reached; PSA: prostate-specific antigen. Rest of world includes Australia, Japan, Singapore and South Korea. Hazard ratio is based on an unstratified Cox regression model (with treatment as the only covariate) and is relative to placebo with < 1 favoring enzalutamide. Source: Study MDV3100-03 CSR

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Figure 6 MDV3100-03 Forest Plot for Duration of Radiographic Progression-Free Survival Based on Independent Central Review and Data Analysis Cutoff Date for the Interim Analysis - Subgroup Analysis (ITT Population)

CI: confidence interval; ECOG: Eastern Cooperative Oncology Group; ITT: intent-to-treat; LDH: lactate dehydrogenase; mo: months; NYR: not yet reached; PSA: prostate-specific antigen. The analysis data cutoff date is 06 May 2012. Patients randomized after the data cutoff date are not included in the analysis. Rest of world includes Australia, Japan, Singapore and South Korea. Hazard ratio is based on an unstratified Cox regression model (with treatment as the only covariate) and is relative to placebo with < 1 favoring enzalutamide. Source: MDV3100-03

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Table 3 MDV3100-03 Summary of Efficacy Results (ITT Population) Hazard Ratio (95% CI) or Enzalutamide Placebo Difference in Response Rates Endpoint (n = 872) (n = 845) (95% CI) P-Value Coprimary Efficacy Endpoints Overall survival, Events/N† 241/872 299/845 0.706 (0.596, 0.837) < 0.0001 Radiographic progression-free survival, Events/N†‡ 118/832 321/801 0.186 (0.149, 0.231) < 0.0001 Secondary Efficacy Endpoints Time to first skeletal-related event, Events/N† 278/872 309/845 0.718 (0.610, 0.844) < 0.0001 Time to initiation of cytotoxic chemotherapy, Events/N† 308/872 515/845 0.349 (0.303, 0.403) < 0.0001 Time to PSA progression, Events/N† 532/872 548/845 0.169 (0.147, 0.195) < 0.0001 PSA response ≥ 50%, n/N (%)§ 666/854 (78.0%) 27/777 (3.5%) 74.51% (71.45, 77.57%)¶ < 0.0001 Best overall soft tissue response (CR or PR), n/N (%)†† 233/396 (58.8%) 19/381 (5.0%) 53.85% (48.53, 59.17%)¶ < 0.0001 Exploratory Efficacy Endpoints‡‡ Time to FACT-P degradation, Events/N† 456/872 409/845 0.625 (0.542, 0.720) < 0.0001 Brief Pain Inventory: pain emergence, Events/N§§ 222/698 133/358 -5.35% (-11.43, 0.74%)¶ 0.0819 Time to first postbaseline antineoplastic therapy, Events/N¶¶ 382/872 642/845 0.273 (0.240, 0.311) < 0.0001 PSA response ≥ 90%, n/N (%)§ 400/854 (46.8%) 9/777 (1.2%) 45.68% (42.25, 49.11%)¶ < 0.0001 CI: confidence interval; CR: complete response; FACT-P: Functional Assessment of Cancer Therapy - Prostate; ITT: intent-to-treat; PR: partial response; PSA: prostate-specific antigen; rPFS : radiographic progression-free survival. The analysis data cutoff date is 16 Sep 2013 for all efficacy analyses except rPFS that used the analysis data cutoff date of 06 May 2012. †Number of events observed on or prior to analysis data cutoff/ITT sample size. Hazard ratio and its 95% CI from a Cox proportional hazards model with treatment group as a covariate. P-value from an unstratified log-rank test. ‡Based on earliest contributing event (radiographic progression or death due to any cause within 168 days after treatment discontinuation). §Confirmation required a subsequent consecutive assessment conducted at least 3 weeks later. ¶Difference in response rate (95% CI). ††Based on investigator assessment of target, nontarget and new lesions for patients with measurable disease at baseline. ‡‡No corrections for multiplicity were made for prespecified exploratory endpoints. §§Pain progression is defined as an increase of  30% from baseline in the mean pain intensity score at month 6. ¶¶Includes cytotoxic, hormonal or investigational therapies. Source: Module 2.7.3, Table 2.7.3.3.1.3.1-1

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5.2.1.1.2 Study CRPC2 (Postchemotherapy Metastatic CRPC Patients) CRPC2 is a phase 3, randomized, double-blind, placebo-controlled, multicenter study evaluating the efficacy and safety of enzalutamide 160 mg/day administered orally in 1199 patients with CRPC whose disease progressed after 1 or 2 prior chemotherapy regimens, 1 of which was docetaxel based. The primary efficacy endpoint was OS. Secondary efficacy endpoints included time to PSA progression; rPFS; time to first skeletal related event; QoL measures using FACT-P, EQ-5D and BPI; and circulating tumor cell conversion rate. Between Sep 2009 and Nov 2010, 1199 patients were randomized across 156 study centers in North America, South America, Europe, Australia and South Africa. The primary endpoint was OS and the primary analysis was planned to occur at the time of 650 death events; a single interim analysis was to occur at 520 death events. The interim analysis was prepared by an independent statistical unit and presented to the DMC during a closed session on 02 Nov 2011. Based on a benefit in OS in patients receiving enzalutamide, the DMC recommended halting the study and allowing patients randomized to placebo to receive open label enzalutamide. Therefore, the interim analysis of OS was the final analysis. The treatment level blind was maintained for study sites, patients and the sponsors up through the lock of the blinded database on 16 Dec 2011, after which time complete efficacy and safety analyses were performed as specified in the statistical analysis plan. The results of this study formed the basis for the initial approval for treatment of patients with metastatic CRPC who previously received docetaxel. The clinical study report was submitted in the original marketing application with a data cutoff date for efficacy analyses of 25 Sep 2011. This study demonstrated that enzalutamide treatment decreased the risk of death by 37% (HR: 0.631; P < 0.0001) compared with placebo treatment [Figure 7 and Table 4]. The statistically significant and clinically meaningful benefit of enzalutamide treatment as measured by OS was seen in all prespecified patient subgroups and observed despite 42.0% of enzalutamide-treated and 61.4% of placebo-treated patients receiving subsequent therapies to treat prostate cancer, including abiraterone (20.9% vs 24.3%) and cabazitaxel (9.8% vs 13.8%), both shown to improve OS following docetaxel treatment. Enzalutamide treatment also resulted in significant improvements over placebo treatment in all key secondary efficacy endpoints that were rank-prioritized in the statistical analysis plan including: time to PSA progression, rPFS and time to first skeletal-related event [Table 4]. Enzalutamide treatment resulted in statistically significant improvements over placebo treatment in the other secondary and exploratory efficacy endpoints of PSA response, radiographic response, QoL as assessed by FACT-P, pain palliation rate at week 13, pain progression at week 13 and time to pain progression based on FACT-P.

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Figure 7 CRPC2 Forest Plot for Duration of Overall Survival - Subgroup Analysis (ITT Population)

CI: confidence interval; ECOG: Eastern Cooperative Oncology Group; ITT: intent-to-treat; LDH: lactate dehydrogenase; mo.: month; PSA: prostate-specific antigen. Based on data analysis cutoff date for the CRPC2 interim analysis. Source: Study CRPC2

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Table 4 CRPC2 Summary of Efficacy Results (ITT Population) Hazard Ratio (95% CI) or Enzalutamide Placebo Difference in Response Endpoint (n = 800) (n = 399) Rates (95% CI) P-Value Primary Efficacy Endpoint Overall survival, Events/N 308/800 212/399 0.631 (0.529, 0.752) < 0.0001 Key Secondary Efficacy Endpoints Time to PSA progression, Events/N 400/800 190/399 0.248 (0.204, 0.303) < 0.0001 Radiographic progression-free 524/800 337/399 0.404 (0.350, 0.466) < 0.0001 survival, Events/N Time to first skeletal-related event, 287/800 161/399 0.688 (0.566, 0.835) 0.0001 Events/N Other Secondary Efficacy Endpoints† FACT-P response rate, n/N (%)‡ 281/651 (43.2%) 47/257 (18.3%) 24.9% (18.8%, 30.9%) < 0.0001 PSA response rate for ≥ 50% 395/731 (54.0%) 5/330 (1.5%) 52.5% (48.7%, 56.4%) < 0.0001 decrease, n/N (%)§ PSA response rate for ≥ 90% 181/731 (24.8%) 3/330 (0.9%) 23.9% (20.6%, 27.1%) < 0.0001 decrease, n/N (%)§ Rate of pain palliation at week 13, 22/49 (44.9%) 1/15 (6.7%) 38.2% (19.4%, 57.0%) 0.0079 n/N (%)¶ Exploratory Efficacy Endpoints† Overall radiographic tumor response, 129/446 (28.9%) 8/208 (3.8%) 25.1% (20.1%, 30.0%) < 0.0001 n/N (%)†† Partial response 112/446 (25.1%) 6/208 (2.9%) na na Complete response 17/446 (3.8%) 2/208 (1.0%) na na Mean QOL scores decreased more at weeks 13-25 in placebo group than EQ-5D‡‡ in enzalutamide group Mean ECOG PS deteriorated more in placebo group than in ECOG performance status§§ enzalutamide group 101/259 Pain progression rate, n/N (%)¶¶ 174/625 (27.8%) -11.2% (-18.1%, -4.3%) 0.0018 (39.0%) Time to pain progression, Events/N 141/800 57/399 0.564 (0.409, 0.777) 0.0004 ¶¶ CI: confidence interval; ECOG: Eastern Cooperative Oncology Group; EQ-5D: European Quality of Life Five-Domain Scale; FACT-P: Functional Assessment of Cancer Therapy-Prostate; ITT: intent-to-treat; na: not applicable; PS: performance status; PSA: prostate-specific antigen; QOL: quality of life; RECIST: Response Evaluation Criteria in Solid Tumors. Key secondary endpoints were rank-prioritized. †No corrections for multiplicity were made for other secondary or exploratory efficacy endpoints. ‡Analyzed in patients who were part of the ITT Population, had a global FACT-P score at baseline and at least 1 postbaseline assessment. §Analyzed in patients who were part of the ITT Population, had a PSA level measured at baseline and at least 1 postbaseline assessment. ¶Evaluated in patients who were part of the ITT Population and had: metastatic bone disease at baseline; provided answers to Question #3 of the Brief Pain Inventory – Short Form for a minimum of 4 out of 7 days in the baseline run-in period; had stable baseline pain (no greater than a 2-point variation in daily pain scores); had stable analgesic use (no greater than 30% variation in analgesic use); and had an average pain score during the baseline run-in period ≥ 4. Footnotes continued on next page

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††Analyzed in patients who were part of the ITT Population and had measurable soft tissue disease at screening, defined by at least 1 target lesion according to RECIST v1.1. ‡‡Evaluated in patients who were part of the ITT Population and had a baseline EQ-5D assessment, which was offered at sites in 5 European countries (France, United Kingdom, Germany, Italy and Spain) and only after the second protocol amendment (Version 3.0). Per the statistical analysis plan, no statistical tests were conducted on EQ-5D data. §§Analyzed in the ITT Population. Per the statistical analysis plan, no statistical tests were conducted on ECOG performance status data. ¶¶Evaluated in patients who were part of the ITT Population and had valid pain score entries in a pain diary for a minimum of 4 out of 7 days during the baseline run-in period and during the 7 days preceding the Week 13 visit. Data cutoff date: 25 Sep 2011 Source: Module 2.7.3; Table 2.7.3.3.2.2-1 and Study CRPC2

5.2.1.1.3 Study 9785-CL-0222 (TERRAIN) 9785-CL-0222 (TERRAIN) is a multinational, randomized, double-blind, double-dummy, parallel-group phase 2 study in men with prostate cancer that had progressed while on ADT with an luteinizing hormone-releasing hormone (LHRH) agonist/antagonist or subsequent to bilateral orchiectomy. A total of 375 chemotherapy-naïve metastatic CRPC patients were randomized to receive either enzalutamide orally at a dose of 160 mg once daily (n = 184) or bicalutamide orally at a dose of 50 mg once daily (n = 191). Patients were stratified by whether bilateral orchiectomy or receipt of LHRH agonist/antagonist therapy started before or after the diagnosis of metastases. For the study duration, all patients maintained ADT with an LHRH agonist/antagonist or had undergone prior bilateral orchiectomy. The median duration of treatment was 11.6 months in the enzalutamide group vs 5.8 months in the bicalutamide group. The primary efficacy objective was to determine the PFS of enzalutamide as compared to bicalutamide based on independent central review (ICR), where a progression event was defined as an objective evidence of radiographic disease progression, skeletal-related event, initiation of new antineoplastic therapy or death by any cause, whichever occurred first. Secondary efficacy variables included PFS based on investigator assessment, PSA response and time to PSA progression. As of the data cutoff date (19 Oct 2014), treatment with enzalutamide compared to bicalutamide resulted in a clinically meaningful and statistically significant improvement in the primary efficacy endpoint of ICR-based PFS (HR: 0.44; 95% CI: 0.34, 0.57). The median (95% CI) PFS was 15.7 (11.5, 19.4) months in the enzalutamide group and 5.8 (4.8, 8.1) months in the bicalutamide group (P < 0.0001). A consistent PFS benefit was seen across all prespecified subgroups including age, geographic region, ECOG performance status, initial Gleason score, disease localization at baseline, baseline PSA value, diagnosis of metastases occurring before or after medical or surgical castration and previous use of antiandrogen therapy. In addition, there were statistically significant improvements in all secondary efficacy endpoints. Results for the investigator-based PFS showed enzalutamide was associated with a 58% reduction in the risk of a progression event (HR: 0.42; 95% CI: 0.33, 0.55; P < 0.0001). The median PSA response by week 13 in the enzalutamide group showed a decrease of 89%, with an increase of 0.36% in the bicalutamide group. Likewise,

Jun 2018 Astellas/Medivation Page 65 of 126 Enzalutamide (MDV3100) CONFIDENTIAL Cancer Investigator’s Brochure Edition 10 median (95% CI) time to PSA progression was 19.4 (16.6, not reached [NR]) months in the enzalutamide group and 5.8 (5.6, 8.3) months in the bicalutamide group (P < 0.0001). Analysis of ICR-based rPFS showed the beneficial effect of enzalutamide vs bicalutamide was significant with an HR of 0.51 (95% CI: 0.36, 0.74). The median rPFS was NR in the enzalutamide group and was 16.4 months in the bicalutamide group. As of the data cutoff date, the median follow-up time for patients was 19.4 months. Since the median follow-up time is longer than the median rPFS of the control arm, the results are adequately mature to permit a valid statistical inference. 5.2.1.1.4 Study MDV3100-09 (STRIVE) MDV3100-09 (STRIVE) is a phase 2, multicenter, double-blind, randomized study in 396 patients with CRPC (257 patients with metastatic prostate cancer and 139 patients with nonmetastatic prostate cancer). Patients were randomly assigned to blinded enzalutamide 160 mg once daily vs bicalutamide at a dose of 50 mg once daily in a 1:1 ratio and stratified by disease stage (metastatic vs nonmetastatic). For the study duration, all patients maintained ADT with an LHRH agonist/antagonist or had undergone prior bilateral orchiectomy. The median time on treatment was 14.7 months in the enzalutamide group vs 8.4 months in the bicalutamide group. The primary endpoint was PFS, defined as time from randomization to radiographic progression, PSA progression or death due to any cause, whichever occurred first. Key secondary endpoints included time to PSA progression, PSA response and rPFS (metastatic patients). The study demonstrated that enzalutamide was more efficacious than bicalutamide in nonmetastatic and metastatic CRPC patients. As of the data cutoff date (09 Feb 2015), treatment with enzalutamide compared to bicalutamide resulted in a clinically meaningful and statistically significant improvement in the primary efficacy endpoint of PFS (HR: 0.24; 95% CI: 0.181, 0.320; P < 0.0001). Median (95% CI) PFS was 19.4 (16.5, NR) months in the enzalutamide group compared with 5.7 (5.6, 8.1) months in the bicalutamide group. The treatment effect of enzalutamide vs bicalutamide on PFS as measured by the estimated HR was consistently favorable across all prespecified subgroups, including disease stage at study entry; ECOG performance status at baseline; age; Gleason score at diagnosis; type of progression at study entry; use of a bone targeting agent at baseline; and baseline PSA, LDH and hemoglobin values. In addition, there were statistically significant improvements in all key secondary endpoints. Treatment with enzalutamide was associated with an 81% reduction in the risk of PSA progression compared with treatment with bicalutamide, with an HR of 0.190 (95% CI: 0.137, 0.264; P < 0.0001. The median time to PSA progression was NR in the enzalutamide group vs 8.3 months in the bicalutamide group at the data analysis cutoff date. Likewise, 81.3% of patients in the enzalutamide group and 31.3% of patients in the bicalutamide group had a 50% reduction in PSA from baseline (P < 0.0001). Treatment with enzalutamide was associated with a 68% reduction in the risk of radiographic PFS compared with treatment with bicalutamide in patients with M1 disease, with an HR of 0.324 (95% CI: 0.211, 0.497; P < 0.0001. The median duration of rPFS was

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NR in the enzalutamide group compared with 8.3 months (95% CI: 8.1, 11.1 months) in the bicalutamide group. 5.2.1.1.5 Study S-3100-1-01 S-3100-1-01 is a phase 1, open-label, uncontrolled, dose-escalation study with dose-expansion at the tolerated doses for patients with progressive CRPC, both with and without previous chemotherapy. This was the first-in-human study for enzalutamide and the key roles of this study in the clinical development plan were to determine the maximum tolerated dose (MTD) and initial safety profile of enzalutamide, to provide data on the pharmacokinetics of enzalutamide, to identify evidence of an antitumor effect and if observed, to determine the optimal dose to move forward into phase 3 clinical evaluation. The results from this open-label study demonstrated that enzalutamide treatment has substantial antitumor activity in patients with metastatic CRPC, as observed in men with or without previous exposure to chemotherapy. This antitumor activity was seen consistently across several efficacy endpoints, including decreases in levels of PSA, time to PSA progression, radiographic response rates, favorable numbers of circulating tumor cells and decreases in levels of bone turnover markers. In general, the antitumor effects were more pronounced in patients with metastatic CRPC with no prior chemotherapy compared with patients with metastatic CRPC who previously received docetaxel. The extent and proportion of patients with PSA decreases were dose dependent from 30 mg to 150 mg daily, but reached a plateau between doses of 150 mg and 240 mg daily, above which no additional antitumor effects were observed. Based on these results and considering the MTD of 240 mg determined during this study, a dose of 160 mg daily was selected as the optimal dose for evaluation in the subsequent phase 3 studies, CRPC2 and MDV3100-03. 5.2.1.1.6 Study CRPC-MDA-1 CRPC-MDA-1 was a phase 2, single-center, single arm, open-label study of patients with metastatic CRPC (both chemotherapy-naïve and those previously treated with docetaxel) who received enzalutamide 160 mg/day. The study enrolled 60 patients. The key objectives were to provide additional safety, tolerability and antitumor data at the daily dose of 160 mg and to provide evidence of the impact of enzalutamide treatment on AR signaling in bone metastases. This study demonstrated antitumor effects by PSA response in patients with metastatic CRPC who were chemotherapy-naïve as well as those who previously received docetaxel. A greater proportion of patients who were chemotherapy-naïve achieved a ≥ 90% reduction in PSA from baseline compared with patients who previously received docetaxel. Treatment with enzalutamide was associated with reduction in nuclear AR levels, suggesting that enzalutamide inhibited nuclear translocation. 5.2.1.1.7 Study 9785-CL-0111 9785-CL-0111 is a phase 1/2, multicenter, open-label, uncontrolled, dose-escalation study in 47 Japanese patients with metastatic CRPC, including 43 previously treated with docetaxel and 4 chemotherapy-naïve. Nine patients were in the dose-escalation cohort and 38 patients

Jun 2018 Astellas/Medivation Page 67 of 126 Enzalutamide (MDV3100) CONFIDENTIAL Cancer Investigator’s Brochure Edition 10 were in the dose-expansion cohort used for efficacy analyses. After receiving single doses of enzalutamide 80, 160 or 240 mg, patients received 80 or 160 mg once daily during a multiple-dose period and subsequently commenced long-term dosing with enzalutamide 160 mg/day. Efficacy endpoints included radiographic objective response at day 85, PSA response, circulating tumor cells and markers of bone turnover. Radiographic response was evaluated by an independent Response Evaluation Criteria in Solid Tumors (RECIST) evaluation committee and by the investigator. This study demonstrated the antitumor effects of enzalutamide (160 mg/day) by radiographic response, PSA response and circulating tumor cells in Japanese patients with metastatic CRPC, the majority of whom previously received docetaxel. The magnitudes of the benefits observed in this study were not as large as those observed in study CRPC2; however, this study population was small and uncontrolled and included patients treated with a higher number of previous therapies. 5.2.1.1.8 Study 9785-CL-0410 9785-CL-0410 was a phase 4, multicenter, single-arm, open-label study of patients with metastatic CRPC with PD following treatment with abiraterone acetate. The key objective was to evaluate rPFS, defined as the time from first dose to the first objective evidence of radiographic disease progression or death from any cause, whichever occurred first. In this study, 215 patients were enrolled and 214 patients received enzalutamide 160 mg/day. A total of 69 patients (32.2%) received prior taxane therapy (previous chemotherapy group) and 145 patients (67.8%) had not previously received taxane therapy (no previous chemotherapy group). Statistical analyses were not powered to compare results for patients with and without previous chemotherapy. At the last evaluation date, enzalutamide exposure was 5.5 months in the previous chemotherapy group and 5.9 months in the no previous chemotherapy group. The efficacy results showed that some patients enrolled in this study obtained clinical benefit with enzalutamide treatment regardless of whether or not they had received previous chemotherapy. 5.2.1.1.9 Study 9785-MA-1008 9785-MA-1008 was a phase 4, multicenter, single-arm, open-label study of patients with metastatic CRPC who had previously been treated with enzalutamide and chemotherapy (docetaxel and/or cabazitaxel). The key objective was to determine rPFS of re-treatment with enzalutamide + releasing hormone analogue. Four patients were enrolled in the study and received enzalutamide 160 mg/day. All discontinued before the study was terminated by the sponsor. Because of the few patients enrolled, no conclusion can be drawn about optimum efficacy. However, it appears that using enzalutamide re-treatment following intervening chemotherapy may allow some patients to obtain clinical benefit.

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5.2.1.2 Summary of Efficacy in Metastatic CRPC The efficacy of enzalutamide in patients with metastatic prostate cancer who progressed on ADT has been demonstrated in 2 randomized controlled phase 3 studies including MDV3100-03 in asymptomatic or mildly symptomatic patients and CRPC2 in patients with more advanced disease who previously received docetaxel. Both studies showed a statistically significant advantage of enzalutamide treatment over placebo across multiple clinically relevant endpoints such as OS, rPFS, time to first skeletal-related event, time to PSA progression, PSA response rate, best overall soft tissue response and QoL as measured by the FACT-P. Notably, MDV3100-03 showed a significant benefit of enzalutamide in time to initiation of cytotoxic chemotherapy. Additional efficacy data from open-label studies S-3100-1-01, CRPC-MDA-1 and 9785-CL-0111 and double-blinded studies 9785-CL-0222 and MDV3100-09 in patients with metastatic CRPC provided supportive data on PSA response rate, time to PSA progression and/or best overall soft tissue response, although the magnitude of these treatment effects varied based on the characteristics of the enrolled populations. In general, the treatment effect across these endpoints was larger in patients with metastatic CRPC who had not yet received chemotherapy compared with patients who previously received docetaxel, but the benefit was consistently demonstrated across endpoints within a patient population. In both phase 3 studies of patients with metastatic CRPC (MDV3100-03 and CRPC2), the benefit of enzalutamide treatment on OS as measured by the estimated HR was observed across all prespecified subgroups. The statistically significant benefit on OS was also observed despite substantially higher and earlier use in the placebo groups compared with the enzalutamide groups of subsequent therapies that have demonstrated a survival benefit in patients with prostate cancer. These findings limit the ability to observe the isolated treatment effect of enzalutamide on this endpoint. This is especially true for MDV3100-03, based on the wider availability during this study of subsequent therapies demonstrated to prolong survival in patients with metastatic CRPC. In MDV3100-03, rPFS was a coprimary endpoint and was rigorously evaluated through use of blinded central reviewers as well as through a variety of sensitivity analyses of this endpoint. The magnitude of the relative treatment benefit (unstratified HR: 0.186; 95% CI: 0.149, 0.231) was coupled with a statistically greater best overall radiographic soft tissue response of 58.8% in the enzalutamide group vs 5.0% in the placebo group (difference of 53.9% [95% CI: 48.5%, 59.2%]). Another clinically important finding in this patient population with earlier-stage disease included a 17.2-month delay in the median time to initiation of cytotoxic chemotherapy, which also delays treatment-associated morbidities. The decrease in risk of a skeletal-related event and PSA progression and improvement in radiographic response in enzalutamide-treated patients provide additional evidence of clinical benefit. Furthermore, the benefit on time to degradation of FACT-P scores suggests that treatment with enzalutamide may prolong QoL. In summary, the efficacy results in MDV3100-03 provide evidence of the benefit of enzalutamide treatment in asymptomatic or mildly symptomatic patients with metastatic

Jun 2018 Astellas/Medivation Page 69 of 126 Enzalutamide (MDV3100) CONFIDENTIAL Cancer Investigator’s Brochure Edition 10 prostate cancer who progressed on ADT, which is consistent with the benefit observed with enzalutamide treatment in patients with metastatic CRPC who previously received docetaxel. The magnitude of the treatment benefit across a range of clinically relevant endpoints demonstrates that treatment with enzalutamide not only prolongs life in these patients, but delays the onset of disease-related and treatment-related morbidities that can negatively impact QoL. The benefit of enzalutamide for men with prostate cancer is consistently observed across studies of differing patient populations and across the majority of efficacy endpoints assessed. 5.2.1.3 Efficacy in Nonmetastatic CRPC MDV3100-14 (PROSPER) is a phase 3, randomized, double-blind, placebo-controlled, multinational study of enzalutamide 160 mg/day in patients with nonmetastatic CRPC at high risk of disease progression based on rising PSA levels and sufficiently short (≤ 10-month) PSA doubling time. The primary objective was to determine the benefit of enzalutamide treatment on metastasis-free survival (MFS) assessed by blinded independent central review (BICR), defined as the time from randomization to radiographic progression or death within 112 days of treatment discontinuation without evidence of radiographic progression, whichever occurred first. Patients maintained androgen deprivation during the study, either using an LHRH analogue or having a history of bilateral orchiectomy. Secondary objectives included the evaluation of time to PSA progression, time to first use of new antineoplastic therapy, time to pain progression, time to first use of cytotoxic chemotherapy, chemotherapy-free disease-specific survival, chemotherapy-free survival, PSA response rates, OS, QoL and safety. As of the data cutoff date (28 Jun 2017), 1401 patients were centrally randomly assigned in a 2:1 ratio to receive treatment (933 enzalutamide and 468 placebo) and were included in the ITT population, which was used for the efficacy analyses. Three patients in each treatment group did not receive study drug. Randomization was stratified by PSA doubling time (< 6 months vs ≥ 6 months) and prior or current use of bone targeting agents (yes vs no). The median duration of treatment was 18.4 months in the enzalutamide group and 11.1 months in the placebo group. The treatment groups were generally well balanced with respect to clinically relevant baseline demographic and disease characteristics. Treatment with study drug was to be continued until radiographic disease progression was confirmed by independent, blinded, radiology experts at a central location, allowing for investigator discretion to determine whether continuing study drug after confirmed radiographic progression was clinically beneficial for the patient. This study took into account the Prostate Cancer Clinical Trials Working Group 2 (PCWG2) guidelines with a goal of ensuring that study drug was not discontinued because of inappropriate outcome measures or before it had a chance to demonstrate a benefit, and the protocol did not include rising PSA in its definition of disease progression. Investigators were discouraged from discontinuing study drug due to PSA rise alone consistent with recommendations by the PCWG2 guidelines, as increases in PSA without radiographic progression may not reflect

Jun 2018 Astellas/Medivation Page 70 of 126 Enzalutamide (MDV3100) CONFIDENTIAL Cancer Investigator’s Brochure Edition 10 overall disease status. Continuing treatment until confirmed radiographic disease progression avoided discontinuation of study drug in patients with bone flare who may have been responding to study drug. As of the data cutoff date (28 Jun 2017), treatment with enzalutamide in men with nonmetastatic CRPC and rapidly rising PSA levels resulted in substantial improvement over placebo as demonstrated by a clinically meaningful and statistically significant 70.8% decrease in the relative risk of an MFS event (radiographic progression assessed by BICR), with an HR of 0.292 (95% CI: 0.241, 0.352; P < 0.0001) [Table 5]. The median (95% CI) MFS was 36.6 (33.1, NR) months in the enzalutamide group vs 14.7 (14.2, 15.0) months in the placebo group, for a difference of 21.9 months. The improvement in MFS was robust and consistent across all prespecified sensitivity and subgroup analyses. Improvement observed in the primary MFS endpoint was supported by clinically meaningful and statistically significant improvements in 2 key secondary endpoints: time to PSA progression and time to first use of new antineoplastic therapy. Treatment with enzalutamide was associated with a 93.4% decrease in the risk of a PSA progression event compared with treatment with placebo (HR: 0.066; 95% CI: 0.054, 0.081; P < 0.0001) and a 79.2% reduction in the risk of initiating a new antineoplastic therapy compared with treatment with placebo (HR: 0.208; 95% CI: 0.168, 0.258; P < 0.0001). With only 11.8% of deaths needed for the planned analysis, the OS data are not yet mature as of the data cutoff date for this IB; however, at the time of the primary MFS analysis, the first interim analysis of OS showed a favorable trend, with an HR of 0.795 (95% CI: 0.580, 1.089; P = 0.1519). Treatment with enzalutamide resulted in a clinically meaningful and statistically significant improvement over placebo in the other secondary endpoints, with the exception of time to pain progression (P = 0.6534) and a measure of QoL, i.e., the time to degradation of the global FACT-P score (P = 0.3128) [Table 5]. Table 5 MDV3100-14 Summary of Primary and Secondary Efficacy Results (ITT Population) Enzalutamide Placebo Endpoint Statistic (n = 933) (n = 468) P value Primary efficacy endpoint Events (%) 219 (23.5) 228 (48.7) Metastasis-free Median (95% CI) (month) 36.6 (33.1, NR) 14.7 (14.2, 15.0) survival† Hazard ratio (95% CI)‡ 0.292 (0.241, 0.352) < 0.0001‡ Key secondary efficacy endpoints Events (%) 208 (22.3) 324 (69.2) Time to PSA Median (95% CI) (month) 37.2 (33.1, NR) 3.9 (3.8, 4.0) progression§ Hazard ratio (95% CI)‡ 0.066 (0.054, 0.081) < 0.0001‡ Time to first use of Events (%) 142 (15.2) 226 (48.3) new antineoplastic Median (95% CI) (month) 39.6 (37.7, NR) 17.7 (16.2, 19.7) agent¶ Hazard ratio (95% CI)‡ 0.208 (0.168, 0.258) < 0.0001‡ Events (%) 103 (11.0) 62 (13.2) Overall survival†† Median (95% CI) (month) NR (NR, NR) NR (NR, NR) Hazard ratio (95% CI)‡ 0.795 (0.580, 1.089) < 0.1519‡ Table continued on next page

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Enzalutamide Placebo Endpoint Statistic (n = 933) (n = 468) P value Other secondary efficacy endpoints Events (%) 399 (42.8) 175 (37.4) Time to pain Median (95% CI) (month) 18.5 (17.0, 22.1) 18.4 (14.8, 22.1) progression‡‡ Hazard ratio (95% CI)‡ 0.959 (0.801, 1.149) < 0.6534‡ Chemotherapy-free Events (%) 112 (12.0) 119 (25.4) disease-specific Median (95% CI) (month) 39.6 (37.7, NR) 38.9 (30.9, 41.3) survival§§ Hazard ratio (95% CI)‡ 0.398 (0.307, 0.515) < 0.0001‡ Events (%) 157 (16.8) 132 (28.2) Chemotherapy-free Median (95% CI) (month) 38.1 (37.7, NR) 34.0 (30.3, 39.7) survival¶¶ Hazard ratio (95% CI)‡ 0.504 (0.400, 0.636) < 0.0001‡ Other secondary efficacy endpoints (cont.) Time to first use of Events (%) 85 (9.1) 96 (20.5) cytotoxic Median (95% CI) (month) NR (38.1, NR) 39.7 (38.9, 41.3) chemotherapy††† Hazard ratio (95% CI)‡ 0.378 (0.282, 0.507) < 0.0001‡ Time to Events (%) 506 (54.2) 239 (51.1) degradation of Median (95% CI) (month) 11.1 (11.0, 14.7) 11.1 (11.0, 12.5) FACT-P global < 0.3128‡ Hazard ratio (95% CI)‡ 0.922 (0.787, 1.080) score‡‡‡ PSA response rate, Responders/n Evaluable patients, n¶¶¶ 887 439 (%)§§§ Confirmed ≥ 50% PSA responders, n 712 (76.3) 11 (2.4) Decrease from (%)§§§ baseline  50% 95% CI for response rate††††, % 73.5, 79.0 1.2, 4.2 Difference in response rates (95% CI), % 73.96 (70.91, 77.02) < 0.0001‡‡‡‡ Confirmed ≥ 50% PSA responders, n 522 (55.9) 2 (0.4) Decrease from (%)§§§ baseline  90% 95% CI for response rate††††, % 52.7, 59.2 0.1, 1.5 Difference in response rates (95% CI), % 55.52 (52.28, 58.76) < 0.0001‡‡‡‡ Confirmed ≥ 50% PSA responders, n 90 (9.6) 0 (0.0) Decrease to (%)§§§ undetectable 95% CI for response rate††††, % 7.8, 11.7 99.2, 100.0 Difference in response rates (95% CI), % 9.65 (7.75, 11.54) < 0.0001‡‡‡‡ All patients randomly assigned to study treatment and based on randomized treatment assignment regardless of whether or not treatment was administered (ITT Population). The analysis data cutoff date was 28 Jun 2017. For all endpoints, number of events observed on or prior to analysis data cutoff date / ITT sample size. CI: confidence interval; FACT-P: Functional Assessment of Cancer Therapy-Prostate; ITT: intent-to-treat; IXRS: interactive voice/web recognition system; PSA: prostate-specific antigen † Number of earliest contributing events (radiographic progression or death due to any cause within 112 days after treatment discontinuation) observed / ITT sample size. ‡ Hazard ratio and its 95% CI was based on a Cox regression model with treatment group as the only covariate stratified by PSA doubling time and prior or concurrent use of a bone-targeting agent as per IXRS and was relative to the placebo group with < 1 favoring the enzalutamide group. P value from a stratified log-rank test by PSA doubling time and prior or concurrent use of a bone-targeting agent as per IXRS. Footnotes continued on next page

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§ Based on the Prostate-specific Antigen Progression compliant with Prostate Cancer Clinical Trials Working Group 2 criteria. For patients with PSA declines at week 17, the PSA progression date was defined as the date that a  25% increase and an absolute increase of  2 ng/mL above the nadir was documented, which was confirmed by a second consecutive value obtained at least 3 weeks later. For patients without PSA decline at week 17, the PSA progression date was defined as the date that a  25% increase and an absolute increase of  2 ng/mL above baseline was documented, which was confirmed by a second consecutive value at least 3 weeks later. PSA progression could only have been declared on or after the week 17 assessment. ¶ Based on the first postbaseline use of antineoplastic therapy for prostate cancer. †† Number of patients known to have died as of the analysis data cutoff date. ‡‡ Pain progression was defined as a 2-point or greater increase from baseline in the Brief Pain Inventory-Short Form question 3. §§ Based on the first postbaseline use of cytotoxic chemotherapy for prostate cancer or death due to prostate cancer as assessed by the investigator. ¶¶ Based on the first postbaseline use of cytotoxic chemotherapy for prostate cancer or death due to any cause. ††† Based on the first postbaseline use of cytotoxic chemotherapy for prostate cancer. ‡‡‡ Degradation of FACT-P was defined as at least a 10-point decrease from baseline for the global score. §§§ Confirmation required a subsequent assessment that was consecutive and conducted at least 3 weeks later. ¶¶¶ Evaluable patients for PSA response were patients with a baseline PSA value and at least 1 postbaseline PSA value. †††† Clopper-Pearson exact binomial CI. ‡‡‡‡ P-value was based on Cochran-Mantel-Haenszel mean score test stratified by PSA doubling time (< 6 months,  6 months) and prior or concurrent use of a bone-targeting agent (yes, no) as per IXRS. Source: Study MDV3100-14 Tables 14.2.1.1, 14.2.2.1, 14.2.2.2, 14.2.2.3, 14.2.3.1, 14.2.3.2, 14.2.3.3, 14.2.3.4, 14.2.3.6, 14.2.3.7, 14.2.3.8 and 14.2.3.18. In summary, treatment with enzalutamide in study MDV3100-14 has demonstrated a consistent and clinically meaningful improvement in the primary MFS endpoint, as well as a delay in the time to onset of new antineoplastic therapies, including cytotoxic chemotherapy. Although OS data from study MDV3100-14 are not yet mature as of the data cutoff date for this IB, the observed trend suggested an OS benefit with enzalutamide treatment in the nonmetastatic disease setting and is further supported by the consistent correlation between improvement in rPFS and OS established with enzalutamide in patients with metastatic CRPC. The overall efficacy observed with enzalutamide in study MDV3100-14 represents a clinically meaningful benefit to patients with nonmetastatic CRPC. Overall, enzalutamide has consistently and robustly demonstrated substantial clinical benefits to patients across the CRPC disease continuum. 5.2.1.4 Efficacy in Hormone-naïve Prostate Cancer 9785-CL-0321 was a phase 2, multicenter, open label, single-arm efficacy and safety study of enzalutamide 160 mg/day in patients with prostate cancer who had noncastrate levels of testosterone at study entry. The primary objective was to evaluate PSA response rate ≥ 80% at week 25. Secondary and exploratory efficacy objectives included an evaluation of the effect of enzalutamide on circulating hormones (bone specific ALP and N-telopeptide), QoL using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30 and QLQ-PR25 and objective tumor response (in the subset of patients with metastatic disease). Patients who had clinical benefit at week 25 could continue to receive enzalutamide until objective or clinical disease

Jun 2018 Astellas/Medivation Page 73 of 126 Enzalutamide (MDV3100) CONFIDENTIAL Cancer Investigator’s Brochure Edition 10 progression, or occurrence of an unacceptable toxicity at the discretion of the investigator. Sixty-seven men were enrolled; all patients received at least 1 dose of enzalutamide. Of these, 66 (98.5%) patients were white and 1 (1.5%) patient was black or African American. The median age was 73 years (range, 48 – 86 years) and the mean duration of prostate cancer was 2.8 years. Tumor was confined to the prostate in 31 (46.3%) patients and Gleason score was 8 to 10 at initial diagnosis in 16 (23.9%) patients. Overall, 62 (92.5%) patients had a PSA response ≥ 80% at week 25. Of the 5 patients categorized as nonresponders, 4 patients did not complete 25 weeks of treatment; and 1 patient with a 57.0% PSA decline at week 25 had a 90.7% PSA decline at week 9. Of the 63 patients who completed 25 weeks of treatment, 62 (98.4%) patients had a ≥ 80% decline in PSA. The mean maximum PSA decline was 98.3% through week 25. At week 49 (1 year of treatment), 54 of 67 (80.6%) patients had a PSA response ≥ 80%; the 13 patients considered nonresponders were those who did not complete 49 weeks of treatment. At week 97 (2 years of treatment), 45 of 67 (67.2%) patients had a PSA response ≥ 80%; the 22 patients who were nonresponders did not complete 97 weeks of treatment. All 45 (100%) patients who were on treatment for 2 years had a ≥ 80% decline in PSA from baseline. The mean maximum PSA decline was 99.1% through the cutoff date of 28 Dec 2013. At week 25 and week 49, increases were observed in mean bone specific ALP (14.8% and 12.4%) and N-telopeptide (66.6% and 62.3%). Increases in N-telopeptide were also observed at week 97 (36.4%). Based on responses to the QLQ-C30, global health status was maintained at week 25, week 49 and week 97. At week 25, week 49 and week 97, sexual activity and sexual function were decreased, based on limited responses to the QLQ-PR25. Of 26 evaluable patients at week 25, 11.5% had a CR and 19.2% had a PR; at week 49, 19.2% had a CR and 11.5% had a PR; and at week 97, 19.2% had a CR and 7.7% had a PR. At week 97, 7 additional patients had an objective response; 6 patients had a CR and 1 patient had a PR since week 49. Of the 26 evaluable patients with metastatic disease at study entry, the best overall response by 2 years (week 97) was 13 (50.0%) patients with CR, 4 (15.4%) patients with PR, 3 (11.5%) patients with non-CR/non-progressive disease (PD), 2 (7.7%) patients with stable disease, 3 (11.5%) patients with PD and 1 (3.8%) patient was not evaluated. Seventeen (65.4%) patients had an objective response (CR + PR). All 45 patients still on treatment at week 97 had a PSA response (defined as ≥ 80% decline in PSA from baseline). The 22 patients who did not complete week 97 of treatment were considered nonresponders; therefore, at 2 years (week 97), 45 out of 67 (67.2%) enrolled patients had a PSA response. During the second year on treatment, a low PSA level was maintained for all patients up to treatment discontinuation and the PSA level kept decreasing for a few patients. Based on responses to the EORTC QLQ-C30, global health status was maintained and the role functioning and fatigue scales worsened (> 10 point change from baseline) at week 97. At 3 years (week 169), of the 26 evaluable patients with metastatic disease at study entry, the best overall response was CR in 14 (53.8%) patients, PR in 3 (11.5%) patients, non-CR/non-PD in 4 (15.4%) patients, stable disease in 1 (3.8%) patient and PD in

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3 (11.5%) patients; 1 (3.8%) patient was not evaluated. Seventeen (65.4%) patients had an objective response (CR + PR). Sixteen patients completed the 3-year visit: 7 (26.9%) had a CR, 1 (3.8%) had a PR, 5 (19.2%) were non-CR/non-PD, 1 (3.8%) had stable disease and 1 (3.8%) had PD; 1 (3.8%) patient was not evaluated. At 3 years, 38 of 67 (56.7%) patients had a PSA response ≥ 80%. Among the 29 nonresponders, 4 (13.8%) had completed 169 weeks of treatment. Of the 42 patients who were on treatment up to the 3-year visit, 38 (90.5%) had a ≥ 80% decline in PSA from baseline. The mean PSA decline was 91.74% at the 3-year analysis. Based on responses to the EORTC QLQ-C30, global health status was minimally decreased and physical functioning, fatigue and dyspnea worsened (> 10 point change from baseline) at week 169. 5.2.1.5 Efficacy in Breast Cancer Four clinical studies are evaluating enzalutamide safety and efficacy in patients with advanced breast cancer: ● MDV3100-08 is a phase 1 dose-escalation and dose-expansion study evaluating enzalutamide as a single agent and in combination with exemestane (25 mg or 50 mg), anastrozole (1 mg) or fulvestrant (500 mg) in approximately 100 patients with advanced breast cancer. ● MDV3100-11 is a phase 2, Simon 2-stage study evaluating enzalutamide as a single agent in approximately 118 patients whose advanced TNBC expresses the AR. ● MDV3100-12 is a randomized, placebo-controlled, phase 2 study evaluating exemestane with or without enzalutamide in approximately 240 patients with advanced ER+/PgR+ and human epidermal growth factor receptor 2-negative (HER2-) breast cancer. ● 9785-CL-1121 is a phase 2, Simon 2-stage study evaluating enzalutamide in combination with trastuzumab in approximately 80 evaluable patients with advanced HER2+, AR+ breast cancer. 5.2.1.5.1 Study MDV3100-08 In MDV3100-08 (data cutoff date 08 Jan 2016), single-agent enzalutamide was assessed in dose-escalation (stage 1) (n = 15) and dose-expansion (stage 2) cohorts (n = 14) of patients with advanced breast cancer. The phase 2 enzalutamide dose was identified as 160 mg/day. Additional cohorts examined the effects of 160 mg/day enzalutamide on the pharmacokinetics of 1 mg/day anastrozole (n = 20; 14 evaluable for pharmacokinetics), 25 mg/day exemestane (n = 16; 13 evaluable for pharmacokinetics), 50 mg/day exemestane (n = 23; 17 evaluable for pharmacokinetics) and 500 mg/month fulvestrant (n = 11; 8 evaluable for pharmacokinetics). Combination cohorts required patients to have hormone receptor-positive/HER2- metastatic breast cancer. The median (range) age was 57 (37 to 78) years in patients enrolled in stage 1 and was 62 (30 to 84) years in patients in stage 2 who received combination therapy. Sixty-three (90%) patients in the stage 2 combination therapy cohorts had received prior therapy for metastatic disease, including 26 (37%) patients who received prior treatment with the same hormonal agent that was given in combination with enzalutamide. Per protocol, all patients who received single-agent enzalutamide had received at least 2 prior therapies for metastatic disease. Visceral metastases were present in 55% and

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59% of patients treated with enzalutamide alone or in combination with hormone therapies, respectively; bone metastases were present in 79% of all patients and 41% of patients had ≥ 3 metastatic sites of disease. The median (range) duration of treatment for single-agent enzalutamide was 8 (3 to 65) weeks and for the combination with was 8 (1 to 152) weeks for all cohorts and 19 (4 to 77) weeks for fulvestrant. One patient remains on study and continues to receive enzalutamide plus exemestane 25 mg and has been treated for > 2.5 years. Across all cohorts, 14 patients remained on study > 6 months, including 1 patient treated for > 1 year in each of the cohorts of enzalutamide alone, exemestane 50 mg and fulvestrant. The efficacy endpoints in this phase 1 study were exploratory. No patient had an objective response (CR or PR). The determination of CBR included patients with stable disease only. CBR16 was 6.9% for the enzalutamide monotherapy group and 20.0% for the combination therapy group. CBR16 was highest for patients who received enzalutamide plus fulvestrant (45.5%). CBR24 was 3.4% for the monotherapy group and 8.6% for the combination therapy group. CBR24 was highest for patients who received enzalutamide plus fulvestrant (18.2%). 5.2.1.5.2 Study MDV3100-11 MDV3100-11 (data cutoff date 15 Sep 2015) is an open-label, single-arm, Simon 2-stage study of enzalutamide in patients with locally advanced or metastatic TNBC (advanced TNBC). There was no restriction on the prior amount of treatment administered for advanced TNBC prior to receiving enzalutamide in this study. Patients with CNS metastases or history of seizure were excluded. The primary endpoint was CBR16 in evaluable patients (i.e., patients with AR+ total nuclear staining ≥ 10% and a postbaseline tumor assessment). ITT patients had AR staining > 0% by IHC by central assessment and received at least 1 dose of study drug. Evaluable patients had AR staining ≥ 10% by IHC and at least 1 postbaseline tumor assessment. CBR16 was defined as CR or PR or stable disease lasting ≥ 16 weeks. Secondary and exploratory endpoints included OS, PFS, CBR24, response rate and safety. All endpoints were assessed in both evaluable and ITT patients. Expansion of enrollment to stage 2 required that ≥ 3 of 26 evaluable patients achieve CBR16 in the first stage of the study and rejection of the null hypothesis for the overall study required that ≥ 9 of 62 evaluable patients achieve CBR16. As an exploratory study endpoint, a qualitative gene expression profile was evaluated and assessed for its ability to identify tumors biologically driven by androgen and/or hormonal signaling and that may respond to enzalutamide [Parker et al, 2015]. Data from 178 samples from both enzalutamide-treated (n = 118) and untreated (n = 60) study patients was used to derive a gene expression profile that reflects androgen-driven biology. The profile is a binary categorization that separates the population into diagnostic-positive and diagnostic-negative groups of patients. A total of 118 patients were enrolled in the study, of whom 78 patients met the criteria for the evaluable population.

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The primary efficacy endpoint, CBR16, was 33% (26 of 78 patients) in the evaluable population and 25% (29 of 118) in the ITT population; CBR24 was 28% (22 of 78) in the evaluable population and 20% (24 of 118) in the ITT population. Seven of the 118 patients in the ITT population had a confirmed best overall response of CR or PR; 6 of whom met the criteria for the evaluable population. Median PFS was also similar between the evaluable population and ITT population (14.3 weeks and 12.6 weeks, respectively). The median OS (exploratory endpoint) after a median follow-up of 72 weeks was 75.6 weeks for the evaluable population and 54.7 weeks for the ITT population. Of the 118 patients in MDV3100-11, 56 (47%) patients had diagnostic-positive TNBC and 62 (53%) patients had diagnostic-negative TNBC based on a qualitative gene expression profile. Compared with patients with diagnostic-negative TNBC, patients with diagnostic-positive TNBC were older (median 66 vs 52 years), had a longer disease-free interval (median 37 vs 20 months), had a higher proportion of patients with a primary ER+ tumor (30% vs 7%) and had more bone metastases (57% vs 24%). A higher proportion of patients with diagnostic-positive TNBC achieved CBR16 and CBR24 and had a longer duration of PFS and OS compared with patients with diagnostic-negative TNBC. Efficacy results for the ITT population and by diagnostic status are summarized in [Table 6]. Table 6 MDV3100-11 Summary of Efficacy Results for the ITT Population and by Diagnostic Status CBR16 CBR24 PFS (months) OS (months) (%, 95% CI) (%, 95% CI) (Median, 95% CI) (Median, 95% CI) ITT (n = 118) 25 (17, 33) 20 (14, 29) 2.9 (1.9, 3.7) 12.7 (8.5, NYR) Dx+ (n = 56) 39 (27, 53) 36 (24, 49) 3.7 (2.4, 6.4) 21.3 (12.9, 21.3) Dx– (n = 62) 11 (5, 21) 6.5 (2, 16) 1.8 (1.7, 2.9) 7.5 (4.8, 11.2) Data cutoff date 15 Sep 2016 CBR16: clinical benefit rate at 16 weeks; CBR24: clinical benefit rate at 24 weeks; CI: confidence interval; Dx-: diagnostic-negative; Dx+: diagnostic-positive; ITT: intent-to-treat; NYR: not yet reached; OS: overall survival; PFS: progression-free survival. Kaplan-Meier curves for PFS and OS by diagnostic subgroup are provided in Figure 8.

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Figure 8 Kaplan-Meier Curves for Progression-free Survival (Weeks) (A) and Overall Survival (Weeks) (B) by Diagnostic Subgroup in MDV3100-11 A.

B.

Data cutoff date 15 Sep 2015 CI: confidence interval; PR-AR DX+: diagnostic-positive; PR-AR DX-: diagnostic-negative.

5.2.1.5.3 Study MDV3100-12 MDV3100-12 (data cutoff date 23 Sep 2016) is a phase 2, randomized, double-blind, placebo-controlled study of once daily 160 mg enzalutamide plus 50 mg exemestane (hereafter referred to as enzalutamide) vs once daily placebo plus 25 mg exemestane (hereafter referred to as placebo) in patients with ER+/PgR+, HER2 normal, advanced breast

Jun 2018 Astellas/Medivation Page 78 of 126 Enzalutamide (MDV3100) CONFIDENTIAL Cancer Investigator’s Brochure Edition 10 cancer. The primary objective was to determine the benefit of exemestane plus enzalutamide vs exemestane plus placebo as assessed by PFS. The extent of AR expression and the genomic signature indicating AR-driven disease (referred to as diagnostic status) that may correlate with enzalutamide efficacy was unknown and was an objective of this study. Therefore, all patients, regardless of AR or diagnostic status, were enrolled to receive standard of care exemestane with or without enzalutamide. Eligible patients with disease progression on double-blind treatment with placebo plus exemestane 25 mg could receive once daily open-label treatment with enzalutamide 160 mg plus exemestane 50 mg. Treatment continued until disease progression. Prior chemotherapy and prior hormonal treatment in the neoadjuvant/adjuvant setting and up to 1 prior chemotherapy (defined as completion of ≥ 1 cycle) for advanced disease were acceptable for all patients. Patients with CNS metastases or history of seizure were excluded. AR expression (i.e., diagnostic status) in tumor cells was assessed using IHC in the first 112 patients with available data. However, results showed that the assay was not sensitive enough for use as a companion diagnostic test. Therefore, RNA sequencing data from tumor tissue was used to classify patients based on a gene signature score composed of a linear combination of weighted expression values from 43 genes. If the tissue sample provided a genomic signature indicating AR-driven disease likely to respond to enzalutamide therapy, the patient was referred to as Dx+. Patient cohorts were defined, based on treatment history, as follows: ● Cohort 1: patients who had not previously received hormone treatment for advanced breast cancer and the subset that is also Dx+ ● Cohort 2: patients who previously progressed following 1 hormone treatment for advanced breast cancer and the subset that is also Dx+ The ITT population included all patients randomly assigned to double-blind study treatment. The primary endpoint was PFS in evaluable patients. PFS was defined as the time from randomization to documented disease progression (per RECIST 1.1) or death on study due to any cause, whichever occurred first. A sensitivity analysis of PFS was performed that included progressive disease (by RECIST 1.1 and not by RECIST 1.1), death and start of a new antineoplastic or investigational therapy. Secondary and exploratory endpoints included CBR24, best objective response rate, duration of response (DOR), time to response (TTR), time to progression (TTP), PFS at 6 months, pharmacokinetics and safety. Cohort 1: A total of 127 patients (63 enzalutamide, 64 placebo) were included in the ITT population, of whom 50 patients (24 enzalutamide, 26 placebo) were considered Dx+. For the Cohort 1 ITT population, the age at baseline ranged from 34 to 89 years overall and the median age at baseline were similar for both the enzalutamide and placebo groups (59.0 and 63.5 years, respectively). No major differences in ethnicity and race were apparent between the 2 treatment groups. In the enzalutamide and placebo groups, ECOG performance status was 0 in 69.8% vs 57.8% of patients and was 1 in 28.6% vs 40.6% of patients.

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Cohort 2: A total of 120 patients (60 enzalutamide, 60 placebo) were included in the ITT population, of whom 35 patients (15 enzalutamide, 20 placebo) were considered Dx+. Age at baseline ranged from 34 to 89 years overall, the median age at baseline was similar for both treatment groups (58.0 and 60.5 years, respectively). No clinically relevant differences in ethnicity, race or ECOG performance status were apparent between the 2 treatment groups.

For the Cohort 1 ITT population primary analysis, the incidence of PFS events was lower in the enzalutamide group than in the placebo group (66.7% and 75.0%, respectively)[Figure 9]. The difference between the treatment groups was not statistically significant (P = 0.3631, stratified log-rank test). Similar results were obtained for the Cohort 2 ITT population primary analysis: the incidence of PFS events was lower in the enzalutamide group than in the placebo group (73.3% and 83.3%, respectively). The difference between the treatment groups was not statistically significant (P = 0.9212, stratified log-rank test). No statistically significant differences between treatment groups were observed for the secondary efficacy endpoints in the Cohort 1 ITT population or the Cohort 2 ITT population.

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Figure 9 Kaplan-Meier Curves for Duration of Progression-free Survival (Cohort 1, ITT Population) (A) and Duration of Progression-free Survival (Cohort 2, ITT Population) (B) in MDV3100-12 A.

B.

Data cutoff date 23 Sep 2016 CI: confidence interval; PFS: progression-free survival Source: MDV3100-12 CSR, Figures 10 and 16

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5.2.1.5.4 Study 9785-CL-1121 9785-CL-1121 (data cutoff date 28 Feb 2017) is a phase 2, open-label, single-arm, 2-stage, multinational, multicenter study evaluating the efficacy, safety and tolerability of enzalutamide with trastuzumab. The study population included female patients with HER2+ and AR+ metastatic or locally advanced breast cancer who had progressed on at least 1 prior line of anti-HER2 therapy in the metastatic or advanced setting. Patients could have been either ER/PgR positive or negative according to the local assessment for hormone receptor diagnostics. Eligible patients could receive open-label treatment with enzalutamide 160 mg once daily plus trastuzumab 6 mg/kg every 21 days. Treatment continued until disease progression, unacceptable toxicity or any other discontinuation criteria was met. Patients with previously treated brain metastasis or active leptomeningeal disease or history of seizure were excluded. The primary objective was to evaluate the efficacy of enzalutamide with trastuzumab as measured by CBR (defined as the proportion of evaluable patients with best objective response of confirmed CR or PR per RECIST 1.1, or prolonged stable disease [≥ 24 weeks]). Secondary objectives were best ORR, ORR at 24 weeks, PFS, TTP, DOR and TTR. Sponsor-derived best overall response was used in the analysis. If there was a discrepancy between the investigator rated best overall response and sponsor-derived best overall response, a sensitivity analysis was to be done using investigator rated best overall response. A total of 103 patients were enrolled in the study and received at least 1 dose of study drug. The full analysis set (FAS) consisted of 96 (93.2%) patients who had a central assessment of AR+ expression ≥ 10%. The efficacy evaluable set consisted of 89 (86.4%) patients from the FAS who had at least 1 postbaseline tumor assessment. All patients were female. Overall, the median patient age was 60.0 years, the majority of the patients were white (90 [87.4%] patients) and 49 (47.6%) patients had a baseline ECOG performance status score of 1 at baseline. Overall, the CBR for patients with confirmation was 23.6% (95% CI: 15.2, 33.8), with 4 (4.5%) patients achieving PR and 17 (19.1%) patients achieving durable stable disease at week 24. This rejected the null hypothesis (CBR ≤ 10%); therefore, the study met its primary endpoint. The best confirmed ORR was 4.5% (95% CI: 1.2, 11.1). CBR was similar across the majority of the subgroups including lines of prior therapy, ER/PR status, AR% nuclear staining and patients with or without measurable disease. The median (95% CI) PFS was 105 (61, 116) days. 5.2.1.6 Efficacy in HCC 9785-CL-3021 (data cutoff date 02 Oct 2017) is an ongoing phase 2, multicenter, randomized, double-blind, placebo-controlled phase 2 study evaluating the efficacy, safety and tolerability of enzalutamide 160 mg/day monotherapy in 165 patients in Europe, Asia and North America with HCC of any etiology who had progressed on or were intolerant to sorafenib or other anti-VEGF therapy in the advanced setting. The primary efficacy endpoint was OS. The secondary efficacy endpoint was PFS.

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At the data cutoff date, 75 (68.2%) patients in the enzalutamide group and 38 (69.1%) patients in the placebo group had died. In the enzalutamide group, the median (95% CI) OS was 7.75 (6.05, 9.92) months; 6- and 12-month survival rates were 60.6% (95% CI: 50.6%, 69.3%) and 35.8% (95% CI: 26.3%, 45.4%). In the placebo group, the median (95% CI) OS was 7.69 (5.82, 13.77) months; 6- and 12-month survival rates were 63.6% (95% CI: 49.5%, 74.8%) and 43.2% (95% CI: 29.9%, 55.8%). The corresponding HR was 1.146 (95% CI: 0.774, 1.696). As of the data cutoff date, 96 (87.3%) patients in the enzalutamide group and 52 (94.5%) patients in the placebo group had experienced a progression event. Median (95% CI) PFS duration was 2.23 (1.87, 3.52) months in the enzalutamide group and 1.87 (1.84, 3.45) months in the placebo group. The corresponding HR based on the stratified analysis was 1.039 (95% CI: 0.732, 1.474). In summary, the efficacy results show that enzalutamide was not significantly different from placebo in the treatment of patients with HCC of any etiology who had progressed on or were intolerant to sorafenib or other anti-VEGF therapy in the advanced setting. 5.2.2 Safety The safety profile of enzalutamide is summarized for a combination of 4 phase 3 studies [Sections 5.2.2.1 and 5.2.2.2], which consisted of 4697 unique patients with either nonmetastatic or metastatic CRPC from the following clinical studies: ● One randomized, placebo-controlled, phase 3 study in patients with nonmetastatic CRPC (MDV3100-14) ● Two randomized, placebo-controlled, phase 3 studies in chemotherapy-naïve patients with metastatic CRPC (MDV3100-03 and 9785-CL-0232) ● One randomized, placebo-controlled, phase 3 study in patients with metastatic CRPC previously treated with docetaxel-based chemotherapy (CRPC2) In addition, final safety data from all other completed company-sponsored studies in prostate cancer are presented as well as safety data from all ongoing studies for which the primary analysis has been completed [Table 2 and Appendix 7]. Limited safety data are presented for the breast cancer studies [Section 5.2.2.3] and a study in patients with HCC [Section 5.2.2.4]. In studies conducted in patients with cancer, the severity of TEAEs was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events. 5.2.2.1 Exposure 5.2.2.1.1 Total Cumulative Exposure Forty-three clinical studies of enzalutamide, an expanded access program and 2 compassionate use programs have been initiated and were ongoing or completed as of the 30 Aug 2017 data cutoff date for this IB. The cumulative exposure to enzalutamide is estimated to be more than 4800 male prostate cancer patients and over 300 subjects with no known cancer including healthy male subjects and subjects with hepatic impairment who received at least 1 dose in any clinical study (i.e., not including the expanded access or

Jun 2018 Astellas/Medivation Page 83 of 126 Enzalutamide (MDV3100) CONFIDENTIAL Cancer Investigator’s Brochure Edition 10 compassionate use programs). In addition, over 400 female patients with breast cancer and over 100 patients with HCC have received enzalutamide in clinical studies [Table 2]. 5.2.2.2 Summary of Safety in CRPC Studies 5.2.2.2.1 MDV3100-03 (PREVAIL) MDV3100-03 (data cutoff date 15 Jan 2014) is a phase 3, randomized, double-blind, placebo- controlled, multinational study evaluating the efficacy and safety of enzalutamide in 1717 chemotherapy-naïve patients with metastatic CRPC who progressed on ADT. Of the 1717 patients randomized, 1715 patients received at least 1 dose of study drug (safety population). The coprimary objectives were to determine the benefit of enzalutamide treatment on OS and rPFS. Secondary and exploratory objectives included evaluations of time to first skeletal related event, time to first use of cytotoxic chemotherapy, time to PSA progression, PSA response rate, best overall soft tissue response rate, time to first use of a subsequent antineoplastic treatment (cytotoxic, hormonal, or investigational) and QoL measures. 5.2.2.2.2 CRPC2 (AFFIRM) CRPC2 (data cutoff date 01 Jul 2013) is a phase 3, randomized, double-blind, placebo-controlled, multinational study evaluating the efficacy and safety of enzalutamide in 1199 patients with CRPC whose disease had progressed after prior treatment with docetaxel based chemotherapy. The primary objective was to determine the benefit of enzalutamide treatment on OS. Secondary objectives included evaluations of rPFS; time to first skeletal related event; QoL; time to PSA progression; pain palliation; and circulating tumor cell count conversion rate. A comprehensive ECG evaluation (including QT/QTc assessments performed by a central laboratory) was embedded in the protocol and pharmacokinetic data were collected to allow for an exposure response analysis (for efficacy as well as AE/AE clusters) and to contribute to a population pharmacokinetic analysis. 5.2.2.2.3 MDV3100-14 (PROSPER) MDV3100-14 (data cutoff date 28 Jun 2017) is a phase 3, randomized, double-blind, placebo-controlled, multinational study conducted to demonstrate the efficacy and safety of enzalutamide 160 mg/day patients with nonmetastatic CRPC at high risk of disease progression based on rising PSA and PSA doubling time. Of the 1401 patients randomly assigned, 1395 received at least 1 dose or partial dose of the study drug. The primary objective was to determine the benefit of enzalutamide treatment on MFS. Patients maintained androgen deprivation during the study, either using a LHRH analogue or having a history of bilateral orchiectomy. Secondary objectives included the evaluation of time to PSA progression, time to first use of new antineoplastic therapy, time to pain progression, time to first use of cytotoxic chemotherapy, chemotherapy-free disease-specific survival, chemotherapy-free survival, PSA response rates, OS, QoL and safety. The study is ongoing.

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5.2.2.2.4 9785-CL-0232 (Asian PREVAIL) 9875-CL-0232 (data cutoff date 20 Sep 2015) is a phase 3, randomized, double blind, placebo controlled, multinational study evaluating the efficacy and safety of enzalutamide in 388 chemotherapy-naïve Asian patients with progressive metastatic CRPC who progressed on ADT. All 388 randomly assigned patients received at least 1 dose of study drug. The primary objective was to assess the effect of enzalutamide on time to PSA progression as compared with placebo. Key secondary objectives included OS, rPFS, time to first skeletal-related event, time to initiation of cytotoxic chemotherapy, PSA response ≥ 50%, as well as the pharmacokinetics of enzalutamide and its major metabolites following single and multiple doses of enzalutamide in Asian patients and safety. The open-label portion of the study is ongoing. 5.2.2.2.5 Combined Controlled Phase 3 Studies In this section, the safety profile of enzalutamide in patients with either nonmetastatic or metastatic CRPC is derived from the combination of 4 controlled phase 3 studies which consists of MDV3100-14, MDV3100-03, 9785-CL-0232 and CRPC2 (hereafter called the combined phase 3 studies). In the combined phase 3 studies, the median duration of exposure to enzalutamide was 13.7 months and the median duration of exposure to placebo was 4.8 months. Approximately 55% of patients treated with enzalutamide remained on study drug for at least 1 year compared with 21% of patients treated with placebo; approximately 19% of patients treated with enzalutamide remained on study drug for at least 2 years compared with approximately 5% of patients treated with placebo. 5.2.2.2.5.1 Demographics and Baseline Disease Characteristics of the Combined Phase 3 Studies Demographic and baseline disease characteristics for the combined phase 3 studies are summarized in Table 7. The enzalutamide and placebo groups were well balanced in terms of baseline disease characteristics: advanced disease at study entry as noted by baseline median PSA levels (36.0 μg/mL vs 36.3 μg/mL), proportion of patients with a medium (5 to 7) total Gleason score at initial diagnosis (46.5% and 44.0%), history of cardiovascular disease (18.5% vs 18.4%), history of hypertension (58.0% vs 59.1%) and percentage of patients entering the study with ECOG performance status of ≥ 2 (2.5% vs 1.7%). The majority of all patients were considered chemo-naïve; only 28.6% of patients in the enzalutamide group and 21.0% of patients in the placebo group had previously received docetaxel, but about half had received prior radiotherapy (50.6% vs 48.7%) [Table 7].

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Table 7 Demographic and Baseline Characteristics in the Combined Phase 3 Studies (Male Prostate Cancer Patients) Enzalutamide Placebo Baseline Characteristic (n = 2799) (n = 1898) Age (years) Mean 71.4 71.1 Median 72.0 71.0 Min, max 41, 95 42, 93 Age category (years) (n [%]) < 65 578 (20.7%) 425 (22.4%) 65 to < 75 1193 (42.6%) 808 (42.6%) ≥ 75 1028 (36.7%) 665 (35.0%) Race (n [%]) American Indian or Alaska Native 2 (0.1%) 1 (0.1%) Asian 430 (15.4%) 368 (19.4%) Black or African American 69 (2.5%) 43 (2.3%) Native Hawaiian or other Pacific Islander 5 (0.2%) 3 (0.2%) White 2082 (74.4%) 1337 (70.4%) Other, multiple, or unknown 211 (7.5%) 146 (7.7%) Ethnicity (n [%]) Not Hispanic or Latino 2335 (83.4%) 1508 (79.5%) Hispanic or Latino 122 (4.4%) 81 (4.3%) Not reported or unknown 342 (12.2%) 309 (16.3%) Geographic region (n [%]) North America 622 (22.2%) 402 (21.2%) Europe 1381 (49.3%) 898 (47.3%) Rest of world 796 (28.4%) 598 (31.5%) Baseline weight (kg)† Mean (SD) 83.26 (15.78) 82.93 (16.30) Median 81.8 81.0 Min, max 43.1, 162.7 33.9, 167.0 Disease stage at study entry, n (%) Nonmetastatic 908 (32.4%) 451 (23.8%) Metastatic 1891 (67.6%) 1447 (76.2%) Baseline ECOG performance status (n [%]) 0 1739 (62.1%) 1246 (65.6%) 1 989 (35.3%) 620 (32.7%) ≥ 2 70 (2.5%) 32 (1.7%) History of hypertension (or related term) (n [%])‡ 1623 (58.0%) 1121 (59.1%) History of cardiovascular disease (n [%])§ 518 (18.5%) 349 (18.4%) Prior docetaxel, n (%) 800 (28.6) 399 (21.0%) Prior radiotherapy, n (%) 1416 (50.6%) 924 (48.7%) Time from initial diagnosis to randomization/enrollment (months) n 2792 1890 Median 71.6 66.3 Min, max 0.2, 381.8 0.1, 275.7 Total Gleason score category (n [%]) Low (2–4) 38 (1.4%) 27 (1.4%) Medium (5–7) 1301 (46.5%) 835 (44.0%) High (8–10) 1307 (46.7%) 939 (49.5%) Baseline PSA (µg/mL) n 2799 1897 Median 36.0 36.3 Min, max 0.1, 11794.1 0.0, 19000.0 ECOG: Eastern Cooperative Oncology Group; max: maximum; min: minimum; PSA: prostate-specific antigen; SCS: summary of clinical safety. Footnotes continued on next page

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All enrolled patients who received any amount of study drug (enzalutamide or placebo) in their respective study (Safety Population). Patients with multiple events for a given preferred term were counted only once for each preferred term. Events are sorted by SOC alphabetically and then by decreasing frequency of preferred term in the enzalutamide group in MDV3100-14. The combined phase 3 studies (data cutoff dates) include MDV3100-14 (28 Jun 2017), MDV3100-03 (15 Jan 2014), CRPC2 (01 Jul 2013) and 9785-CL-0232 (20 Sep 2015). † Based on n = 2790 in the enzalutamide group and n = 1892 in the placebo group. ‡ Hypertension-related events in narrow standardized MedDRA query of ‘hypertension.’ § Narrow SMQs of ‘myocardial infarction,’ ‘haemorrhagic cerebrovascular conditions,’ ‘ischemic cerebrovascular conditions’ and ‘heart failure.’ Source: SCS-PROSPER Table 7, Table 8 5.2.2.2.5.2 TEAEs in the Combined Phase 3 Studies Based on the difference in exposure between enzalutamide- and placebo-treated patients in the combined phase 3 studies (13.7 months enzalutamide vs 4.8 months placebo), the median TEAE reporting period for the enzalutamide group was nearly 3-fold longer than for the placebo group, resulting in approximately 9 months of additional safety data collected for patients receiving enzalutamide compared with placebo. Overall, TEAEs were experienced by 93.2% of patients in the enzalutamide group and 89.1% of patients in the placebo group of the combined phase 3 studies [Table 8]. A summary of the most common TEAEs of any grade or causality occurring in at least 5% of patients in either treatment group is presented by SOC in Table 8. AEs more common in the enzalutamide treatment group with at least a 2% higher absolute incidence over placebo are shown in bold font; the remaining events are comparable between groups or more common in the placebo group. Table 8 TEAEs Reported in at Least 5% of Patients in Either Treatment Group by System Organ Class in the Combined Phase 3 Studies System Organ Class Enzalutamide Placebo Preferred Term (n = 2799) (n = 1898) Any TEAE 2610 (93.2%) 1691 (89.1%) Blood and Lymphatic System Disorders 301 (10.8%) 213 (11.2%) Anemia 238 (8.5%) 180 (9.5%) Gastrointestinal Disorders 1474 (52.7%) 923 (48.6%) Nausea 593 (21.2%) 407 (21.4%) Constipation 502 (17.9%) 302 (15.9%) Diarrhoea 416 (14.9%) 241 (12.7%) Vomiting 221 (7.9%) 184 (9.7%) General Disorders and Administration Site Conditions 1549 (55.3%) 809 (42.6%) Fatigue 914 (32.7%) 412 (21.7%) Asthenia 356 (12.7%) 171 (9.0%) Oedema peripheral 266 (9.5%) 143 (7.5%) Infections and Infestations 919 (32.8%) 478 (25.2%) Urinary tract infection 170 (6.1%) 119 (6.3%) Nasopharyngitis 148 (5.3%) 72 (3.8%) Injury, Poisoning and Procedural Complications 523 (18.7%) 206 (10.9%) Fall 256 (9.1%) 69 (3.6%) Table continued on next page

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System Organ Class Enzalutamide Placebo Preferred Term (n = 2799) (n = 1898) Investigations 530 (18.9%) 306 (16.1%) Weight decreased 271 (9.7%) 131 (6.9%) Metabolism and Nutrition Disorders 743 (26.5%) 419 (22.1%) Decreased appetite 510 (18.2%) 294 (15.5%) Musculoskeletal and Connective Tissue Disorders 1458 (52.1%) 976 (51.4%) 551 (19.7%) 337 (17.8%) Arthralgia 443 (15.8%) 250 (13.2%) Musculoskeletal pain 264 (9.4%) 137 (7.2%) Pain in extremity 280 (10.0%) 191 (10.1%) Musculoskeletal chest pain 150 (5.4%) 83 (4.4%) Bone pain 210 (7.5%) 204 (10.7%) Nervous System Disorders 1156 (14.3%) 494 (26.0%) Headache 282 (10.1%) 105 (5.5%) Dizziness 241 (8.6%) 103 (5.4%) Psychiatric Disorders 491 (17.5%) 207 (10.9%) 190 (6.8%) 92 (4.8%) Renal and Urinary Disorders 671 (24.0%) 476 (25.1%) Haematuria 201 (7.2%) 116 (6.1%) Respiratory, Thoracic and Mediastinal Disorders 618 (22.1%) 342 (18.0%) Dyspnoea 195 (7.0%) 116 (6.1%) Cough 162 (5.8%) 105 (5.5%) Vascular Disorders 829 (29.6%) 300 (15.8%) Hot flush 444 (15.9%) 145 (7.6%) Hypertension 302 (10.8%) 72 (3.8%) All enrolled patients who received any amount of study drug (enzalutamide or placebo) in their respective study (Safety Population). Patients with multiple events for a given preferred term were counted only once for each preferred term. Events are sorted by SOC alphabetically and then by decreasing frequency of preferred term in the enzalutamide group. The combined phase 3 studies (data cutoff dates) include MDV3100-14 (28 Jun 2017), MDV3100-03 (15 Jan 2014), CRPC2 (01 Jul 2013) and 9785-CL-0232 (20 Sep 2015). TEAEs with at least a 2% higher absolute incidence in the enzalutamide group compared with the placebo group are shown in bold font. SCS: summary of clinical safety; TEAE: treatment-emergent adverse event. Source: SCS-PROSPER, Table 14.3.1.2.1.1 TEAEs reported in at least 5% of patients and with at least a 2% higher incidence in the phase 3 enzalutamide group were further analyzed by event rate per 100 patient-years of treatment and incidence within the first 90 days of treatment. When TEAEs occurring in at least 5% of patients in the enzalutamide group and with a ≥ 2% higher incidence than the placebo group were adjusted for treatment duration, the differences between the enzalutamide group and the placebo group were reduced (event rate per 100 patient-years of treatment): hot flush (13.1 enzalutamide vs 11.3 placebo), hypertension (9.4 vs 5.7), headache (9.5 vs 9.1) and fall (9.1 vs 5.6). Some common TEAEs, when adjusted for treatment duration had event rates per 100 patient-years of treatment that were lower in the enzalutamide group compared with the placebo group: fatigue (29.5 enzalutamide vs 33.0 placebo), decreased appetite (16.2 vs 23.6), constipation (16.0 vs 25.1), arthralgia (16.2 vs 24.0), (15.0 vs 22.1), asthenia (12.4 vs 14.2), musculoskeletal pain (8.8 vs 11.6), weight decreased (8.1 vs 10.4) and dizziness (7.7 vs 8.5). Regarding the time of onset of TEAEs, the incidence of TEAEs

Jun 2018 Astellas/Medivation Page 88 of 126 Enzalutamide (MDV3100) CONFIDENTIAL Cancer Investigator’s Brochure Edition 10 within the first 30, 180 and 365 days in the enzalutamide group of the combined phase 3 studies (60.6%, 86.0% and 90.7%) was similar to that in the placebo group of the combined phase 3 studies (59.5%, 84.2% and 87.8%). The incidence of grade ≥ 3 TEAEs was higher in the phase 3 enzalutamide group (40.1%) compared with the phase 3 placebo group (36.6%) [Table 9]. The grade ≥ 3 TEAEs occurring in ≥ 1% of patients in the phase 3 enzalutamide group and with ≥ 0.5% higher incidence than the phase 3 placebo group were hypertension (4.6% enzalutamide vs 1.8% placebo), fatigue (3.5% vs 2.5%), fall (1.0% vs 0.5%), asthenia (1.6% vs 1.1%), pneumonia (1.4% vs 0.8%) and spinal cord compression (3.1% vs 2.2%). Table 9 Grade 3 or Higher TEAEs Experienced by at Least 1% of Patients in the Combined Phase 3 Studies Enzalutamide Placebo Preferred Term (MedDRA v16.1), n (%) (n = 2799) (n = 1898) Any grade ≥ 3 TEAE 1121 (40.1%) 695 (36.6%) Hypertension 130 (4.6%) 34 (1.8) Anaemia 104 (3.7%) 76 (4.0%) Fatigue 98 (3.5%) 48 (2.5%) Spinal cord compression 88 (3.1%) 41 (2.2%) Back pain 67 (2.4%) 44 (2.3%) Asthenia 46 (1.6%) 20 (1.1%) Haematuria 43 (1.5%) 32 (1.7%) General physical health deterioration 41 (1.5%) 20 (1.1%) Pneumonia 38 (1.4%) 15 (0.8%) Bone pain 37 (1.3%) 39 (2.1%) Arthralgia 35 (1.3%) 20 (1.1%) Urinary tract infection 33 (1.2%) 18 (0.9%) Syncope 31 (1.1%) 14 (0.7%) Metastatic pain 30 (1.1%) 19 (1.0%) Fall 28 (1.0%) 9 (0.5%) Pain in extremity 19 (0.7%) 21 (1.1%) Urinary retention 17 (0.6%) 25 (1.3%) Hydronephrosis 8 (0.3%) 24 (1.3%) All enrolled patients who received any amount of study drug (enzalutamide or placebo) in their respective study (Safety Population). Patients with multiple events for a given preferred term were counted only once for each preferred term. Events are sorted by decreasing frequency of preferred term in the enzalutamide group. The combined phase 3 studies (data cutoff dates) include MDV3100-14 (28 Jun 2017), MDV3100-03 (15 Jan 2014), CRPC2 (01 Jul 2013) and 9785-CL-0232 (20 Sep 2015). Preferred terms shown in bold font are grade ≥ 3 with ≥ 0.5% higher incidence in the enzalutamide group than placebo group. SCS: summary of clinical safety; TEAE: treatment-emergent adverse event. Source: SCS-PROSPER, Table 13

In the combined phase 3 studies, the Kaplan-Meier curve for the placebo group was lower than the curve for the enzalutamide group suggesting a shorter time to first grade ≥ 3 TEAE. In the combined phase 3 studies, the median time to first grade ≥ 3 TEAE was 24.7 months for the enzalutamide group and 17.6 months for the placebo group.

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5.2.2.2.5.3 Deaths in the Combined Phase 3 Studies TEAEs leading to death reported in more than 2 patients in either treatment group as well as fatal TEAEs within the SOC of Cardiac Disorders are summarized for the combined phase 3 studies in Table 10. The proportion of patients with TEAEs leading to death was higher in the enzalutamide group of the combined phase 3 studies compared with the placebo group (3.8% vs 3.0%). The most common preferred term leading to death in both treatment groups was general physical health deterioration (0.6% enzalutamide vs 0.5% placebo), which likely represented disease progression. Table 10 TEAEs Resulting in Death by Preferred Term in at Least 2 Patients and Fatal TEAEs Within the SOC of Cardiac Disorders in the Combined Phase 3 Studies Enzalutamide Placebo Preferred Term (MedDRA v16.1), n (%) (n = 2799) (n = 1898) Any TEAE resulting in death 107 (3.8%) 56 (3.0%) General physical health deterioration 18 (0.6%) 9 (0.5%) Death 7 (0.3%) 3 (0.2%) Disease progression 7 (0.3%) 6 (0.3%) Pneumonia 5 (0.2%) 1 (0.1%) Cerebrovascular accident 4 (0.1%) 0 Septic shock 3 (0.1%) 2 (0.1%) Cachexia 2 (0.1%) 1 (0.1%) Hepatic failure 2 (0.1%) 0 Pulmonary embolism 2 (0.1%) 1 (0.1%) Sepsis 2 (0.1%) 0 Arteriosclerosis coronary artery 1 (0.0%) 1 (0.1%) Multi-organ failure 1 (0.0%) 1 (0.1%) Sudden death 1 (0.0%) 1 (0.1%) Hepatic encephalopathy 0 2 (0.1%) Prostate cancer metastatic 0 2 (0.1%) Renal failure acute 0 2 (0.1%) Respiratory failure 0 2 (0.1%) Cardiac Disorders Acute myocardial infarction 5 (0.2%) 0 Cardiac failure 5 (0.2%) 0 Myocardial infarction 4 (0.1%) 1 (0.1%) Cardiac arrest 2 (0.1%) 2 (0.1%) Cardiopulmonary failure 2 (0.1%) 0 Cardio-respiratory arrest 1 (0.0%) 0 All enrolled patients who received any amount of study drug (enzalutamide or placebo) in their respective study (Safety Population). Events are sorted by decreasing frequency of preferred term in the enzalutamide group and then in alphabetical order. The combined phase 3 studies (data cutoff dates) include MDV3100-14 (28 Jun 2017), MDV3100-03 (15 Jan 2014), CRPC2 (01 Jul 2013) and 9785-CL-0232 (20 Sep 2015). SCS: summary of clinical safety; TEAE: treatment-emergent adverse event. Source: SCS-PROSPER Table 17

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5.2.2.2.5.4 SAEs in the Combined Phase 3 Studies All treatment-emergent SAEs reported in ≥ 1% of patients in either the enzalutamide or placebo groups of the combined phase 3 studies are presented in Table 11. In the combined phase 3 studies, treatment-emergent SAEs in ≥ 1% patients that were ≥ 0.5% higher in the enzalutamide group compared with placebo group were pneumonia (1.3% vs 0.7%) and spinal cord compression (3.0% vs 2.2%). Conversely, the only treatment-emergent SAE in ≥ 1% of patients that was ≥ 0.5% higher in the placebo group of the combined phase 3 studies compared with the enzalutamide group was urinary retention (1.6% for placebo vs 0.9% for enzalutamide). When adjusted for treatment duration, the event rates per 100 patient-years of treatment were similar between the phase 3 enzalutamide and placebo groups for pneumonia (1.1 enzalutamide vs 1.1 placebo) and were lower in the phase 3 enzalutamide group than in the placebo group for anemia (1.4 vs 2.4), general physical health deterioration (1.0 vs 1.4), spinal cord compression (2.5 vs 3.2) and metastatic pain (1.0 vs 1.7) [Table 11]. Table 11 Treatment-emergent SAEs Experienced by at Least 1% of Patients in the Combined Phase 3 Studies Preferred Term (MedDRA v16.1) Enzalutamide Placebo Category n patients (%) (n = 2799) (n = 1898) Haematuria 44 (1.6%) 33 (1.7%) Event rate (e) 1.7 (61) 2.9 (38) Pneumonia 35 (1.3%) 14 (0.7%) Event rate (e) 1.1 (38) 1.1 (14) Urinary retention 24 (0.9%) 30 (1.6%) Event rate (e) 0.9 (30) 2.3 (31) Anaemia 42 (1.5%) 26 (1.4%) Event rate (e) 1.4 (50) 2.4 (32) General physical health deterioration 35 (1.3%) 18 (0.9%) Event rate (e) 1.0 (35) 1.4 (19) Spinal cord compression 84 (3.0%) 41 (2.2%) Event rate (e) 2.5 (87) 3.2 (42) Metastatic pain 30 (1.1%) 20 (1.1%) Event rate (e) 1.0 (37) 1.7 (23) All enrolled patients who received any amount of study drug (enzalutamide or placebo) in their respective study (Safety Population). The combined phase 3 studies (data cutoff dates) include MDV3100-14 (28 Jun 2017), MDV3100-03 (15 Jan 2014), CRPC2 (01 Jul 2013) and 9785-CL-0232 (20 Sep 2015). Time-adjusted rate per 100-patient-years and number of events (e) are shown. Time-adjusted rate per 100 patient-years is calculated as the total number of occurrences of event divided by the total treatment-emergent period for each treatment group times 100. SCS: summary of clinical safety; SAE: serious adverse event. Source: SCS-PROSPER Table 18

No new safety signals were identified in a review of the treatment-emergent SAEs in the combined phase 3 studies.

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Overall, study drug-related treatment-emergent SAEs were reported infrequently with no meaningful difference between treatment groups (3.3% of enzalutamide-treated patients and 3.2% of placebo-treated patients). 5.2.2.2.5.5 TEAEs Leading to Study Drug Discontinuation in the Combined Phase 3 Studies The combined phase 3 studies enzalutamide and placebo groups had similar rates of discontinuation due to TEAE (8.2% vs 8.1%, respectively) [Table 12]. For the TEAEs that were the primary reason for study drug discontinuation in more than 2 patients in either treatment group, the absolute difference in incidence between treatment groups was ≤ 0.2%. Table 12 TEAEs Reported as the Primary Reason for Study Drug Discontinuation in More Than 2 Patients in Either Treatment Group of the Combined Phase 3 Studies Enzalutamide Placebo Preferred Term (MedDRA v16.1), n (%) (n = 2799) (n = 1898) Any TEAE as primary reason for study drug discontinuation 230 (8.2%) 154 (8.1%) Fatigue 23 (0.8%) 11 (0.6%) Nausea 10 (0.4%) 4 (0.2%) Cerebrovascular accident 8 (0.3%) 3 (0.2%) Asthenia 6 (0.2%) 4 (0.2%) Bone pain 6 (0.2%) 7 (0.4%) Cardiac failure 6 (0.2%) 1 (0.1%) Acute myocardial infarction 4 (0.1%) 1 (0.1%) Cognitive disorder 4 (0.1%) 0 Convulsion 4 (0.1%) 0 Dysphagia 4 (0.1%) 6 (0.3%) Hypertension 4 (0.1%) 0 Myocardial infarction 4 (0.1%) 1 (0.1%) Syncope 4 (0.1%) 2 (0.1%) Back pain 3 (0.1%) 4 (0.2%) Cerebral infarction 3 (0.1%) 1 (0.1%) Decreased appetite 3 (0.1%) 2 (0.1%) Depression 3 (0.1%) 1 (0.1%) Dizziness 3 (0.1%) 1 (0.1%) General physical health deterioration 3 (0.1%) 3 (0.2%) Pneumonia 3 (0.1%) 0 Transient ischaemic attack 3 (0.1%) 0 Vomiting 3 (0.1%) 5 (0.3%) Anaemia 2 (0.1%) 3 (0.2%) Haematuria 2 (0.1%) 4 (0.2%) Pyrexia 1 (0.0%) 3 (0.2%) Subdural haematoma 1 (0.0%) 3 (0.2%) Headache 0 3 (0.2%) All enrolled patients who received any amount of study drug (enzalutamide or placebo) in their respective study (Safety Population). Footnotes continued on next page

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Events are sorted by decreasing frequency of preferred term in the enzalutamide group and then in alphabetical order. The combined phase 3 studies (data cutoff dates) include MDV3100-14 (28 Jun 2017), MDV3100-03 (15 Jan 2014), CRPC2 (01 Jul 2013) and 9785-CL-0232 (20 Sep 2015). SCS: summary of clinical safety; TEAE: treatment-emergent adverse event. Source: SCS-PROSPER Table 19 Adverse Events Leading to Dose Interruption Overall, the proportion of patients with TEAEs leading to a dose interruption was higher in the phase 3 enzalutamide group compared with the placebo group (13.2% vs 10.8%). The most frequent TEAEs leading to an interruption in the dose of study drug in the enzalutamide group of the combined phase 3 studies included fatigue (1.5%) followed by hypertension (0.8%), decreased appetite (0.7%) and asthenia (0.7%). Of all TEAEs leading to a dose interruption reported in > 2 patients, the absolute difference in incidence between treatment groups was ≤ 1%. Adverse Events Leading to Dose Reduction Overall, the proportion of patients with TEAEs leading to a dose reduction was higher in the enzalutamide group compared with the placebo group in the combined phase 3 studies (4.7% vs 1.8%). In the enzalutamide group, the most frequent TEAEs leading to a reduction in the dose of study drug included fatigue (1.6%) followed by asthenia (0.5%), nausea (0.4%), hypertension (0.3%) and dizziness (0.3%). Fatigue was the only TEAE reported in at least 1% of patients in either treatment group (1.6% enzalutamide vs 0.3% placebo). 5.2.2.2.6 TEAEs of Interest TEAEs of interest were selected based on previously recognized important identified risks and/or feedback from regulatory authorities recommending surveillance for specific events. An important identified risk is an untoward occurrence for which there is adequate evidence of an association with the medicinal product of interest and that could have an impact on the risk-benefit balance of the product or have implications for public health. The TEAEs of interest described in this IB are convulsions, cognitive and memory impairment, selected fatigue-related events, falls, fractures, syncope, hypertension, cardiovascular events (ischemic heart disease) and second primary malignancies excluding nonmelanoma skin cancer [Table 13]. Table 13 Overall Summary of TEAEs of Interest in the Combined Phase 3 Studies Enzalutamide Placebo Category, n (%) (n = 2799) (n = 1898) Convulsions (seizure) 10 (0.4%) 1 (0.1%) Cognitive and memory impairment 136 (4.9%) 29 (1.5%) Selected fatigue-related events 1265 (45.2%) 597 (31.5%) Falls† 256 (9.1%) 69 (3.6%) Fractures† 285 (10.2%) 84 (4.4%) Syncope†,‡ 34 (1.2%) 17 (0.9%) Hypertension 317 (11.3%) 81 (4.3%) Table continued on next page

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Enzalutamide Placebo Category, n (%) (n = 2799) (n = 1898) Cardiovascular events (ischaemic heart disease)† 72 (2.6%) 25 (1.3%) Second primary malignancies excluding nonmelanoma skin cancer 66 (2.4%) 17 (0.9%) All enrolled patients who received any amount of study drug (enzalutamide or placebo) in their respective study (Safety Population). The combined phase 3 studies (data cutoff dates) include MDV3100-14 (28 Jun 2017), MDV3100-03 (15 Jan 2014), CRPC2 (01 Jul 2013) and 9785-CL-0232 (20 Sep 2015). † Nonprespecified TEAE of interest. ‡ In addition to syncope, the preferred terms of presyncope, loss of consciousness, dizziness and postural dizziness were also evaluated. SCS: summary of clinical safety; TEAE: treatment-emergent adverse event. Source: SCS-PROSPER Table 22 and ad hoc tables (available upon request) 5.2.2.2.6.1 Convulsion (Seizure) TEAEs of convulsion (seizure) were defined per the ‘convulsion’ SMQ (narrow). (Narrow SMQ terms are those that are highly likely to represent the condition of interest.) Overall, the incidence of any event of convulsion was low but slightly higher in the enzalutamide group compared with the placebo group in the combined phase 3 studies (0.4% vs 0.1%). In the combined phase 3 studies, the incidence was higher in the enzalutamide group compared with the placebo group but low overall for the following convulsion events: SAEs of convulsion (0.4% vs 0.1%), grade ≥ 3 convulsion events (0.3% vs 0), TEAEs of convulsion leading to dose interruption (0.0% vs 0) and convulsion as the primary reason for discontinuation (0.2% vs 0.1%). No convulsion TEAE led to dose reduction in the combined phase 3 studies. TEAEs of convulsion leading to death were not reported in any treatment group. One patient in the enzalutamide group of MDV3100-14 experienced a complication of seizure that resulted in aspiration pneumonia leading to fatal outcome. Study 9785-CL-0403 was conducted in patients with metastatic CRPC known to have risk factor(s) for seizure. As of the data cutoff date of 01 Feb 2016, 4 of 366 (1.1%) patients in the seizure risk evaluation set experienced a seizure event within 4 months of treatment, while a total of 7 of 366 (1.9%) patients experienced a seizure event during the study period (Independent Adjudication Committee-confirmed). 5.2.2.2.6.2 Cognitive and Memory Impairment Cognitive and memory impairment were defined as preferred terms within the high-level group term of ‘mental impairment disorders’. Overall, the incidence of TEAEs of cognitive and memory impairment was higher in the enzalutamide group of the combined phase 3 studies compared with placebo (4.9% vs 1.5%). When adjusted for the length of the treatment duration, the event rate for these TEAEs was 4.3 vs 2.3 per 100 patient-years of treatment in the combined phase 3 studies. The most frequent preferred term reported was memory impairment. In the combined phase 3 studies, the incidence of memory impairment events in the enzalutamide group was higher than in the placebo group (1.8% vs 0.6%). Disturbance in attention was the next most

Jun 2018 Astellas/Medivation Page 94 of 126 Enzalutamide (MDV3100) CONFIDENTIAL Cancer Investigator’s Brochure Edition 10 common preferred term. In the combined phase 3 studies, the incidence of disturbance in attention was higher in enzalutamide group compared with the placebo group (1.2% vs 0.3%). TEAEs of cognitive and memory impairment did not lead to any deaths for patients in any treatment group. SAEs of cognitive and memory impairment and grade ≥ 3 cognitive and memory impairment events were low overall (≤ 0.1%) in both the enzalutamide and placebo groups of the combined phase 3 studies. Two enzalutamide-treated patients in CRPC2 experienced a grade 3 event (cognitive disorder) and 2 placebo-treated patients in MDV3100-03 experienced a grade 3 event (memory impairment, dementia). The incidence of TEAEs of cognitive and memory impairment leading to dose interruption in the phase 3 enzalutamide group was also low but slightly higher than in the placebo group (0.2% vs 0.1%). The same is true for the TEAEs of cognitive and memory impairment leading to dose reduction (0.1% vs 0) and TEAEs of cognitive and memory impairment as the primary reason for discontinuation (0.3% vs 0.1%). 5.2.2.2.6.3 Selected Fatigue-related Events Fatigue-related events were analyzed using the preferred terms of ‘fatigue’, ‘asthenia’, ‘lethargy’ and ‘malaise’. The incidence of fatigue-related TEAEs was higher in the enzalutamide group compared with the placebo group in the combined phase 3 studies (45.2% vs 31.5%). The most common TEAE preferred terms contributing to fatigue-related events were fatigue and asthenia. In the combined phase 3 studies, the incidence of fatigue was higher in enzalutamide group compared with the placebo group (32.7% vs 21.7%). When adjusted for the length of treatment, the event rate for fatigue per 100 patient-years of treatment was lower in the enzalutamide group compared with the placebo group (29.5 vs 33.0). Asthenia was the next most commonly reported preferred term. In the combined phase 3 studies, the incidence of asthenia was higher in the enzalutamide group compared with the placebo group (12.7% vs 9.0%). When adjusted for the length of treatment, the event rate for asthenia per 100 patient-years of treatment was lower in the enzalutamide group (12.4 vs 14.2). No deaths were associated with TEAEs of fatigue in any treatment group. In the combined phase 3 studies, SAEs of fatigue were higher in the enzalutamide group compared with the placebo group but low overall (0.7% vs 0.6%). Similarly, grade ≥ 3 fatigue events were higher in the enzalutamide group compared with the placebo group (5.0% vs 3.6). The incidence of TEAEs of fatigue leading to dose interruption in the enzalutamide group was also higher than in the placebo group (2.1% vs 0.8%). The same is true for the TEAEs of fatigue leading to dose reduction (2.1% vs 0.4%) and TEAEs of fatigue as the primary reason for discontinuation (1.1% vs 0.9%).

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5.2.2.2.6.4 Fall Fall was analyzed using the preferred term ‘fall’. Overall, the incidence of TEAEs of fall was higher in the enzalutamide group compared with the placebo group of the combined phase 3 studies (9.1% vs 3.6%). When adjusted for treatment duration, the event rate for fall per 100 patient-years of treatment was higher in the enzalutamide group of the combined phase 3 studies compared with the placebo group (9.1 vs 5.6). No deaths were associated with TEAEs of fall in any treatment group across the studies. In the combined phase 3 studies, the incidence was low overall but higher in the enzalutamide group compared with the placebo group for SAEs of fall (0.6% vs 0.3%) and grade ≥ 3 events (1.0% vs 0.5%). There were no events of fall as the primary reason for discontinuation in the combined phase 3 studies. The incidence of fall increased with age. In the combined phase 3 studies, the incidence of fall in enzalutamide-treated patients < 75 years was 5.9% vs 14.8% for enzalutamide-treated patients ≥ 75 years old. An exploratory analysis of TEAEs of syncope-related events (syncope, presyncope, loss of consciousness, dizziness and postural dizziness) reported within 1 day prior to TEAEs of fall was performed to evaluate the possible association of syncope-related events with fall. Among patients with fall in the combined phase 3 studies, a similar proportion in the enzalutamide and placebo groups had 1 or more syncope-related events within 1 day prior to a fall (3.5% [9/256] vs 2.9% [2/69]). Among the 256 patients with a TEAE of fall in the enzalutamide group of the combined phase 3 studies, 6 (2.3%) patients reported dizziness, 2 (0.8%) patients had syncope and 1 (0.4%) patient had a presyncope event within 1 day prior to the TEAE of fall. There were no enzalutamide-treated patients with postural dizziness or loss of consciousness reported within 1 day prior to a TEAE of fall in the combined phase 3 studies. Overall, an exploratory analysis of TEAEs of syncope, presyncope, loss of consciousness, dizziness and postural dizziness reported within 1 day prior to TEAEs of fall does not suggest an association of these events with fall among enzalutamide-treated patients. 5.2.2.2.6.5 Fracture The events of fractures were analyzed using all preferred terms that included ‘fracture’. The incidence of TEAEs of any event of fracture in the combined phase 3 studies was higher in the enzalutamide group compared with placebo (10.2% vs 4.4%). When adjusted for differences in treatment duration, the event rates per 100 patient-years of treatment were 8.1 vs 4.8. The most common types of fracture reported among the enzalutamide group of the combined phase 3 studies were rib fracture (2.4%) followed by spinal compression fracture (1.2%), femur fracture (0.4%) and upper limb fracture (0.3%). The incidence of SAEs of fractures was low in the enzalutamide group of the combined phase 3 studies (2.9%) as were grade ≥ 3 events of fracture (2.6%) and any event of fracture as the primary reason for discontinuation (0.1%).

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One event of fracture, occurring in an enzalutamide-treated patient in MDV3100-14, led to a fatal outcome due to complications of fracture. The incidence of fractures increased with the length of treatment duration. The incidence of any event of fracture during the first 30 days of treatment in the combined phase 3 studies was 0.5% for both the enzalutamide and placebo groups. During the first 180 days of treatment, the incidence of fractures was slightly higher in the enzalutamide group compared with the placebo group (3.1% vs 2.6%). 5.2.2.2.6.6 Syncope, Presyncope, Loss of Consciousness, Dizziness and Postural Dizziness TEAEs of syncope, presyncope, loss of consciousness, dizziness and postural dizziness are not ADRs for enzalutamide but are included as events of clinical interest based on requests by regulatory authorities. These events of interest were analyzed using TEAEs with the preferred terms ‘syncope’, ‘presyncope’, ‘loss of consciousness’, ‘dizziness’ and ‘postural dizziness’. Overall, the incidence of TEAEs of syncope was low. In the combined phase 3 studies, syncope was slightly higher in the enzalutamide group compared with placebo (1.2% vs 0.9%). When adjusted for the differences in treatment duration, the event rates for syncope per 100 patient-years of treatment were similar between the enzalutamide and placebo groups (1.0 vs 1.3). In the combined phase 3 studies, the incidence was similar in the enzalutamide and placebo groups for SAEs of syncope (0.5% vs 0.3%) and for syncope as the primary reason for discontinuation (0.1% vs 0.1%). The incidence of grade ≥ 3 syncope was higher in the enzalutamide group compared with the placebo group (1.1% vs 0.7%). In the combined phase 3 studies, the incidence of TEAEs of presyncope was higher in the enzalutamide group compared with the placebo group (1.0% vs 0.2%). When adjusted for the differences in treatment duration, the event rate for presyncope per 100 patient-years of treatment was 0.8 vs 0.3. The incidence was similar in the enzalutamide and placebo groups for SAEs of presyncope (0.2% vs 0) and grade ≥ 3 presyncope (0.3% vs 0) and presyncope leading to dose interruption (0.1% vs 0). No event of presyncope was the primary reason for discontinuation in the combined phase 3 studies. In the combined phase 3 studies, the incidence of TEAEs of loss of consciousness was low and similar in the enzalutamide group compared with the placebo group (0.2% vs 0.1%). The event rate adjusted for duration of treatment for loss of consciousness per 100 patient-years of treatment was 0.2 vs 0.2 in the combined phase 3 studies. The incidence was low in the phase 3 enzalutamide and placebo groups for SAEs of loss of consciousness (0.1% vs 0.1%) and grade ≥ 3 events of loss of consciousness (0.2% vs 0.1%). No loss of consciousness event was the primary reason for discontinuation for enzalutamide-treated patients in the combined phase 3 studies. The incidence of TEAEs of dizziness was higher in the enzalutamide group compared with the placebo group in the combined phase 3 studies (8.6% vs 5.4%). Event rates adjusted for duration of treatment for dizziness per 100 patient-years of treatment were lower in the enzalutamide group compared with placebo (7.7 vs 8.5). The incidence of SAEs of dizziness

Jun 2018 Astellas/Medivation Page 97 of 126 Enzalutamide (MDV3100) CONFIDENTIAL Cancer Investigator’s Brochure Edition 10 in the enzalutamide group compared with the placebo group in the combined phase 3 studies was 0.1% for both groups. The incidence of grade ≥ 3 dizziness in the enzalutamide group of the combined phase 3 studies was slightly higher compared with the placebo group (0.4% vs 0.1%). The incidence of dizziness as the primary reason for discontinuation in the combined phase 3 studies was similar and low in both treatment groups (0.1% vs 0.1%). The incidence of TEAEs of postural dizziness was slightly higher in the enzalutamide group compared with the placebo group in the combined phase 3 studies (0.2% vs 0.1%). Event rates adjusted for duration of treatment for postural dizziness per 100 patient-years of treatment in the phase 3 enzalutamide and placebo groups were 0.2 vs 0.1. There were no SAEs of postural dizziness, no grade ≥ 3 TEAEs of postural dizziness and no incidence of postural dizziness as the primary reason for discontinuation in the combined phase 3 studies. No enzalutamide-treated patients died due to a TEAE of syncope, presyncope, loss of consciousness, dizziness or postural dizziness. In summary, in the combined phase 3 studies, SAEs, grade ≥ 3 TEAEs and TEAEs as the primary reason for discontinuation were uncommon for events of syncope, presyncope, loss of consciousness, dizziness and postural dizziness. The incidence and/or event rates of syncope, loss of consciousness and postural dizziness were similar between the enzalutamide and placebo groups. The incidence of presyncope was low, but higher in the enzalutamide group compared with placebo (1.0% vs 0.2%). The incidence of dizziness was also higher in the enzalutamide group (8.6% vs 5.4%); however, event rates adjusted for duration of treatment were lower in the enzalutamide group (7.7 vs 8.5), suggesting that the higher incidence observed in the enzalutamide group may be attributable to a longer observation period compared with the placebo group. An exploratory analysis of TEAEs of syncope, presyncope, loss of consciousness, dizziness and postural dizziness reported within 1 day prior to fall TEAEs does not suggest an association of these events with falls among enzalutamide-treated patients. 5.2.2.2.6.7 Hypertension The events of hypertension were analyzed using ‘hypertension’ SMQ (narrow). In the combined phase 3 studies, the incidence of TEAEs of hypertension was higher in the enzalutamide group compared with the placebo group (11.3% vs 4.3%). When adjusted for treatment duration, the event rate for hypertension per 100 patient-years of treatment was higher in enzalutamide group compared with placebo (9.4 vs 5.7). The most common TEAE within the hypertension SMQ (narrow) was hypertension, which occurred more frequently in the enzalutamide group compared with the placebo group of the combined phase 3 studies (10.8% vs 3.8%). TEAEs of hypertension leading to death were not reported in any treatment group. In MDV3100-14, 1 enzalutamide-treated patient experienced an event of grade 4 hypertension. In the combined phase 3 studies, the incidence was low and higher in the enzalutamide group than in the placebo group for SAEs of hypertension (0.3% vs 0.1%), grade ≥ 3 TEAEs of

Jun 2018 Astellas/Medivation Page 98 of 126 Enzalutamide (MDV3100) CONFIDENTIAL Cancer Investigator’s Brochure Edition 10 hypertension (4.8% vs 2.1%) and hypertension as the primary reason for study drug discontinuation (0.1% vs 0). In the combined phase 3 studies, TEAEs of hypertension leading to dose interruption were low but more frequent in the enzalutamide group compared with the placebo group (0.8% vs 0.3%); similar low incidences were reported for TEAEs of hypertension leading to dose reduction (0.3% vs 0.1%). More than half of the patients in all studies had a medical history of hypertension; the proportion was lower in the enzalutamide group compared with the placebo group of the combined phase 3 studies (58.0% vs 59.1%) [Table 7]. The TEAEs of hypertension occurred with similar frequencies in enzalutamide-treated patients with and without history of hypertension and were higher in the patients in the enzalutamide groups compared with those in the placebo groups. The incidence of TEAEs of hypertension in the enzalutamide group vs the placebo group of the combined phase 3 studies was 12.0% vs 4.6% in patients with prior history of hypertension and 9.1% vs 2.6% in patients without hypertension history. The mechanism of hypertension associated with enzalutamide treatment is unknown, but hypertension has been reported with other antiandrogens such as bicalutamide [CASODEX®, 2015] and [Erleada™, 2018]. In general, hypertension was successfully treated with standard of care measures and rarely required treatment discontinuation or dose modification. 5.2.2.2.6.8 Cardiovascular Events Ischemic Heart Disease Events of ischemic heart disease were analyzed using the narrow SMQs of ‘myocardial infarction’ and ‘other ischaemic heart disease’. In the combined phase 3 studies, the incidence of ischemic heart disease events was higher in the enzalutamide group compared with the placebo group (2.6% vs 1.3%). Grade ≥ 3 events of ischemic heart disease occurred in 1.5% of patients in the enzalutamide group compared with 0.7% in the placebo group. Events of ischemic heart disease that led to death were reported in 0.4% of patients in the enzalutamide group compared with 0.1% in the placebo group 5.2.2.2.6.9 Second Primary Malignancies Second primary malignancies were identified using the narrow SMQ of ‘malignant tumours’, the narrow SMQ of ‘myelodysplastic syndrome’ and the high level term of ‘myeloproliferative disorders (excluding leukaemias)’. The TEAEs in the narrow SMQ ‘malignant tumours’ were customized to exclude preferred terms of congenital fibrosarcoma, congenital malignant neoplasm, congenital retinoblastoma, malignant neoplasm progression, all “metastases to…”, metastasis, metastatic neoplasm, neonatal leukemia, neonatal retinoblastoma, neoplasm progression. Nonmelanoma skin cancers (e.g., basal cell carcinoma, squamous cell carcinoma of the skin, etc.) were not included because the primary risk factor for nonmelanoma skin cancer is cumulative ultraviolet light exposure.

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In the combined phase 3 studies, the incidence of second primary malignancies was higher in the enzalutamide group compared with the placebo group (2.4% vs 0.9%). Enzalutamide-treated patients had a notably longer median treatment-emergent period than patients in the placebo groups. In the combined phase 3 studies, the median duration of exposure for patients with a second primary malignancy was higher for patients in the enzalutamide group compared with the placebo group (19.1 months vs 7.0 months). After adjustment for length of treatment duration, second primary malignancy event rates per 100 patient-years of treatment were higher for the enzalutamide-treated patients compared with the placebo group (2.0 vs 1.4). In the combined phase 3 studies, the proportion of patients with a second primary malignancy that led to death was slightly higher in the enzalutamide group than in the placebo group (0.3% vs 0.1%). In the combined phase 3 studies, second primary malignancy incidence was similar between treatment groups (enzalutamide vs placebo) in days 1 to 90 (0.3% vs 0.2%), days 91 to 180 (0.5% vs 0.3%), days 181 to 365 (0.8% vs 0.6%) and days 366 to 730 (1.0% vs 1.0%). In the time to onset analysis, no treatment group reached the median or 25th percentile time to first event of second primary malignancy. A Kaplan-Meier plot of time to onset of a second primary malignancy (excluding nonmelanoma skin cancer) is provided in Figure 10. In the Kaplan-Meier plot, the phase 3 enzalutamide and placebo group curves overlapped, suggesting minimal treatment group differences in time-to-first event of second primary malignancy. Of note, the median age at enrollment of patients with any event of second primary malignancy was > 70 years of age in all treatment groups. The incidence of most cancers increases with age and the cumulative risk for all cancers combined increases with age [White, 2014]. As indicated in the Surveillance, Epidemiology and End Results (SEER) Cancer Statistics Review, 1975-2014, the highest incidence of occurrence of cancer is seen in the 65 to 74 year old age group followed by individuals aged 55 to 64 years, followed by the 75 to 84 year old age group [Howlader, 2016]. The observed incidence of second primary malignancies in this IB was compared with the expected overall incidence of malignancy in the general population and the incidence of each type of malignancy using cancer statistics data from the SEER program database (www.seer.cancer.gov). This analysis was performed using the SEER-based incidence rates expressed as the number of new cases per 100000 individuals at risk. The overall incidence of second primary malignancy in enzalutamide-treated patients was lower than and within the expected incidence for all cancer sites combined per SEER-18 program data (77 events observed in the total enzalutamide group vs a total of 96.2 events expected in a population ≥ 65 years of age). Assessment of the onset of second malignancy by anatomic type in the context of current knowledge of the long latency period for the observed nonprostate malignancies, independent of any additional potential risk associated with prior prostate cancer malignancy, suggests

Jun 2018 Astellas/Medivation Page 100 of 126 Enzalutamide (MDV3100) CONFIDENTIAL Cancer Investigator’s Brochure Edition 10 that the relatively short and comparable time to onset in both enzalutamide and placebo and active control groups is inconsistent with a relationship between enzalutamide treatment and the development of second primary malignancies. Overall, the incidence of individual types of second primary malignancies was low in enzalutamide-treated patients and comparable across the studies. The relatively short and comparable median time to onset and the incidence of malignancies across a variety of different organ systems and cell types suggest that a relationship between these malignancies and enzalutamide is unlikely.

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Figure 10 Time to Onset of Second Primary Malignancy (Excluding Nonmelanoma Skin Cancer)

All enrolled patients who received any amount of study drug (enzalutamide or placebo) in their respective study (safety population). The data cutoff date for MDV3100-14 (PROSPER) was 28 Jun 2017. The data cutoff dates for the other phase 3 studies were 15 Jan 2014, 01 Jul 2013 and 20 Sep 2015 for MDV3100-03, CRPC2 and 9785-CL-0232, respectively. Trt1: enzalutamide in MDV3100-14, n = 930; Trt2: placebo in MDV3100-14, n = 465; Trt3: enzalutamide in phase 3 studies, n = 2799; Trt4: placebo in phase 3 studies n = 1898 CI: confidence interval; NR: not reached; SCS: summary of clinical safety Source: SCS-PROSPER Figure 2 Jun 2018 Astellas/Medivation Page 102 of 126 Enzalutamide (MDV3100) CONFIDENTIAL Cancer Investigator’s Brochure Edition 10

5.2.2.2.7 Laboratory Findings In the combined phase 3 studies, the most common grade 3 and 4 postbaseline hematology laboratory toxicity was low lymphocytes (3.6% in both the enzalutamide and placebo groups). The second most common grade 3 and 4 postbaseline hematology laboratory toxicity was low hemoglobin (2.2% vs 2.0% for enzalutamide and placebo, respectively). A total of 23 patients (0.8%) in the enzalutamide group and 7 (0.4%) patients in the placebo group of the combined phase 3 studies had any grade ≥ 3 event of neutrophil count decreased. The proportion of patients who had an event of neutrophil count decreased leading to dose interruption in the enzalutamide and placebo groups was 0.3% and 0.1%, respectively. The proportion of patients with neutrophil count decreased-related TEAEs increased over time in the enzalutamide and placebo groups of the combined phase 3 studies at 30, 180 and 365 days of treatment. When adjusted for treatment duration, event rates for neutrophil count decreased-related TEAEs per 100 patient-years of treatment remained higher in the patients in the enzalutamide group of the combined phase 3 studies compared with the placebo group. In the combined phase 3 studies, the most common grade 3 and 4 postbaseline chemistry laboratory toxicity was high ALP; however, the proportion of patients with high ALP in the enzalutamide group was lower compared with placebo (5.6% vs 8.4%). The second most common grade 3 and 4 postbaseline chemistry laboratory toxicity was high glucose (2.9% vs 2.3%). The proportion of all other grade 3 and 4 postbaseline laboratories toxicities occurred in < 2% of patients in any treatment group. Treatment-emergent liver tests were also analyzed. In the enzalutamide group of the combined phase 3 studies, the proportion of patients with ALP ≥ 1.5 x upper limits of normal was lower than in the placebo group (24.2% vs 29.5%). All other treatment-emergent liver tests occurred in < 2% of patients in all the other treatment groups. In both the enzalutamide and placebo groups of the combined phase 3 studies, the proportion of patients with hepatic impairment-related TEAEs within the first 30 days of treatment was low (0.4% vs 0.6%); however, the proportion increased over time within the first 180 days (1.3% vs 1.8%) and increased slightly within the first 365 days of treatment (1.4% vs 2.1%). This may in part be indicative of liver metastases present within a metastatic study population. The proportion of patients with hepatic impairment-related TEAEs increased over time in the placebo group of the combined phase 3 studies within the first 30, 180 and 365 days of treatment (0.4%, 1.4% and 1.7%). No events met Hy’s Law criteria in the combined phase 3 studies. 5.2.2.2.8 Vital Signs, Pulse and Blood Pressure Enzalutamide treatment was associated with increased blood pressure. In the combined phase 3 studies, the proportion of patients with any blood pressure abnormalities was higher in the enzalutamide group compared with the placebo group: abnormalities in systolic blood pressure (83.1% vs 71.5%), diastolic blood pressure (67.4% vs 53.6%) and heart rate (2.1% vs 1.3%). The proportion of patients with a heart rate

Jun 2018 Astellas/Medivation Page 103 of 126 Enzalutamide (MDV3100) CONFIDENTIAL Cancer Investigator’s Brochure Edition 10 abnormality of ≤ 50 bpm and a decrease from baseline ≥ 20 bpm in the enzalutamide group was comparable to placebo (1.6% vs 0.6%). The proportion of patients with a heart rate abnormality of ≥ 120 bpm and increase from baseline ≥ 30 bpm in the enzalutamide group was low and comparable to placebo (0.5% vs 0.7%). 5.2.2.2.9 Electrocardiogram None of the patients in study MDV3100-14 presented with morphological changes on ECG that were reported as AEs. While there was a higher incidence of patients with new morphological changes on ECG in the enzalutamide groups than the placebo groups in studies MDV3100-03 and CRPC2, the majority were not considered clinically significant and were reflective of atrial or ventricular ectopy, T wave changes and first degree atrioventricular block. Additionally, in both studies, the longer exposure to study drug resulted in a larger number of ECGs obtained in the enzalutamide group, which confounds the interpretation of these data. All clinically significant morphology changes (e.g., new atrial fibrillation, ECG evidence of myocardial infarction, clinically relevant QT prolongation) were reported as AEs. A comprehensive ECG evaluation was conducted during study CRPC2 and results demonstrated no clinically relevant changes in heart rate, atrioventricular conduction as determined by the PR interval, or cardiac depolarization as determined by the QRS duration in patients treated with enzalutamide. A pharmacokinetic/pharmacodynamics analysis of the effect of enzalutamide treatment on cardiac repolarization in that study suggested a possible +3 msec effect with an upper CI of < 4 msec on QT interval corrected using Fridericia’s formula (QTcF). In an analysis of mean QTcF over time in study MDV3100-03, results were generally comparable. At baseline, mean QTcF was similar in the 2 treatment groups (427.2 msec in the enzalutamide group vs 427.1 msec in the placebo group). In general over the first year of treatment in MDV3100-03, mean postbaseline QTcF values were above baseline in the enzalutamide group whereas mean postbaseline QTcF values were at or below baseline in the placebo group. Over the first 2 years of treatment, the maximum mean change from baseline in QTcF was 3.8 msec in the enzalutamide group (week 73) and 1.7 msec in the placebo group (week 61). The largest placebo-adjusted increase was 3.4 msec (95% CI: 1.2-5.6 msec) observed at week 37. However, no additional increase in QTcF was observed in enzalutamide-treated patients with high QTcF at baseline compared with placebo. There was a comparable incidence between treatment groups in MDV3100-03, but higher incidence in CRPC2 (0.9% of enzalutamide-treated patients with new QTcF > 500 msec vs 0% of placebo-treated patients; 1.0% of enzalutamide treated patients with ≥ 60 msec change from baseline in QTcF vs 0% of placebo treated patients). However, the overall incidences of clinically relevant QTc changes reported as AEs of prolonged QT in MDV3100-03 and CRPC2 were comparable between enzalutamide and placebo groups (1.3% and 1.1% of enzalutamide- and placebo-treated patients, respectively, in study MDV3100-03 and 0.3% of patients in both groups of study CRPC2), as were the incidences of grade 3 or higher AEs of prolonged QT (0.3% vs 0.5% of study MDV3100-03; 0% in both groups of study CRPC2).

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Similarly, there was no safety signal when the ‘torsades de pointes/QT prolongation’ SMQ was evaluated in either study. 5.2.2.3 Safety in Female Patients With Breast Cancer Safety data are available from approximately 400 female patients with breast cancer who received enzalutamide as a single agent in studies MDV3100-08 and MDV3100-11 or in combination with endocrine agents in studies MDV3100-08, MDV3100-12 and 9785-CL-1121. Safety data from these studies include data in the clinical database as of 29 Sep 2017 (28 Feb 2017 for 9785-CL-1121). Key features of each study are presented in Table 14. Table 14 Summary of Clinical Studies of Enzalutamide in Breast Cancer Study Phase Design Population Treated/Treatments MDV3100-08 1 Open-label Cohort 1: Total n = 101 (Safety population = 99) Incurable breast cancer Stage 1 (n = 15): Cohorts 2–4: Enzalutamide dose-escalation Hormone Stage 2 (n = 86 [safety population = 84]): receptor-positive breast Cohort 1 (n = 14): cancer Enzalutamide Cohort 2 (n = 21 [20 treated]): Enzalutamide + anastrozole 1 mg Cohort 3 (n = 16): Enzalutamide + exemestane 25 mg Cohort 3B (n = 24 [23 treated]): Enzalutamide + exemestane 50 mg Cohort 4 (n = 11): Enzalutamide + fulvestrant 500 mg MDV3100-11 2 Open-label, Simon Advanced triple-negative Total n = 118 2-stage breast cancer Stage 1 (n = 42): Enzalutamide Stage 2 (n = 76): Enzalutamide MDV3100-12 2 Double-blind, Advanced hormone Double-blind Treatment Period placebo-controlled receptor-positive, Cohort 1 (n = 127 [125 treated]): HER2-normal breast Enzalutamide + exemestane 50 mg, n = 63 cancer (62 treated) Placebo + exemestane 25 mg, n = 64 (63 treated) Cohort 2 (n = 120 [120 treated]): Enzalutamide + exemestane 50 mg, n = 60 (60 treated) Placebo + exemestane 25 mg, n = 60 (60 treated) Open-label Treatment Period Cohort 1: Enzalutamide + exemestane 50 mg, n = 21 (21 treated) Cohort 2: Enzalutamide + exemestane 50 mg, n = 12 (11 treated) Table continued on next page

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Study Phase Design Population Treated/Treatments 9785-CL-1121 2 Open-label, Simon HER2+ AR+ metastatic Total n = 103 (103 treated) 2-stage or locally advanced Enzalutamide + trastuzumab breast cancer AR+: androgen receptor-positive; HER2, human epidermal growth factor receptor 2.

The data from the breast cancer studies support a safety profile consistent with the safety profile of enzalutamide in men with prostate cancer and the expected consequences of advanced disease in women with breast cancer. All enzalutamide doses were given as a single daily dose. The median (range) time on study drug was 8 (0.9, 152) weeks in MDV3100-08 stages 1 and 2 for all cohorts, except fulvestrant (19 weeks; range: 4 to 76.6 weeks). The median (range) enzalutamide exposure was 8.1 (0.9, 87.0) weeks in study MDV3100-11 and was 70.0 (1 to 660) days in study 9785-CL-1121. In study MDV3100-12, the median (range) exposure to enzalutamide was 40.9 (0.1, 115.4) weeks in the Cohort 1 ITT population, 10.2 (0.4, 20.1) weeks in the Cohort 2 ITT population, 11.1 weeks in the Cohort 1 open-label period and 8.3 weeks in the Cohort 2 open-label period. For consistency of presentation, the same AE terms are presented across the 3 studies based on the most common TEAEs reported in MDV3100-11 (5% threshold). TEAEs are summarized for the 3 open-label studies in Table 15. Adverse reactions associated with enzalutamide treatment in men with prostate cancer are noted. Common (≥ 5% of patients in the Cohort 1 or Cohort 2 safety populations) TEAEs are summarized for the double-blind treatment period in study MDV3100-12 by cohort and treatment group (i.e., once daily 160 mg enzalutamide plus 50 mg exemestane [(hereafter referred to as enzalutamide] vs once daily placebo plus 25 mg exemestane [hereafter referred to as placebo]) in Table 16. Because each cohort in study MDV3100-12 reflects a difference in patient population based on treatment history, the analyses were not integrated. All results are presented separately for Cohort 1 and Cohort 2; a discussion of TEAEs that occurred in the open-label period follows the table.

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Table 15 Summary of Common TEAEs in 3 Open-label Studies of Enzalutamide in Female Patients With Advanced Breast Cancer (MDV3100-08, MDV3100-11 and 9785-CL-1121) MDV3100-08 MDV3100-08 Study Stage 1 Stage 2 MDV3100-11† 9785-CL-1121 Enzalutamide Enzalutamide + Enzalutamide + Enzalutamide + Enzalutamide+ Enzalutamide+ Treatment‡ Dose Escalation Enzalutamide Anastrozole 1 mg Exemestane 25 mg Exemestane 50 mg Fulvestrant 500 mg Enzalutamide Trastuzumab 6 mg Enrolled (n) 15 14 21 16 24 11 118 103 Safety population 15 (15) 14 (14) 20 (20) 16 (15) 23 (21) 11 (11) 118 (109) 103 (97) (patients with TEAEs) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) Fatigue§ 2 (13%) 8 (57%) 12 (60%) 8 (50%) 12 (52%) 8 (73%) 49 (42%) 35 (34%) Nausea§ 4 (27%) 8 (57%) 9 (45%) 7 (44%) 12 (52%) 8 (73%) 40 (34%) 28 (27%) Decreased appetite§ 2 (13%) 1 (7%) 10 (50%) 5 (31%) 4 (17%) 2 (18%) 22 (19%) 15 (15%) Constipation§ 2 (13%) 2 (14%) 3 (15%) 3 (19%) 3 (13%) 3 (27%) 19 (16%) 13 (13%) Diarrhoea§ 4 (27%) 2 (14%) 6 (30%) 3 (19%) 3 (13%) 4 (36%) 18 (15%) 13 (13%) Back pain§ 1 (7%) 5 (36%) 3 (15%) 2 (13%) 5 (22%) 6 (55%) 16 (14%) 14 (14%) Headache§ 2 (13%) 3 (21%) 3 (15%) 1 (6%) 2 (9%) 4 (36%) 16 (14%) 14 (14%) Insomnia 2 (13%) 1 (7%) 5 (25%) 2 (13%) 2 (9%) 1 (9%) 16 (14%) 4 (4%) Arthralgia§ 1 (7%) 1 (7%) 3 (15%) 1 (6%) 4 (17%) 0 15 (13%) 12 (12%) Dyspnoea 1 (7%) 4 (29%) 2 (10%) 2 (13%) 2 (9%) 4 (36%) 13 (11%) 15 (15%) Hot flush§ 0 4 (29%) 5 (25%) 2 (13%) 4 (17%) 3 (27%) 12 (10%) 17 (17%) Vomiting 1 (7%) 5 (36%) 3 (15%) 2 (13%) 7 (30%) 3 (27%) 11 (9%) 11 (11%) Musculoskeletal pain 4 (27%) 1 (7%) 2 (10%) 2 (13%) 6 (26%) 3 (27%) 10 (9%) 4 (4%) Pain 0 0 1 (5%) 0 0 0 10 (9%) 1 (1%) Pain in extremity 0 1 (7%) 2 (10%) 2 (13%) 1 (4%) 2 (18%) 9 (8%) 11 (11%) Weight decreased§ 2 (13%) 0 3 (15%) 4 (25%) 1 (4%) 3 (27%) 8 (7%) 1 (1%) Anxiety 3 (20%) 1 (7%) 3 (15%) 2 (13%) 1 (4%) 2 (18%) 7 (6%) 9 (9%) Cough 4 (27%) 2 (14%) 3 (15%) 3 (19%) 4 (17%) 1 (9%) 7 (6%) 9 (9%) Abdominal pain 0 3 (21%) 1 (5%) 0 0 2 (18%) 6 (5%) 5 (5%) Asthenia§ 0 1 (7%) 5 (25%) 0 1 (4%) 0 6 (5%) 6 (6%) 0 1 (7%) 0 0 1 (4%) 0 6 (5%) 4 (4%) Dizziness§ 3 (20%) 3 (21%) 2 (10%) 3 (19%) 2 (9%) 3 (27%) 6 (5%) 14 (14%) Table continued on next page

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MDV3100-08 MDV3100-08 Study Stage 1 Stage 2 MDV3100-11† 9785-CL-1121 Enzalutamide Enzalutamide + Enzalutamide + Enzalutamide + Enzalutamide+ Enzalutamide+ Treatment‡ Dose Escalation Enzalutamide Anastrozole 1 mg Exemestane 25 mg Exemestane 50 mg Fulvestrant 500 mg Enzalutamide Trastuzumab 6 mg Muscle spasms 1 (7%) 0 2 (10%) 2 (13%) 1 (4%) 0 6 (5%) 5 (5%) Nasopharyngitis 0 0 0 1 (6%) 0 0 6 (5%) 2 (2%) Neuropathy peripheral 3 (20%) 0 2 (10%) 1 (6%) 0 0 6 (5%) 2 (2%) Data cutoff date: 23 Sep 2016 † Data are sorted by frequency (high to low) with a 5% threshold for the study that contributed the most data (MDV3100-11). ‡ Enzalutamide was given once daily. § Common (≥ 5%) adverse reactions associated with enzalutamide treatment in men with prostate cancer. TEAE: treatment-emergent adverse event. Source: Study MDV3100-08 CSR, Tables 33 and 34; Study MDV3100-11 CSR, Table 43; 9785-CL-1121 CSR, Table 14

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Table 16 Summary of TEAEs in at Least 5% of Patients in the Cohort 1 or Cohort 2 Safety Populations, Double-blind Treatment Period, Study MDV3100-12 Cohort 1 Cohort 2 Enzalutamide Enzalutamide 160 mg + Placebo + 160 mg + Placebo + Exemestane 50 mg Exemestane 25 mg Exemestane 50 mg Exemestane 25 mg Preferred Term n = 62 n = 63 n = 60 n = 60 Any TEAE 59 (95.2%) 58 (92.1%) 58 (96.7%) 53 (88.3%) Nausea 24 (38.7%) 10 (15.9%) 18 (30.0%) 11 (18.3%) Fatigue 23 (37.1%) 21 (33.3%) 22 (36.7%) 13 (21.7%) Hot flush 19 (30.6%) 14 (22.2%) 14 (23.3%) 9 (15.0%) Arthralgia 14 (22.6%) 11 (17.5%) 10 (16.7%) 7 (11.7%) Diarrhoea 12 (19.4%) 10 (15.9%) 6 (10.0%) 10 (16.7%) Back pain 11 (17.7%) 5 (7.9%) 4 (6.7%) 12 (20.0%) Vomiting 11 (17.7%) 7 (11.1%) 6 (10.0%) 3 (5.0%) Asthenia 10 (16.1%) 7 (11.1%) 6 (10.0%) 4 (6.7%) Constipation 10 (16.1%) 7 (11.1%) 8 (13.3%) 8 (13.3%) Cough 9 (14.5%) 6 (9.5%) 2 (3.3%) 4 (6.7%) Dyspnoea 9 (14.5%) 7 (11.1%) 5 (8.3%) 5 (8.3%) Headache 9 (14.5%) 6 (9.5%) 9 (15.0%) 10 (16.7%) Alopecia 8 (12.9%) 3 (4.8%) 5 (8.3%) 2 (3.3%) Dizziness 8 (12.9%) 4 (6.3%) 5 (8.3%) 2 (3.3%) Anxiety 7 (11.3%) 4 (6.3%) 2 (3.3%) 1 (1.7%) Musculoskeletal chest pain 7 (11.3%) 4 (6.3%) 2 (3.3%) 3 (5.0%) Musculoskeletal pain 7 (11.3%) 1 (1.6%) 2 (3.3%) 2 (3.3%) Decreased appetite 6 (9.7%) 6 (9.5%) 6 (10.0%) 2 (3.3%) Hypertension 6 (9.7%) 4 (6.3%) 2 (3.3%) 1 (1.7%) Insomnia 5 (8.1%) 4 (6.3%) 5 (8.3%) 4 (6.7%) Pain in extremity 5 (8.1%) 8 (12.7%) 3 (5.0%) 5 (8.3%) Neuropathy peripheral 4 (6.5%) 3 (4.8%) 0 1 (1.7%) Anaemia 4 (6.5%) 1 (1.6%) 6 (10.0%) 3 (5.0%) Depression 3 (4.8%) 1 (1.6%) 3 (5.0%) 3 (5.0%) Abdominal pain upper 2 (3.2%) 2 (3.2%) 4 (6.7%) 2 (3.3%) Bone pain 2 (3.2%) 4 (6.3%) 5 (8.3%) 2 (3.3%) Hypercalcaemia 2 (3.2%) 1 (1.6%) 3 (5.0%) 3 (5.0%) Abdominal pain 1 (1.6%) 2 (3.2%) 2 (3.3%) 4 (6.7%) Dyspepsia 1 (1.6%) 6 (9.5%) 5 (8.3%) 4 (6.7%) Alanine aminotransferase 0 3 (4.8%) 2 (3.3%) 4 (6.7%) increased Data cutoff date: 23 Sep 2016 Cohort 1: patients who had not previously received hormone treatment for advanced breast cancer. Cohort 2: patients who previously progressed following 1 hormone treatment for advanced breast cancer. Patients with multiple events for a given preferred term were counted only once for each preferred term. Events are sorted by frequency of preferred term in the enzalutamide group in Cohort 1 and then in alphabetical order. TEAE: treatment-emergent adverse event Source: Study MDV3100-12 CSR, Tables 14.3.1.2.1.1.1.5 and 14.3.1.2.2.1.1.5 In MDV3100-12, of the 21 Cohort 1 patients and 11 Cohort 2 patients who entered the open-label treatment period and received study drug, 14 (66.7%) patients in Cohort 1 and 10 (90.9%) patients in Cohort 2 had at least 1 TEAE. The most frequently reported TEAEs

Jun 2018 Astellas/Medivation Page 109 of 126 Enzalutamide (MDV3100) CONFIDENTIAL Cancer Investigator’s Brochure Edition 10 were, in Cohort 1, asthenia (3 [14.3%] patients) and fatigue (2 [9.5%] patients) and, in Cohort 2, fatigue (5 [45.5%] patients). All other TEAEs were reported by 1 patient each. Grade 3 or higher TEAEs were reported in 5 (33%) patients in stage 1 and 28 (33.3%) patients in stage 2 of MDV3100-08; 36 (30.5%) patients in MDV3100-11; 35 (28.0%) patients in Cohort 1 (20 [32.3%] patients enzalutamide vs 15 [23.8%] patients placebo) and 24 (28.3%) patients in Cohort 2 (22 [36.7%] patients enzalutamide vs 12 [20.0%] patients placebo) in the MDV3100-12 double-blind treatment period; 1 (4.8%) patient in Cohort 1 and none in Cohort 2 in the MDV3100-12 open-label period); and 22 (21.4%) patients in 9785-CL-1121. Grade 3 or higher TEAEs reported for at least 2 patients in each study or cohort included the following: ● Study MDV3100-08 stage 1: anemia (n = 2) ● Study MDV3100-08 stage 2: hypertension (n = 5), fatigue (n = 4), neutropenia (n = 3); anemia, hyperglycemia, hypokalemia, pathological fracture, pneumonia, thrombocytopenia and urinary tract infection (n = 2 each) ● Study MDV3100-11: fatigue (n = 6); pleural effusion (n = 4); disease progression, dyspnea, malignant pleural effusion and metastatic pain (n = 3 each); anemia, metastatic breast cancer, pain, pericardial effusion, sepsis and vomiting (n = 2 each) ● Study MDV3100-12 (double-blind treatment period): o Cohort 1: hypertension (n = 8 [6 enzalutamide vs 2 placebo]), hypercalcemia (n = 3 [2 vs 1], back pain (n = 2 [0 vs 2]), aspartate aminotransferase (AST) increased (n = 3 [0 vs 3]), pain in extremity (n = 3 [1 vs 2]), dyspnea (n = 2 [0 vs 2]), hyponatremia (n = 2 [1 vs 1]) and pleural effusion (n = 2 [0 vs 2]) o Cohort 2: anemia (n = 6 [4 enzalutamide vs 2 placebo]), hypercalcemia (n = 4 [2 vs 2]), back pain (n = 2 [1 vs 1]), fatigue (n = 3 [3 vs 0]), headache (n = 3 [3 vs 0]) and hypoesthesia (n = 2 [1 vs 1]) ● Study 9785-CL-1121: dyspnea (n = 4); abdominal pain, back pain, fatigue, malignant neoplasm progression, pneumonia, thrombocytopenia and vomiting (n = 2 each). Treatment-emergent SAEs across the breast cancer program were generally a consequence of disease progression. None of the treatment-emergent SAEs reported in stage 1 of study MDV3100-08 occurred in more than 1 patient. The only treatment-emergent SAE reported in more than 1 patient in stage 2 of study MDV3100-08 was pneumonia (n = 2). Treatment-emergent SAEs reported in more than 1 patient in study MDV3100-11 were disease progression, malignant pleural effusion, metastatic pain and pleural effusion (n = 3 each); and metastatic breast cancer, constipation, lung infection, pericardial effusion, sepsis and spinal cord compression (n = 2 each). In study MDV3100-12 (double-blind treatment period), treatment-emergent SAEs reported in more than 1 patient were, in Cohort 1, hypercalcemia (n = 2 [2 enzalutamide vs 0 placebo]), malignant pleural effusion (n = 2 [2 vs 0]), metastatic pain (n = 2 [1 vs 1]) and dyspnea (n = 2 [1 vs 1]) and, in Cohort 2, hypercalcemia (n = 3 [2 enzalutamide vs 1 placebo]). None of the treatment-emergent SAEs reported in study MDV3100-12 (open-label period) in either Cohort 1 or Cohort 2 occurred in more than 1 patient. Treatment-emergent SAEs reported in more than 1 patient in

Jun 2018 Astellas/Medivation Page 110 of 126 Enzalutamide (MDV3100) CONFIDENTIAL Cancer Investigator’s Brochure Edition 10 study 9785-CL-1121 were malignant neoplasm progression (n = 5), and nausea and vomiting (n = 3 each). TEAEs with fatal outcome were reported across the 4 studies. In study MDV3100-08, 1 patient in stage 2 had urosepsis (no fatal TEAEs were reported in stage 1). In study MDV3100-11, 12 patients had fatal TEAEs (2 patients with pericardial effusion, 2 with pleural effusion, 1 with sepsis and 8 with events associated with disease progression). In study MDV3100-12 (double-blind treatment period), fatal TEAEs were experienced by 4 (3.2%) patients in Cohort 1 (2 [3.2%] patients enzalutamide [malignant pleural effusion, cerebrovascular accident] vs 2 [3.2%] patients placebo [disease progression, hemorrhage intracranial]) and 2 (1.7%) patients in Cohort 2 (2 [3.3%] patients enzalutamide [1 general physical health deterioration and 1 disease progression] vs none placebo). In study MDV3100-12 (open-label period), 1 patient in Cohort 1 and none in Cohort 2 had a fatal TEAE (disease progression). In study 9785-CL-1121, 1 (1.0%) patient had a fatal TEAE (malignant neoplasm progression). All fatal events were considered by investigators to be unrelated to study drug. Study drug treatment was permanently discontinued due to TEAEs in 6 (7.1%) patients in stage 2 of study MDV3100-08 (no patients discontinued treatment due to a TEAE in stage 1), 6 (5.1%) patients in study MDV3100-11, 19 (15.2%) patients in Cohort 1 (9 [14.5%] patients enzalutamide vs 10 [15.9%] patients placebo) and 16 (13.3%) patients in Cohort 2 (11 [18.3%] patients enzalutamide vs 5 [8.3%] patients placebo) in study MDV3100-12 (double-blind treatment period), 2 (9.5%) patients in Cohort 1 and none in Cohort 2 in study MDV3100-12 (open-label period) and 21 patients (20.4%) in study 9785-CL-1121. TEAEs that led to permanent study drug discontinuations in at least 2 patients in each treatment group and study were as follows: ● Study MDV3100-08 (stage 2): fatigue (n = 4) ● Study MDV3100-11: and all TEAEs that led to permanent study drug discontinuation occurred in 1 patient each ● Study MDV3100-12 (double-blind treatment period): vomiting (n = 3 [1 enzalutamide vs 2 placebo]) and fatigue (n = 3 [0 enzalutamide vs 3 placebo]) in Cohort 1 and tumor marker increased (n = 3 [1 enzalutamide vs 2 placebo])in Cohort 2 ● Study MDV3100-12 (open-label period): all TEAEs that led to permanent study drug discontinuation occurred in 1 patient each in Cohort 1. No patients in Cohort 2 experienced TEAEs that led to permanent study drug discontinuation. ● Study 9785-CL-1121: malignant neoplasm progression (n = 4); nausea (n = 3); and diarrhea, ejection fraction decreased and skin lesion (n = 2 each) Overall, the safety data to date support enzalutamide monotherapy as generally well tolerated, as reflected by the low rates of grade 3 or higher TEAEs, treatment-emergent SAEs and treatment discontinuations due to a TEAE. One patient in study MDV3100-12 experienced nonconvulsive status epilepticus associated with 2 tonic-clonic seizures, onset 22 days after discontinuation of study drugs following

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2 days on study treatment and 12 days after resection of a brain metastasis, with discontinuation of levetiracetam prophylaxis 2 to 3 days prior to the events. When enzalutamide treatment was combined with aromatase inhibitors (exemestane [studies MDV3100-08 and MDV300-12], anastrozole [study MDV3100-08]), a selective ER modulator (fulvestrant [MDV3100-08]) or a monoclonal antibody (trastuzumab [study 9785-CL-1121]), the safety profile was generally consistent with that observed with single-agent enzalutamide. 5.2.2.4 Summary of Safety in Patients With HCC In study 9785-CL-3021, 162 patients with HCC received a daily single dose of study drug: 107 patients received enzalutamide 160 mg and 55 patients received placebo (data cutoff date 02 Oct 2017). The median time on study drug was 71 days (range: 6 to 574 days) for enzalutamide and 64 days (range: 13 to 385 days) for placebo. Most patients in both groups (54.2% and 60.0%, respectively) received < 3 months of treatment. The most frequently reported TEAEs (≥ 20% of patients in either treatment group) in the enzalutamide group were fatigue (37 [34.6%] patients), decreased appetite (34 [31.8%] patients) and nausea (28 [26.2%] patients); and in the placebo group were diarrhea (13 [23.6%] patients), decreased appetite (12 [21.8%] patients) and asthenia (11 [20.0%] patients). TEAEs that occurred more frequently (≥ 10% difference) with enzalutamide than with placebo were fatigue (34.6% enzalutamide vs 18.2% placebo), decreased appetite (31.8% vs 21.8%), nausea (26.2% vs 10.9%), ascites (14.0% vs 3.6%) and gynecomastia (11.2% vs 0). Grade 3 TEAEs were reported in 42 (39.3%) patients in the enzalutamide group and 20 (36.4%) patients in the placebo group. The most frequently reported (in ≥ 5% of patients) grade 3 TEAEs were, in the enzalutamide group, AST increased (12 [11.2%] patients), fatigue (7 [6.5%] patients) and asthenia (6 [5.6%] patients), and in the placebo group, AST increased (4 [7.3%] patients), diarrhea (4 [7.3%] patients) and abdominal pain (3 [5.5%] patients). Grade 4 TEAEs were reported in 3 (2.8%) patients in the enzalutamide group and included hyponatremia in 2 (1.9%) patients and blood bilirubin increased, hypophosphatemia, thrombocytopenia, hyperkalemia, metabolic acidosis, ECG QRS complex and pulmonary embolism in 1 (0.9%) patient each. Grade 4 TEAEs were reported in 3 (5.5%) patients in the placebo group and included ALT increased and AST increased in 2 (3.6%) patients each and anemia, hyperkalemia and renal failure acute in 1 (1.8%) patient each. Treatment-emergent SAEs that occurred in ≥ 2% of patients in either treatment group included, in the enzalutamide group, malignant neoplasm progression (14 [13.1%] patients), abdominal pain (7 [6.5%] patients), ascites (5 [4.7%] patients), renal failure acute (4 [3.7%] patients), anemia (3 [2.8%] patients) and back pain (3 [2.8%] patients); and in the placebo group, malignant neoplasm progression (6 [10.9%] patients), tumor hemorrhage (2 [3.6%] patients) and renal failure acute (2 [3.6%] patients). All other treatment-emergent SAEs in either treatment group occurred in 1 or 2 patients each.

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TEAEs with fatal outcome occurred in 14 (13.1%) and 6 (10.9%) patients in the enzalutamide and placebo groups, respectively. In the enzalutamide group, fatal TEAEs were malignant neoplasm progression in 11 patients, sepsis in 2 patients and general physical health deterioration and renal failure acute in 1 patient each. In the placebo group, fatal TEAEs were malignant neoplasm progression in 5 patients and septic shock in 1 patient. A total of 35 (32.7%) patients in the enzalutamide group and 14 (25.5%) patients in the placebo group discontinued treatment due to TEAEs. TEAEs leading to withdrawal of treatment and assessed as related to any of the study drugs included , in the enzalutamide group, fatigue in 3 (2.8%) patients, asthenia in 2 (1.9%) patients and abdominal discomfort, dyspepsia, nausea, hepatic failure, weight decreased, decreased appetite, lethargy and dyspnea in 1 (0.9%) patient each; and in the placebo group, ALT increased and AST increased in 2 (3.6%) patients each and rectal hemorrhage and asthenia in 1 (%) patient each. The safety profile of enzalutamide monotherapy in patients with HCC is consistent with the safety data generated in studies of enzalutamide in men with prostate cancer. 5.2.2.5 Safety in Special Populations Hepatic Impairment A hepatic impairment study showed that the composite AUC of enzalutamide plus N-desmethyl enzalutamide after administration of a single dose of enzalutamide was similar in subjects with baseline mild, moderate or severe hepatic impairment (Child-Pugh Class A, B and C, respectively) relative to subjects with normal hepatic function and no starting dose adjustment is needed. A 2.2-fold increase in drug half-life was observed in subjects with severe hepatic, possibly related to increased tissue distribution. The clinical relevance of this observation is unknown; however, prolonged time to reach steady-state concentrations is anticipated. Renal Impairment A dedicated renal impairment study has not been conducted. Based on the population pharmacokinetic analysis using data from clinical studies in patients with metastatic CRPC and healthy volunteers, no significant difference in enzalutamide clearance was observed in patients with pre-existing mild to moderate renal impairment (30 mL/min ≤ CLCR ≤ 89 mL/min) compared to patients and volunteers with baseline normal renal function (CLCR ≥ 90 mL/min). No initial dosage adjustment is necessary for patients with mild to moderate renal impairment. Severe renal impairment (CLCR < 30 mL/min) and end-stage renal disease have not been assessed. Elderly Patients In the 4 combined phase 3 studies, a total of 2799 patients were exposed to enzalutamide. Of these patients, 43% were 65 to 74 years of age and 37% were 75 years of age or older. No overall differences in safety or effectiveness were observed between these patients and younger patients. Other reported clinical experience has not identified differences in

Jun 2018 Astellas/Medivation Page 113 of 126 Enzalutamide (MDV3100) CONFIDENTIAL Cancer Investigator’s Brochure Edition 10 responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Pregnant and Lactating Women The effect of enzalutamide in pregnant and lactating women is not known and the exposure of a fetus or nursing infant is considered a potential risk. Pediatric Patients Enzalutamide has not been evaluated in children and should not be used in children. Enzalutamide should be kept out of reach of children. 5.2.2.6 Overdose, Dependence, Rebound and Abuse The MTD of enzalutamide in S-3100-1-01 was determined to be 240 mg/day, although patients in this study received up to 600 mg/day for up to 12 weeks. Clinical experience with an overdose of enzalutamide is limited to single patient reports, the most notable of which was an accidental overdose of 640 mg/day for 8 days, which occurred in study CRPC2 and was associated with AEs of fatigue and asthenia. Based on data from the dose-escalation study S-3100-1-01, as well as nonclinical studies showing a dose-dependent risk of seizure in animals, patients may be at increased risk of seizure following an overdose of enzalutamide. Nonclinical and clinical evidence suggest that enzalutamide does not have the potential for drug abuse. Specific clinical studies to evaluate abuse potential have not been conducted. The complexity of synthetic pathway, poor solubility, inability to be administered parenterally and absence of large variation between Cmin and Cmax make it unlikely that enzalutamide has abuse potential. Additionally, in clinical studies, there were no signals suggestive of abuse such as increased incidence of AEs of euphoria, excessive use of study drug and refusal to return unused study drug after study termination. No specific studies have been conducted to evaluate for withdrawal or rebound phenomena associated with discontinuation of enzalutamide. In study MDV3100-03, the incidence of any AE with onset after the last dose of study drug and before the end of the treatment-emergent period was lower in the enzalutamide group compared with the placebo group (20.3% vs 31.0%); similar findings were noted in the combined controlled population, (25.5% vs 32.3%). Review of specific AEs occurring after the last dose of study drug and before the end of the safety reporting period did not reveal any safety findings suggestive of withdrawal or rebound effects in any study population. 5.2.2.7 Effects on Ability to Drive or Operate Machinery or Impairment of Mental Ability No studies on the effects on the ability to drive and use machines have been performed. However, there are some adverse effects (such as seizure, amnesia, fatigue, memory impairment, cognitive disorder and disturbance in attention) associated with this product that may affect some patients’ ability to drive or operate machinery.

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5.2.2.8 Safety Data From Individual Completed and Ongoing Studies The safety profile from individual studies was consistent with that of the combined controlled population and is presented in [Appendix 7]. Posterior Reversible Encephalopathy Syndrome One confirmed case of posterior reversible encephalopathy syndrome (PRES), assessed as unrelated to enzalutamide, was reported in S-3100-1-01. The onset of PRES symptoms occurred approximately 27 days after discontinuation of enzalutamide and approximately 19 days after initiating treatment with an investigational insulin-like growth factor (IGF) antibody (onset ~3 days after the second dose). PRES was likely associated with the investigational IGF antibody based on temporal relationship and positive dechallenge. 5.2.2.9 Safety Data From Postmarketing Experience The safety profile of enzalutamide from postmarketing experience is consistent with the safety profile in the integrated safety population. Rare cases of confirmed PRES have been identified from the global safety database (estimated cumulative postmarketing exposure of 184070 patient treatment years as of 30 Aug 2017). No events of PRES were identified or confirmed in phase 2 and phase 3 controlled studies. 5.2.3 Expected Serious Adverse Reactions (Reference Safety Information for Assessment of Expectedness of Serious Adverse Reactions) The data sources for determining expected serious adverse reactions (SARs) for the purpose of sponsor regulatory reporting included serious TEAEs reported from the following clinical studies involving 5464 unique patients: ● One randomized, placebo-controlled, phase 3 pivotal study in patients with nonmetastatic CRPC (MDV3100-14). ● Two randomized, placebo-controlled, phase 3 studies in chemotherapy-naïve patients with metastatic CRPC (MDV3100-03 and 9785-CL-0232). In study 9785-CL-0232, data from Site 105 was excluded due to data quality concerns. ● One randomized, placebo-controlled, phase 3 study in patients with metastatic CRPC previously treated with docetaxel-based chemotherapy (CRPC2). ● Two randomized, bicalutamide-controlled, phase 2 studies in patients with metastatic CRPC (9785-CL-0222) and with nonmetastatic or metastatic CRPC (MDV3100-09). Methodology for Determining Expected SARs To assess adverse reactions associated with enzalutamide treatment, the following methodology, as applicable, was applied to AE analyses in the combined controlled population and from postmarketing sources: ● All AEs observed with greater incidence in the enzalutamide treatment group compared with placebo were evaluated. To further characterize the AEs, seriousness, severity and action taken with study drug as a result of the event (discontinuation, interruption, dose reduction) were reviewed.

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● AEs were further reviewed in the context of mechanism of action, clinical pharmacology and toxicology data in accordance with the Council for International Organization of Medical Sciences Working Group criteria and Hill’s criteria [Hill, 1965], the latter including strength of association, consistency, specificity, temporality, biological gradient, plausibility, coherence, experimental evidence and analogy. ● To assess the effect of the longer duration of exposure in the enzalutamide treatment groups, time-adjusted AE rates per 100 patient-years and incidence of AEs within the first 90 days and 180 days of treatment were considered as appropriate. ● Additional data were also considered where appropriate, such as epidemiologic data, publications in the literature and postmarketing safety data. After applying the above methodology, the following serious TEAEs in Table 17 are considered expected SARs associated with enzalutamide treatment for the purpose of sponsor regulatory reporting. Table 17 SARs for Enzalutamide Considered Expected for Regulatory Reporting Purposes Number of Patients†,‡ (%) (n = 3179) System Organ Class Preferred Term Any SAR Life-threatening SAR Blood and lymphatic system disorders Neutropenia 1 (0.0%) NA Angina pectoris 8 (0.3%) 0 Coronary artery disease 10 (0.3%) 0 Myocardial infarction 13 (0.4%) 1 (0.0%) Acute myocardial infarction 17 (0.5%) 3 (0.1%) Cardiovascular disorders Acute coronary syndrome 9 (0.3%) 1 (0.0%) Angina unstable 2 (0.1%) 0 Myocardial ischaemia 3 (0.1%) 0 Arteriosclerosis coronary artery 2 (0.1%) 1 (0.0%) General disorders and administration site Asthenia 11 (0.3%) NA conditions Fatigue 11 (0.3%) NA Injury, poisoning and procedural Fracture 95 (3.0%) 2 (0.1%) complications Fall 19 (0.6%) 1 (0.0%) Convulsion 8 (0.3%) 0 Grand mal convulsion 2 (0.1%) 0 Partial Seizures 2 (0.1%) 0 Status epilepticus 2 (0.1%) 0 Nervous system disorders Complex partial seizures 1 (0.0%) 0 Cognitive disorder 1 (0.0%) NA Headache 3 (0.1%) NA Amnesia 1 (0.0%) NA Anxiety 1 (0.0%) NA Psychiatric disorders Hallucination 1 (0.0%) NA Hypertension 9 (0.3%) 1 (0.2%) Vascular disorders Accelerated hypertension 2 (0.1%) NA Footnotes appear on next page

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Data set: Patients who received at least 1 dose of enzalutamide (160 mg) in studies MDV3100-14, CRPC2, MDV3100-03, 9785-CL-0232, 9785-CL-0222 or MDV3100-09 Fatal events are not expected with enzalutamide treatment. †The number of patients who experienced the SAR. ‡ Number of patients (%) reflect the combined data for the number of doses of enzalutamide 160 mg NA: not applicable (event of this severity grade is considered unexpected); SAR: serious adverse reaction

Additional information on expected nonserious adverse reactions from clinical studies for enzalutamide is provided in Table 20 [Section 6.1.7]. The expected SARs that have been identified from the evaluation of postmarketing reports for enzalutamide and are considered expected for purposes of expedited reporting to regulatory authorities, investigators and ethics committees/review boards, as applicable, are listed in Table 18. Table 18 Postmarketing SARs for Enzalutamide Considered Expected for Regulatory Reporting Purposes System Organ Class Preferred Term† Tongue oedema Lip oedema Immune system disorders Pharyngeal oedema Face oedema Nervous system disorders Posterior reversible encephalopathy syndrome †ADR Frequency Category is Not known (Cannot be estimated from available data) SAR: serious adverse reaction

Postmarketing nonserious adverse reactions are presented in Table 19 [Section 5.3]. Additional information on potential risks, precautions and special monitoring required for investigational use of enzalutamide in clinical studies is provided in Section 6. 5.3 Marketing Experience Enzalutamide was first approved in the United States on 31 Aug 2012 for the treatment of patients with metastatic CRPC who have previously received docetaxel. XTANDI has subsequently been approved for the treatment of adult men with metastatic CRPC. To date, XTANDI has been approved in 94 countries. The cumulative exposure from postmarketing experience is estimated to be 184070 patient treatment years as of 30 Aug 2017. The expected nonserious adverse reactions that have been identified from the evaluation of postmarketing reports for enzalutamide and are considered expected for purposes of expedited reporting to regulatory authorities, investigators and ethics committees/review boards, as applicable, are listed in Table 19.

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Table 19 Postmarketing Nonserious Adverse Reactions for Enzalutamide Considered Expected for Regulatory Reporting Purposes System Organ Class Preferred Term† Nausea Gastrointestinal disorders Vomiting Diarrhoea Skin and subcutaneous tissue disorders Rash †ADR Frequency Category is Not known (Cannot be estimated from available data)

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White MC, Holman DM, Boehm JE, Peipins LA, Grossman M, Henley SJ. Age and cancer risk: a potentially modifiable relationship. AM J Prev Med. 2014;46:S7-15.

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6 SUMMARY OF DATA AND GUIDANCE FOR THE INVESTIGATOR 6.1 General (Including Indications and Usage) Enzalutamide (MDV3100) is an orally-available synthetic small molecule developed as a treatment for prostate cancer. Enzalutamide is presented in a soft gelatin capsule filled with a formulation containing 40 mg of the active pharmaceutical ingredient and a tablet formulation containing 80 mg and 40 mg of the active pharmaceutical ingredient. The approved therapeutic dose is 160 mg once daily. Indications Enzalutamide is an AR inhibitor indicated for the treatment of patients with metastatic CRPC who have previously received docetaxel, patients with metastatic CRPC and patients with nonmetastatic CPRC. Further development for nonprostate indications has been discontinued. The safety and tolerability of enzalutamide have been and continue to be evaluated in 43 clinical studies, an expanded access program and 2 compassionate use programs as of the data cutoff date for this IB (30 Aug 2017). More than 4800 male patients with prostate cancer and over 300 subjects with no known cancer including healthy male subjects and subjects with hepatic impairment have received at least 1 dose of enzalutamide in completed and ongoing clinical studies. In addition, over 400 female patients in 4 studies in breast cancer and over 100 patients with HCC have received enzalutamide in clinical studies. 6.1.1 Contraindications Enzalutamide is contraindicated in patients who have hypersensitivity to the active substance (enzalutamide) or to any of the excipients. Enzalutamide could cause fetal harm if administered to a pregnant woman based on its mechanism of action. Enzalutamide is contraindicated in women who are or may become pregnant. 6.1.2 Drug and Food Interactions Drugs that Inhibit CYP2C8 Coadministration of a strong CYP2C8 inhibitor (gemfibrozil) increased the composite AUC of enzalutamide plus N-desmethyl enzalutamide in healthy volunteers by 2.2-fold. Coadministration of enzalutamide with strong CYP2C8 inhibitors should be avoided if possible. If coadministration of enzalutamide with a strong CYP2C8 inhibitor cannot be avoided, the dose of enzalutamide should be reduced to 80 mg once daily. If coadministration of the strong inhibitor is discontinued, the enzalutamide dose should be returned to the dose used prior to initiation of the strong CYP2C8 inhibitor. Effect of Enzalutamide on Drug Metabolizing Enzymes Enzalutamide is a strong CYP3A4 inducer. Administration of enzalutamide after multiple oral doses of a strong CYP3A4 inhibitor (itraconazole) increased the AUC0-inf of

Jun 2018 Astellas/Medivation Page 119 of 126 Enzalutamide (MDV3100) CONFIDENTIAL Cancer Investigator’s Brochure Edition 10 enzalutamide plus N-desmethyl enzalutamide in healthy volunteers by 1.3-fold with no effect on Cmax. No dose adjustment is necessary when enzalutamide is coadministered with inhibitors of CYP3A4. In a DDI trial in healthy volunteers, a single 160 mg oral dose of enzalutamide administered after multiple oral doses of a moderate CYP2C8 and strong CYP3A4 inducer (rifampin) decreased the AUC0-inf of enzalutamide plus N-desmethyl enzalutamide in healthy volunteers by 37% with no effect on Cmax. No dose adjustment is necessary when enzalutamide is coadministered with inducers of CYP2C8 or CYP3A4. Enzalutamide is a moderate CYP2C9 and CYP2C19 inducer in humans. At steady state, enzalutamide reduced the plasma exposure to midazolam (CYP3A4 substrate), warfarin (CYP2C9 substrate) and omeprazole (CYP2C19 substrate). Concomitant administration of enzalutamide with narrow therapeutic index drugs that are metabolized by CYP3A4 (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus and tacrolimus), CYP2C9 (e.g., , warfarin) and CYP2C19 (e.g., S-mephenytoin) should be avoided, as enzalutamide may decrease their plasma exposure. If enzalutamide is coadministered with an anticoagulant metabolized by CYP2C9 (such as warfarin or acenocoumarol), additional INR monitoring should be conducted. Groups of medicinal products that can be affected include, but are not limited to: ● Analgesics (e.g., fentanyl, tramadol) ● Antibiotics (e.g., clarithromycin, doxycycline) ● Anticancer agents (e.g., cabazitaxel) ● Antiepileptics (e.g., , clonazepam, phenytoin, primidone, valproic acid) ● Antipsychotics (e.g., ) ● Antithrombotics (e.g., acenocoumarol, warfarin, clopidogrel) ● Betablockers (e.g., bisoprolol, propranolol) ● channel blockers (e.g., diltiazem, felodipine, , nifedipine, verapamil) ● Cardiac glycosides (e.g., digoxin) ● Corticosteroids (e.g., dexamethasone, prednisolone) ● Human immunodeficiency virus antivirals (e.g., indinavir, ritonavir) ● Hypnotics (e.g., , midazolam, ) ● Immunosuppressives (e.g., tacrolimus) ● Proton pump inhibitors (e.g., omeprazole) ● Statins metabolized by CYP3A4 (e.g., atorvastatin, simvastatin) ● Thyroid agents (e.g., levothyroxine) The full induction potential of enzalutamide may not occur until approximately 1 month after the start of treatment, when steady-state plasma concentrations of enzalutamide are reached, although some induction effects may be apparent earlier. Patients taking medicinal products that are substrates of CYP2B6, CYP3A4, CYP2C9, CYP2C19, UGT1A4 or UGT1A1 should be evaluated for possible loss of pharmacological effects (or increase in effects in cases where active metabolites are formed) during the first month of enzalutamide treatment and

Jun 2018 Astellas/Medivation Page 120 of 126 Enzalutamide (MDV3100) CONFIDENTIAL Cancer Investigator’s Brochure Edition 10 dose adjustment should be considered as appropriate. In consideration of the long half-life of enzalutamide (5.8 days), effects on enzymes may persist for 1 month or longer after stopping enzalutamide. A gradual dose reduction of the concomitant medicinal product may be necessary when stopping enzalutamide treatment.

Enzalutamide did not cause a clinically relevant change in the AUC or Cmax of a CYP1A2 substrate (caffeine) or CYP2C8 substrate (pioglitazone). The AUC0-inf of pioglitazone increased by 20% while Cmax decreased by 18%. The AUC0-inf of caffeine decreased by 11% while the Cmax of caffeine remained unchanged. No dose adjustment is indicated when a CYP1A2 or CYP2C8 substrate is coadministered with enzalutamide. Transporters In vitro data show that enzalutamide and N-desmethyl enzalutamide are potential inhibitors and inducers, but not substrates, of the efflux transporter P-gp. The effect of enzalutamide on P-gp substrates has not been evaluated in vivo; however, under conditions of clinical use, enzalutamide may alter the concentrations of coadministered products that are P-gp substrates. Medicinal products with a narrow therapeutic range that are substrates for P-gp (e.g., colchicine, dabigatran etexilate, digoxin) should be used with caution when administered concomitantly with enzalutamide and may require dose adjustment to maintain optimal plasma concentrations. Based on in vitro data, inhibition of BCRP and MRP2 (in the intestine), as well as OAT3 and OCT1 (systemically) cannot be excluded. Theoretically, induction of these transporters is also possible and the net effect is presently unknown. Effect of Food Food has no clinically significant effect on the extent of absorption. Enzalutamide may be taken with or without food. 6.1.3 Use in Special Populations Renal Impairment No dose adjustment is needed for patients with mild to moderate renal impairment. Clinical data are insufficient to assess the potential effect of severe renal impairment (CLCR < 30 mL/min) and end stage renal disease on enzalutamide pharmacokinetics. Hepatic Impairment No dose adjustment is necessary for patients with mild, moderate or severe hepatic impairment (Child-Pugh Class A, B and C, respectively). Elderly No dose adjustment is necessary in the elderly. Of the 2799 patients who received enzalutamide in 4 randomized phase 3 prostate cancer studies, 1193 (43%) patients were 65 to 74 years of age and 1028 (37%) patients were 75 years of age or older. No overall differences in safety or effectiveness were observed between these elderly patients and younger patients

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Pediatric Populations Enzalutamide has not been evaluated in children and should not be used in children. Enzalutamide should be kept out of reach of children. Gender The pharmacokinetics of single- and multiple-dose enzalutamide in women with breast cancer was found to be similar to the pharmacokinetics of enzalutamide in men with prostate cancer. Enzalutamide is not indicated for use in women. 6.1.4 Carcinogenesis, Mutagenesis, Teratogenicity and Impairment of Fertility In a 6-month study in Tg rasH2 mice, enzalutamide did not show carcinogenic potential (absence of neoplastic findings) at doses up to 20 mg/kg per day, which resulted in plasma exposure levels similar to the clinical exposure in metastatic CRPC patients receiving 160 mg daily. In a 104-week carcinogenicity study in WH rats, findings in male rats included increased incidence of Leydig cell tumor in the testis, benign thymoma in the thymus, urothelial papilloma/carcinoma in the urinary bladder, adenoma of pars distalis in the pituitary and fibroadenoma in the mammary gland. In female rats, adenoma of pars distalis in the pituitary and benign granulosa cell tumor in the ovary were noted. Tumors in the testis, mammary gland and ovary have also been reported in rats treated with other antiandrogens such as bicalutamide [Iswaran et al, 1997] or flutamide [Eulexin, 2000]. These tumors and the tumors in the thymus and pituitary in enzalutamide-treated rats are considered related to the pharmacological properties of an antiandrogen drug. Therefore, the impact on the overall risk and benefit balance for patients with advanced cancer is unknown. Tumors in the urinary bladder of rats are thought to be induced by urinary crystals or calculi consisting of the excreted carboxylic acid metabolite of enzalutamide. Because urinary crystals or calculi are not expected in humans taking enzalutamide 160 mg daily, tumors in the urinary bladder are considered not relevant to humans. Enzalutamide did not induce mutations in the bacterial reverse mutation (Ames) assay, was nonmutagenic, nonclastogenic in mammalian cells and nongenotoxic in vivo in mice. Enzalutamide did not induce phototoxicity in cultured mammalian cells. Enzalutamide could cause fetal harm when administered to a pregnant woman based on its mechanism of action and embryo-fetal toxicity observed in mice. Based on nonclinical findings in repeat-dose toxicology studies, which were consistent with the pharmacological activity of enzalutamide, male fertility may be impaired by treatment with enzalutamide. In studies in mice (4 weeks), rats (4 and 26 weeks) and dogs (4, 13 and 39 weeks), changes in the reproductive organs associated with enzalutamide were decreases in organ weight with atrophy of the prostate and epididymis. In a pharmacokinetic study in pregnant rats with a single oral 30 mg/kg enzalutamide administration on gestation day 14, enzalutamide and/or its metabolites were present in the fetus at a Cmax that was approximately 0.3 times the concentration found in maternal plasma and occurred 4 hours after administration.

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6.1.5 Use During Pregnancy and Lactation Pregnancy Enzalutamide is contraindicated for use in pregnant women because the drug can cause fetal harm and potential loss of pregnancy. Enzalutamide is not indicated for use in females. There are no human data on the use of enzalutamide in pregnant women. In animal reproduction studies, oral administration of enzalutamide in pregnant mice during organogenesis caused adverse developmental effects at doses lower than the maximum recommended human dose. Breastfeeding Enzalutamide is not indicated for use in females. There is no information available on the presence of enzalutamide in human milk, the effects of the drug on the breastfed infant or the effects of the drug on milk production. Enzalutamide and/or its metabolites were present in milk of lactating rats. Fertility Based on findings in animal reproduction studies, advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 3 months after the final dose of enzalutamide. Infertility Based on animal studies, enzalutamide may impair fertility in males of reproductive potential. 6.1.6 Warning and Precautions Seizure Use of enzalutamide has been associated with seizure. Permanently discontinue enzalutamide in patients who develop a seizure during treatment. PRES There have been rare reports of PRES in patients receiving enzalutamide. PRES is a rare, reversible, neurological disorder which can present with rapidly evolving symptoms including seizure, headache, confusion, blindness and other visual and neurological disturbances, with or without associated hypertension. A diagnosis of PRES requires confirmation by brain imaging, preferably magnetic resonance imaging. Discontinuation of enzalutamide in patients who develop PRES is recommended. Patients should be informed to contact the study physician as soon as possible if they experience rapidly worsening symptoms possibly indicative of PRES such as seizure, headache, confusion, reduced eyesight or blurred vision. 6.1.6.1 Overdose There is no antidote for enzalutamide. In the event of an overdose, treatment with enzalutamide should be stopped and general supportive measures initiated taking into

Jun 2018 Astellas/Medivation Page 123 of 126 Enzalutamide (MDV3100) CONFIDENTIAL Cancer Investigator’s Brochure Edition 10 consideration depending on the amount of overdose and the half-life of 5.8 days. Patients may be at increased risk of seizures following an overdose. Further information about overdosing of enzalutamide is provided in Section 5.2.2.6. 6.1.6.2 Hypersensitivity Hypersensitivity reactions manifested by symptoms including, but not limited to, face edema, tongue edema, lip edema, pharyngeal edema and rash have been observed with enzalutamide. Advise patients who experience any symptoms of hypersensitivity to discontinue enzalutamide and promptly seek medical care. Enzalutamide should not be administered to any patient who has shown a hypersensitivity reaction to the active pharmaceutical ingredient or any of the capsule components, including Labrasol, butylated hydroxyanisole and butylated hydroxytoluene [Section 3.2]. 6.1.6.3 Ischemic Heart Disease Management of cardiovascular risk factors, such as hypertension, diabetes, hyperlipidemia or dyslipidemia, should be optimized. For grade ≥ 3 events of ischemic heart disease, treatment with enzalutamide should be stopped. 6.1.6.4 Potential AEs Based on Those Reported for Drugs With Similar Pharmacological Activity Enzalutamide has to date been primarily studied in patients who are taking a gonadotropin-releasing hormone analogue or who have undergone surgical castration. As enzalutamide is evaluated in healthy subjects and in patients with prostate cancer who have not been exposed to prior hormonal treatment, a number of such common adverse effects resulting from androgen deficiency are to be expected. These side effects include fatigue and loss of energy, loss of libido, decreased erectile function, infertility, hot flushes, loss of bone mass, weight gain with loss of muscle mass and anemia. Gynecomastia is also a potential that may occur if testosterone levels rise, leading to increased aromatization to estrogen [CASODEX®, 2015; Flutamide, 2008; NILANDRON®, 2014]. Though rare, malignant breast neoplasms have been reported in male patients treated with flutamide [Eulexin, 2000]. Investigators should monitor patients who are not castrate prior to receiving enzalutamide for these potential side effects and should treat them symptomatically as appropriate. 6.1.6.5 Potential AEs Based on the Results of Toxicology Studies in Animals Hepatocellular hypertrophy associated with metabolic enzyme induction in rats is commonly accepted to be an adaptive change and considered not adverse. It is considered a rodent specific change that does not suggest a risk of hepatocellular toxicity for humans. Seizure has been observed in nonclinical models and in patients with CRPC in clinical studies of enzalutamide. Based on the observance of malignancies in a 104-week carcinogenicity study in WH rats (but not in a 26-week carcinogenicity study in Tg rasH2 mice), it may be appropriate to monitor clinically for development of second primary malignancies.

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6.1.7 Expected Nonserious Adverse Reactions From Clinical Studies The nonserious adverse reactions observed in clinical studies that are considered expected are summarized in Table 20. Table 20 Nonserious Adverse Reactions for Enzalutamide Considered Expected for Regulatory Reporting Purposes Number of Patients†,‡ (%) (n = 3179) All Nonserious Adverse System Organ Class Nonserious Adverse Reaction Reactions Blood and lymphatic system disorders Neutropenia 25 (0.8%) Angina pectoris 18 (0.6%) Coronary artery disease 11 (0.3%) Myocardial infarction 1 (0.0%) Acute coronary syndrome 1 (0.0%) Cardiovascular disorders Myocardial ischaemia 3 (0.1%) Arteriosclerosis coronary artery 1 (0.0%) Coronary artery insufficiency 1 (0.0%) Coronary artery stenosis 1 (0.0%) Ischaemic cardiomyopathy 1 (0.0%) Ear and labyrinth disorders Vertigo 71 (2.2%) General disorders and administration site Fatigue 1028 (32.2%) conditions Asthenia 367 (11.5%) Injury, poisoning and procedural Fall 276 (8.7%) complications Fracture 233 (7.2%) Neutrophil count decreased 12 (0.4%) Investigations Blood pressure increased 16 (0.5%) Memory impairment 56 (1.8%) Amnesia 43 (1.4%) Disturbance in attention 34 (1.1%) Nervous system disorders Cognitive disorder 23 (0.7%) Headache 307 (9.7%) Restless legs syndrome 54 (1.7%) Anxiety 127 (4.0%) Psychiatric disorders Hallucination 7 (0.2%) Reproductive system and breast disorders Gynaecomastia 87 (2.7%) Respiratory,thoracic and mediastinal Epistaxis 78 (2.5%) disorders Dry skin 72 (2.3%) Skin and subcutaneous tissue disorders Pruritus 86 (2.7%) Hot flush 502 (15.8%) Hypertension 343 (10.8%) Vascular disorders Blood pressure inadequately controlled 1 (0.0%) Essential hypertension 1 (0.0%) Systolic hypertension 1 (0.0%) Footnotes appear on next page

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Data set: Patients who received at least 1 dose of enzalutamide (160 mg) in studies MDV3100-14, CRPC2, MDV3100-03, 9785-CL-0232, 9785-CL-0222 or MDV3100-09 † The number of patients who have experienced the nonserious adverse reaction. ‡ Number of patients (%) reflects the combined data for the number of doses of enzalutamide 160 mg

List of References CASODEX® (United States Package insert).Wilmington, DE; AstraZeneca Pharmaceuticals LP, February 2015. Eulexin (United States Package insert). Kenilworth, NJ; Schering Corporation, Dec 2000. Iswaran TJ, Imai M, Betton GR, Siddall RA. An overview of animal toxicology studies with bicalutamide (ICI 176,334). J Toxicol Sci. 1997;22:75-88. Flutamide (United States package insert). Genpharm ULC; May 2008. NILANDRON® (United States package insert). Cary, NC, Covis Pharmaceuticals Inc; June 2014.

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7 APPENDIX INDIVIDUAL STUDY SUMMARIES

Table of Contents 7 APPENDIX INDIVIDUAL STUDY SUMMARIES ········································· 1 7.1 Phase 1 Studies in Healthy Volunteers and Special Populations ························· 3 7.1.1 9785-CL-0001 ············································································ 3 7.1.2 MDV3100-05 ············································································· 4 7.1.3 9785-CL-0006 ············································································ 5 7.1.4 9785-CL-0009 ············································································ 6 7.1.5 9785-CL-0010 ············································································ 7 7.1.6 9785-CL-0404 ············································································ 8 7.1.7 9785-CL-0405 ············································································ 9 7.1.8 MDV3100-19 ············································································10 7.1.9 9785-CL-0014 ···········································································11 7.2 Phase 1 Studies in Prostate Cancer Patients ···············································12 7.2.1 S-3100-1-01 ··············································································12 7.2.2 9785-CL-0007 ···········································································14 7.2.3 9785-CL-0003 ···········································································15 7.2.4 9785-CL-0111 ···········································································16 7.2.5 9785-CL-0406 ···········································································18 7.2.6 MDV3100-06 ············································································19 7.3 Phase 2 Studies in Prostate Cancer Patients ···············································21 7.3.1 CRPC-MDA-1 ···········································································21 7.3.2 9785-CL-0011 ···········································································23 7.3.3 9785-CL-0121 ···········································································25 7.3.4 9785-CL-0321 ···········································································26 7.3.5 MDV3100-07 ············································································28 7.3.6 9785-CL-0222 (TERRAIN)····························································30 7.3.7 MDV3100-09 (STRIVE) ·······························································32 7.3.8 9785-CL-0122 ···········································································34 7.3.9 9785-CL-0123 ···········································································35 7.3.10 MDV3100-18 ············································································36 7.3.11 9785-MA-1010 (ENACT)······························································37 7.4 Phase 3 Studies in Prostate Cancer Patients ···············································38

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7.4.1 MDV3100-03 (PREVAIL) ·····························································38 7.4.2 CRPC2 (AFFIRM) ······································································41 7.4.3 MDV3100-13 (EMBARK)·····························································43 7.4.4 MDV3100-14 (PROSPER)·····························································44 7.4.5 9785-CL-0232 (Asian PREVAIL) ····················································46 7.4.6 9785-CL-0335 (ARCHES) ·····························································48 7.4.7 9785-MA-1001 ··········································································49 7.5 Phase 4 Studies in Prostate Cancer Patients ···············································50 7.5.1 MDV3100-10 (PLATO)································································50 7.5.2 9785-CL-0403 (UPWARD)····························································53 7.5.3 9785-CL-0410 ···········································································54 7.5.4 9785-MA-1008 ··········································································56 7.5.5 9785-MA-3051 ··········································································58 7.6 Compassionate Use and Expanded Access Programs in Prostate Cancer Patients ····59 7.6.1 9785-CL-0401 ···········································································59 7.6.2 Named Patient Program ································································60 7.6.3 9785-CL-0402 (Cohort Authorisation Temporaire d’Utilisation) ·················60 7.7 Phase 1 Studies in Breast Cancer Patients ·················································61 7.7.1 MDV3100-08 ············································································61 7.8 Phase 2 Studies in Breast Cancer Patients ·················································64 7.8.1 MDV3100-11 ············································································64 7.8.2 MDV3100-12 ············································································66 7.8.3 9785-CL-1121 ···········································································68 7.9 Phase 2 Studies in Hepatocellular Carcinoma ·············································70 7.9.1 9785-CL-3021 ···········································································70

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7.1 Phase 1 Studies in Healthy Volunteers and Special Populations 7.1.1 9785-CL-0001 Study title A Phase I Open-label Study to Investigate the Mass Balance and Biotransformation of a Single Oral 160 mg (100 µCi) Dose of 14C-MDV3100 (ASP9785) in Healthy Male Subjects Clinical Status Completed Study design Open-label, single dose study Indication Healthy volunteers Key eligibility criteria  Healthy male subjects aged 18-55 years, inclusive  BMI ≥18.5 and ≤ 30.0 kg/m2 Enrollment (planned) 6 Healthy male subjects Primary objective To evaluate the pharmacokinetics, metabolism and excretion of enzalutamide in plasma, urine and feces after a single oral 160 mg (100 µCi) dose of 14C-enzalutamide. Secondary objective To evaluate safety and tolerability of a single oral 160 mg (100 µCi) dose of 14C-enzalutamide. Drug administration Enzalutamide and 14C-enzalutamide Dose 160 mg enzalutamide combined with a tracer dose of 100 µCi 14C-enzalutamide Enrolled/treated 6 enrolled/6 treated Demographics Of the 6 subjects who received study medication, 5 were self-identified as white and 1 was self-identified as mixed (white and black). With a mean of 26.5 years, the age of the subjects included was generally in the lower part of the range allowed (18-55 years). The mean BMI of 23.32 kg/m2 was in the middle of the range allowed (≥ 18.5 and ≤ 30.0 kg/m2). Pharmacokinetics Following oral administration of 14C-enzalutamide, 84.6% of the dose was recovered through day 77 postdose: 71.0% was recovered in urine (primarily as the carboxylic acid metabolite, with trace amounts of enzalutamide and N-desmethyl enzalutamide) and 13.6% was recovered in feces (0.39% as enzalutamide; 9785-ME-0019). Based on this information, renal excretion is a minor elimination pathway for unchanged parent enzalutamide and N-desmethyl enzalutamide. Safety A total of 11 TEAEs (eye irritation, abdominal pain, diarrhea, hunger, injection site irritation, myalgia, pain in extremity, headache (2 events), dry skin and skin depigmentation) were reported by 4 subjects (67%). All TEAEs were of mild severity and transient and 10 of the 11 TEAEs were resolved without sequelae. Subject 1004 had a TEAE (skin depigmentation) that was still resolving at the ESV. Two TEAEs (headache reported at approximately 2 hours postdose by Subject 1004 and myalgia reported at approximately 9 hours postdose by Subject 1006) were considered by the investigator to be possibly related to study medication, whereas the other 9 events were considered by the investigator not to be related. Data cutoff date 20 Feb 2012 (Final CSR) BMI: body mass index; CSR: clinical study report; ESV: end-of-study visit; TEAE: treatment-emergent adverse event

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7.1.2 MDV3100-05 Study title A Phase 1, Single-center, Open-label, Randomized, Two-period Pilot Bioequivalence and Food-Effects Study of Two Formulations of MDV3100 Following a Single 160 mg Dose in Healthy Male Subjects Clinical Status Completed Study design Phase 1, open-label, randomized, 2 period, bioequivalence and food effects Indication Healthy volunteers Key eligibility criteria Healthy male volunteers age 18 to 55 years had to provide written informed consent, weigh greater than 50 kg with a BMI of 18 to 30 kg/m2 and agree to use a condom and additional method of birth control during the study and ≥ 3 months after discharge. Enrollment (planned) Approximately 60 subjects Objectives Bioequivalence of 2 oral formulations of enzalutamide under fasted and fed conditions; food effects on rate/extent of absorption; safety and tolerability Drug administration Enzalutamide Dose Liquid-filled soft gelatin capsules, 160 mg (four 40 mg capsules) as a single oral dose or Tablet containing enzalutamide as a solid tablet, 160 mg (1 tablet) as a single oral dose Enrolled/treated 60 enrolled/60 treated Demographics Mean age 29.3 years (range, 19-55 years); 80% white, 18.3% black or African American; 30% Hispanic or Latino; mean weight 78.94 kg (range, 56.6-104.9 kg); mean BMI 25.38 (range, 19.5-29.9) Pharmacokinetics Food effects (capsule): Total exposure met the acceptance criteria for bioequivalence, while peak exposure did not. Cmax was 30% lower and occurred 1 hour later under fed conditions compared with fasted conditions; however, the extent of absorption (AUC) was similar. The observed food effect on the rate of absorption was not clinically significant and therefore it is recommended that enzalutamide liquid-filled, soft gelatin capsules may be taken with or without food. Pharmacokinetic data for the tablet are not presented, as this formulation is not available. Safety Of 60 subjects, 17 (28.3%) experienced at least 1 AE during the study. The incidence of AEs was similar between subjects receiving capsule and tablet formulations. The overall incidence of AEs was slightly higher under fasted conditions (16.7%) compared with fed conditions (11.7%). The most common AEs were headache (7 [11.7%] subjects) and diarrhea, oropharyngeal pain and skin laceration (2 [3.3] subjects each). Investigators assessed most events as unrelated or unlikely related to enzalutamide. Headache (2 subjects) and cold sweat, somnolence and flatulence (1 subject each) were assessed as at least possibly related to enzalutamide. All AEs were grade 1, except 1 subject experienced a grade 3 event of increased blood creatine phosphokinase more than 8 weeks after the single dose of study drug that was considered unlikely related to treatment; the abnormal value was not associated with clinical symptoms. No deaths, SAEs or AEs leading to study discontinuation occurred during the study. No clinically significant trends were noted in laboratory evaluations, vital signs or electrocardiograms. Single oral doses of enzalutamide, supplied as four 40 mg liquid-filled capsules or as a single 160 mg tablet, were generally well tolerated in healthy male volunteers under fed and fasted conditions. Data cutoff date 22 Nov 2010 (Final CSR) AE: adverse event; BMI: body mass index; CSR: clinical study report; SAE: serious adverse event

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7.1.3 9785-CL-0006 Study title A Phase I Randomized, Open-label, 3-arm Parallel-design Study to Determine the Effect of Multiple-dose Gemfibrozil or Itraconazole on the Pharmacokinetics, Safety and Tolerability of Single-dose MDV3100 (ASP9785) in Healthy Male Subjects Clinical Status Completed Study design Open-label, 3-arm, randomized, parallel DDI study Indication Healthy volunteers Key eligibility criteria Subjects who were eligible to participate in this study were healthy white males aged 18 to 55 years (inclusive) with a body weight between 65.0 and 85.0 kg and a BMI between 18.5 and 30.0 kg/m2. Subjects with a CYP2C8 poor metabolizer genotype were excluded. Enrollment (Planned) 42 Healthy male subjects Primary objective  To investigate the effect of multiple oral doses of 600 mg gemfibrozil twice daily on the pharmacokinetics of a single oral dose of 160 mg enzalutamide.  To investigate the effect of multiple oral doses of 200 mg itraconazole once daily on the pharmacokinetics of a single oral dose of 160 mg enzalutamide. Secondary objective  To evaluate the safety and tolerability of a single oral dose of 160 mg enzalutamide in the presence of multiple oral doses of 600 mg gemfibrozil twice daily.  To investigate the effect of multiple oral doses of 600 mg gemfibrozil twice daily on the pharmacokinetics of enzalutamide metabolites M1 and M2.  To evaluate the safety and tolerability of a single oral dose of 160 mg enzalutamide in the presence of multiple oral doses of 200 mg itraconazole once daily.  To investigate the effect of multiple oral doses of 200 mg itraconazole once daily on the pharmacokinetics of enzalutamide metabolites M1 and M2. Drug administration Enzalutamide Dose  Arm 1: Subjects received a single oral dose of 160 mg enzalutamide on day 1.  Arm 2: Subjects received 600 mg gemfibrozil (CYP2C8 inhibitor) twice daily on day 1 through day 21. On day 4, subjects received a single oral dose of 160 mg enzalutamide with the morning dose of gemfibrozil.  Arm 3: Subjects received 200 mg itraconazole (CYP3A4 inhibitor) once daily from day 1 through day 21. On day 4, subjects received a single oral dose of 160 mg enzalutamide. Enrolled/treated 41 enrolled/41 treated (Arm 1: 13; Arm 2: 14; Arm 3: 14) Demographics All of the participants in this study were white males and most (95.1%) were not Hispanic or Latino. The mean age was 33.4 years and was similar among the 3 treatment arms. BMI was similar across the 3 treatment arms. All subjects were negative for markers of HIV-1/2, hepatitis B and hepatitis C at the time of enrollment based on serology tests performed during the study screening process Pharmacokinetics Coadministration of gemfibrozil (strong CYP2C8 inhibitor) increased the composite AUC of enzalutamide plus N-desmethyl enzalutamide by 2.2-fold. Coadministration of itraconazole (strong CYP3A4 inhibitor) increased the composite AUC of enzalutamide plus N-desmethyl enzalutamide by 1.3-fold. Safety During the study, 13 subjects (3 in Arm 1, 6 in Arm 2 and 4 in Arm 3) experienced at least 1 TEAE. All events were categorized as NCI-CTCAE grade 1, with the exception of grade 2 flatulence in Subject 1062 (Arm 2) that began before study drug dosing of enzalutamide and gemfibrozil on day 4. This event resolved on day 24 and was attributed to a possible relationship to gemfibrozil by the investigator. Four additional subjects experienced at least 1 TEAE that was attributed a possible relationship to the study drug by the investigator. All TEAEs recovered by the end of the study. No deaths, SAEs or AEs resulting in discontinuation occurred during the study. Data cutoff date 02 Jun 2012 (Final CSR) AE: adverse event; BMI: body mass index; CSR: clinical study report; CYP: cytochrome P450; DDI: drug-drug interaction; HIV: human immunodeficiency virus; M1: MDPC0001; M2: MDPC0002 (N-desmethyl enzalutamide); NCI-CTCAE: National Cancer Institute-Common Terminology Criteria for Adverse Events; SAE: serious adverse event; TEAE: treatment-emergent adverse event

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7.1.4 9785-CL-0009 Study title A Phase I, Non-randomized, Open-label, Single-dose Study to Investigate the Pharmacokinetics, Safety and Tolerability of MDV3100 in Male Subjects with Mild or Moderate Hepatic Impairment and Normal Hepatic Function Clinical Status Completed Study design Open-label, nonrandomized, single oral dose, parallel group, 2-arm study Indication Normal, mild and moderate hepatically impaired subjects Key eligibility criteria Male subjects between 18 and 69 years of age, inclusive, with a BMI of at least 18.5 kg/m2 and no greater than 34.0 kg/m2. Eight subjects with mild hepatic impairment (Child-Pugh Classification A) comprised Arm A1 and 8 control subjects matched for age (± 5 years) and BMI (± 15%) with normal hepatic function comprised Arm A2; 8 subjects with moderate hepatic impairment (Child-Pugh Classification B) comprised Arm B1 and 8 control subjects matched for age (± 5 years) and BMI (± 15%) with normal hepatic function comprised Arm B2. Enrollment (Planned) 32; 16 subjects per treatment arm (8 subjects with impaired hepatic function and 8 matched control subjects in each Arm A and Arm B) Primary objective To compare the single-dose pharmacokinetics of enzalutamide in subjects with mild and moderate hepatic impairment to matched control subjects with normal hepatic function Secondary objective  To assess the safety and tolerability of single-dose enzalutamide in subjects with mild and moderate hepatic impairment and matched control subjects  To compare the pharmacokinetics of enzalutamide metabolites, M1 and M2 in subjects with mild and moderate hepatic impairment to matched control subjects Drug administration Enzalutamide Dose Treatment consisted of a single dose of 160 mg enzalutamide on day 1 under fasted conditions (no caloric intake for at least 10 h before and 4 h after enzalutamide administration or fluid intake from 4 h predose through 2 h postdose). Enrolled/treated 33 enrolled/33 treated Mild hepatic impairment: n = 8; matched controls n = 8 Moderate hepatic impairment: n = 8; matched controls n = 9 Demographics All of the participants in this study were white males and none were Hispanic or Latino. The mean age was approximately 42 years in Arms A1 and A2 and approximately 51 years in Arms B1 and B2. The mean BMI was 27.09 kg/m2 to 28.48 kg/m2 across the 4 arms; the mean BMI was lowest in Arm A2. Subjects in Arms A1 and B1 had hepatic impairment; all of the matching healthy normal control subjects in Arms A2 and B2 had no findings on medical history. Pharmacokinetics Following a single oral 160 mg dose of enzalutamide, the AUC for the composite sum of enzalutamide plus N-desmethyl enzalutamide increased by 13% and 18% in subjects with mild and moderate hepatic impairment, respectively, relative to healthy control subjects. Overall, the results indicate that no starting dose adjustment is necessary for patients with baseline mild or moderate hepatic impairment. Safety A single oral dose of enzalutamide (160 mg) was generally safe and well-tolerated in subjects with mild to moderate hepatic impairment and in their matching normal healthy control subjects. One healthy control subject with elevated BP at baseline experienced an SAE of “hypertensive crisis” approximately 6.5 h after a single dose of enzalutamide that recovered with antihypertensive treatment within 1.5 h and was considered related to enzalutamide. Data cutoff date 03 Jun 2012 (Final CSR) BMI: body mass index; BP: blood pressure; CSR: clinical study report; M1: MDPC0001; M2: MDPC0002 (N-desmethyl enzalutamide); SAE: serious adverse event

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7.1.5 9785-CL-0010 Study title A Phase I, Single-center, Open-label, Randomized, Parallel, Relative Bioavailability Study Comparing a Capsule and Tablet Formulations of Enzalutamide Following a Single 160 mg Dose Under Fasted Conditions in Healthy Male Subjects Clinical Status Completed Study design Open-label, randomized, parallel group study Indication Healthy volunteers Key eligibility criteria Healthy male subjects aged 18 to 55 years, inclusive, with a BMI range of 18.5 to 29.9 kg/m2; subjects who were confirmed to have a poor metabolizer status for CYP2C8 (i.e., subjects with the CYP2C8*3 allele) based on genotyping analysis were excluded. Enrollment (Planned) 54 Planned Primary objective To evaluate the relative bioavailability of capsule and tablet formulations of enzalutamide following a single 160 mg dose of enzalutamide under fasted conditions in healthy male volunteers. Secondary objective To evaluate the safety and tolerability of capsule and tablet formulations of enzalutamide in healthy male subjects under fasted conditions. Drug administration Enzalutamide Dose Treatment A: A single oral dose of 160 mg enzalutamide liquid-filled capsule formulation (4 capsules of 40 mg each) Treatment B: A single oral dose of 160 mg enzalutamide tablet formulation, Tablet B (2 tablets of 80 mg each) Treatment C: A single oral dose of 160 mg enzalutamide tablet formulation, Tablet C (2 tablets of 80 mg each) Enrolled/treated 55 enrolled/55 treated (Treatment A: 19; Treatment B: 18; Treatment C: 18) Demographics Across all treatment groups, the mean age was 33.8 years in the Treatment A group, 41.1 years in Treatment B group and 43.2 years in the Treatment C group. The mean body weight was 76.0 kg in the Treatment A group, 83.2 kg in Treatment B group and 80.4 kg in the Treatment C group. The mean BMI was 23.6 kg/m2 in the Treatment A group, 26.0 kg/m2 in Tablet B group and 24.8 kg/m2 in the Treatment C group. Pharmacokinetics The pharmacokinetics of the capsule formulation were consistent with previous studies. Bioavailability comparisons between the tablets and capsule were successfully completed. Safety Across all treatment groups, a total of 31 of 55 subjects reported 50 TEAEs; 12 of 19 (63.2%) subjects treated with capsules reported 21 TEAEs, 11 of 18 (61.1%) subjects treated with Tablet B reported 16 TEAEs and 8 of 18 (44.4%) subjects treated with Tablet C reported 13 TEAEs. The SOCs with the most reported TEAEs across all treatment groups were Infections and Infestations, followed by Gastrointestinal Disorders, Nervous System Disorders and Musculoskeletal and Connective Tissue Disorders. Nine (9) TEAEs, reported by 7 of 19 (36.8%) subjects treated by capsules, 7 TEAEs, reported by 4 of 18 (22.2%) subjects treated with Tablet B and 4 TEAEs, reported by 2 of 18 (11.1%) subjects treated with Tablet C, were considered by the investigator to be possibly related to the study drug. Overall, regardless of the causality relationship to the study drug, nasopharyngitis was the most frequently reported TEAE in all 3 treatment groups. No SAEs, deaths or TEAEs leading to clinical study discontinuation or grade 3 or higher TEAEs occurred during the clinical study. Data cutoff date 12 Dec 2013 (Final CSR) BMI: body mass index; CSR: clinical study report; CYP: cytochrome P450; SAE: serious adverse event; TEAE: treatment-emergent adverse event

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7.1.6 9785-CL-0404 Study title A Phase 1, Non-randomized, Open-label, Single-dose Study to Investigate the Pharmacokinetics, Safety and Tolerability of Enzalutamide in Male Subjects with Severe Hepatic Impairment and Normal Hepatic Function Clinical Status Completed Study design Open-label study Indication Normal and severely hepatic impaired subjects Key eligibility criteria Subject is a male aged 18 to 69 years of age inclusive with a BMI range of 18.5 to 34.0 kg/m2 inclusive. For patients with severe hepatic impairment, subjects were required to have a Child-Pugh classification Class C (severe, 10 to 15 points). Enrollment (Planned) 16 (8 severe hepatic impaired subjects and 8 healthy control subjects) Primary objective To compare the pharmacokinetics of enzalutamide and enzalutamide plus N-desmethyl enzalutamide (M2) in subjects with severe hepatic impairment vs matched healthy control subjects with normal hepatic function after a single oral dose of 160 mg enzalutamide. Secondary objective  To evaluate the safety and tolerability of single-dose enzalutamide in subjects with severe hepatic impairment and matched healthy control subjects.  To compare the pharmacokinetics of a major inactive carboxylic acid metabolite (M1) and M2 in subjects with severe hepatic impairment to matched healthy control subjects. Drug administration Enzalutamide Dose 160 mg (4 x 40 mg capsules) Enrolled/treated 16 enrolled/16 treated Demographics All 16 subjects were white. Among the 8 severe hepatic impairment and the 8 healthy control subjects with normal hepatic function, respectively, the mean age was 54.6 and 54.6 years, mean body weight was 81.3 and 80.5 kg, mean height was 173.4 and 171.8 cm and mean BMI was 27.06 and 27.23 kg/m2. Pharmacokinetics In subjects with severe hepatic impairment, the geometric mean exposure parameters (AUC0-inf, Cmax, AUC0-inf,u and Cmax,u) for enzalutamide, M1, M2 and the sum of enzalutamide plus M2 were no more than 1.35-fold higher than in healthy control subjects. Severe hepatic impairment was associated with a 2.2-fold longer mean t1/2 (249 h [10.4 days] vs 112 hours [4.7 days], respectively). Safety No TEAEs, deaths or treatment-emergent SAEs occurred in this study. Data cutoff date 03 Nov 2014 (Final CSR) BMI: body mass index; CSR: clinical study report; M1: MDPC0001; M2: MDPC0002 (N-desmethyl enzalutamide) ; SAE: serious adverse event; TEAE: treatment-emergent adverse event

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7.1.7 9785-CL-0405 Study title A Phase I, Randomized, Open-label, 2-arm Parallel-design Study to Determine the Effect of Multiple-dose Rifampin on the Pharmacokinetics, Safety and Tolerability of Single-dose Enzalutamide in Healthy Male Subjects Clinical Status Completed Study design Randomized, open-label, 2-arm, parallel-design DDI study Indication Healthy volunteers Key eligibility criteria Healthy male subjects aged 18 to 55 years, inclusive, with a BMI range ≥ 18.5 and ≤ 29.9 kg/m2 Enrollment (Planned) 28 Subjects (14 per arm) Primary objective To evaluate the effect of multiple oral doses of 600 mg rifampin (once daily) on the pharmacokinetics of enzalutamide and enzalutamide plus M2 after a single oral dose of 160 mg enzalutamide. Secondary objectives  To evaluate the safety and tolerability of a single oral dose of enzalutamide, alone or in the presence of multiple oral doses of 600 mg rifampin (once daily).  To investigate the effect of multiple oral doses of 600 mg rifampin (once daily) on the pharmacokinetics of N-desmethyl enzalutamide and the inactive carboxylic acid metabolite. Drug administration Enzalutamide, rifampin Dose Treatment arm 1: Single oral dose of 160 mg enzalutamide, administered under fasted conditions on day 1. Treatment arm 2: Each subject received once daily 600 mg rifampin on days 1 to 21. On day 8, a single oral dose of 160 mg enzalutamide was coadministered with rifampin. Enrolled/treated 28 enrolled/28 treated (14 per treatment group) Demographics A total of 28 healthy male subjects (28 [100.0%] subjects were white) were randomized in this clinical study. Subjects had a mean age of 42.2 years, a mean weight of 83.28 kg, a mean height of 179.4 cm and a mean BMI of 25.89 kg/m2. The distribution across treatment arms was similar. Pharmacokinetics Coadministration of multiple oral doses of 600 mg rifampin once daily had the following effects on the pharmacokinetics of a single oral dose of 160 mg enzalutamide:

 Decreased enzalutamide AUCinf by 66% (GMR: 33.76; 90% CI: 30.31 - 37.60), while Cmax remained unchanged (GMR: 93.03; 90% CI: 83.67 - 103.45);  Decreased sum of enzalutamide plus M2 AUCinf by 37% (GMR 63.26; 90%CI: 58.17 – 68.79), while Cmax remained unchanged (GMR: 94.32; 90% CI: 85.05 – 104.60);  Decreased M2 AUCinf by 15% (GMR: 84.74; 90% CI: 77.13 – 93.11), while Cmax was increased by 34% (GMR: 133.7; 90% CI: 118.63 – 150.76);

 Decreased M1 AUCinf by 32% (GMR 67.53; 90% CI 44.56 – 102.33), while Cmax appeared to be similar (GMR: 96.56; 90% CI: 77.68 – 120.02). Safety There were no deaths, SAEs or AEs leading to discontinuation of the clinical study during the conduct of the clinical study. Overall, 45 TEAEs were reported for 21 (75.0%) subjects (13 TEAEs reported for 7 [50.0%] subjects who received enzalutamide and 32 TEAEs reported for 14 [100.0%] subjects who received enzalutamide + rifampin). The most commonly reported TEAE was in the SOC Renal and Urinary Disorders and included 14 TEAEs of chromaturia reported for all the subjects (100.0%) in the enzalutamide + rifampin treatment arm but none in the enzalutamide treatment arm. The second most commonly reported TEAE was in the SOC Gastrointestinal Disorders and included 3 TEAEs of upper abdominal pain (1 TEAE reported for 1 [7.1%] subject who received single dose enzalutamide and 2 TEAEs reported for 2 [14.3%] subjects who received single dose enzalutamide + rifampin) and 1 TEAE of abdominal pain (reported for 1 [7.1%] subject who received single dose enzalutamide). Data cutoff date 23 Sep 2014 (Final CSR) AE: adverse event; BMI: body mass index; CI: confidence interval; CSR: clinical study report; DDI: drug-drug interaction; GMR: geometric mean ratio; M1: MDPC0001; M2: MDPC0002 (N-desmethyl enzalutamide); SAE: serious adverse event; TEAE: treatment-emergent adverse event

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7.1.8 MDV3100-19 Study title A Phase 1, Single-Center, Open-Label, Randomized, Parallel-Design, Relative Bioavailability Study Comparing Capsule and Tablet Formulations of Enzalutamide Following a Single 160 mg Dose Under Fasted Conditions in Healthy Male Subjects Clinical status Completed Study design Phase 1, open-label, randomized, parallel-design, relative bioavailability study Indication Healthy volunteers Key eligibility criteria Healthy males, 18-55 years of age, BMI 18.5-29.9 kg/m2, weight  50 kg. Male subjects and female partners had to use a condom and an additional method of birth control during the study and for 3 months postdose. Enrollment (Planned) Approximately 42 subjects Primary objective Relative bioavailability of capsule and tablet formulations of enzalutamide Secondary objectives Safety and tolerability Drug administration Oral administration of enzalutamide capsules, tablet E or tablet F Dose Single dose of enzalutamide 160 mg administered in 1 of 3 randomly assigned treatment groups (1:1:1):  Four 40-mg capsules  Two 80-mg tablets (tablet E)  Two 80-mg tablets (tablet F) Enrolled/treated 45 enrolled/45 treated (14, enzalutamide capsules; 16, tablet E; 15, tablet F) Demographics Median age was 34.5 years (range, 20.0-49.0 years) in the enzalutamide capsule group, 30.5 years (range, 19.0-52.0 years) in the tablet E group and 32.0 years (range, 19.0-50.0 years) in the tablet F group. Most subjects were white (71.4% capsule, 68.8% tablet E and 86.7% tablet F) or black (28.6% capsule, 18.8% tablet E, 13.3% tablet F). Baseline weight, height and BMI were generally balanced between treatment groups. Pharmacokinetics The geometric mean ratios for Cmax, AUC0-t and AUCinf for tablet E relative to the capsule were 0.8134 (90% CI, 0.7329-0.9027), 0.9190 (90% CI, 0.8030-1.0516) and 0.9244 (90% CI, 0.8085-1.0569), respectively. The median tmax of tablet E (2.52 hours; range, 1.50-4.00 hours) occurred 1.02 hours later than the median tmax with the capsule (1.50 hours; range, 0.750-2.00 hours). The geometric mean ratios for Cmax, AUC0-t and AUCinf for tablet F relative to the capsule were 0.8319 (90% CI, 0.7239-0.9560), 0.9764 (90% CI, 0.8427-1.1312) and 0.9866 (90% CI, 0.8540-1.1399), respectively. The median tmax of tablet F (2.00 hours; range, 0.500- 4.00 hours) occurred 0.500 hours later than the median tmax of the capsule (1.50 hours; range, 0.750-2.00 hours). Safety Five subjects in each treatment group (35.7% capsule, 31.3% tablet E and 33.3% tablet F) experienced 1 or more TEAEs; the most common were upper respiratory tract infection (5 subjects) and puncture site erythema and vessel puncture site hemorrhage (2 subjects each). All other AEs occurred in 1 subject each. No subject had a grade 3 or higher AE or an SAE. No subject had an AE resulting in death or study discontinuation. Data cutoff date 16 Dec 2014 (CSR Amendment) AE: adverse event; BMI: body mass index; CI: confidence interval; CSR: clinical study report; SAE: serious adverse event; TEAE: treatment-emergent adverse event

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7.1.9 9785-CL-0014 Study title A Phase 1, Randomized, Two-period, Crossover Bioequivalence Study of a Capsule and Tablet Formulation of Enzalutamide Under Fasted and Fed Conditions Clinical status Completed Study design Phase 1, randomized, 2-period, crossover bioequivalence Indication Healthy volunteers Key eligibility criteria Healthy males, 18 - 55 years of age, BMI 18.5 - 30.0 kg/m2, weight  50 kg. Male subjects and female partners had to use a condom and an additional method of birth control during the study and for 3 months postdose. Confirmed CYP2C8 poor metabolizers were excluded from this study. Enrollment (Planned) Approximately 56 subjects Primary objective Relative bioavailability of capsule and tablet formulations of enzalutamide under fasted and fed conditions. Secondary objectives Safety and tolerability Drug administration Enzalutamide capsules and tablets (fasted and fed conditions) Dose Single dose of enzalutamide 160 mg Enrolled/treated 60 enrolled/59 treated (fasted: 29/fed: 30) Demographics Of the 59 subjects treated, 58 (98.3%) subjects were white and 1 (1.7%) subject was Asian. Subjects had a mean age of 42.1 years, a mean weight of 81.99 kg, a mean height of 180.0 cm and a mean BMI of 25.33 kg/m2. Pharmacokinetics Under fasted conditions, the criteria for bioequivalence were met for AUClast and AUCinf but for Cmax, the 90% CIs were below the boundaries for bioequivalence (90% CI: 66.75%, 77.28%) and the GMR indicated an approximate 28% decrease compared with the tablet. The median tmax was 2.000 and 1.000 hours for the tablet and capsule, respectively. Taken together, these data indicate that under fasted conditions, the extent of absorption is the same for the tablet and capsule and the rate of absorption is slower for the tablet. Under fed conditions, the criteria for bioequivalence was met for AUClast and AUCinf but for Cmax the 90% CIs extended below the boundaries for bioequivalence, (90% CI: 79.94%, 101.36%) and the GMR indicated an approximate 10% decrease compared with the tablet. The median tmax was 3.000 and 2.990 hours for the tablet and capsule, respectively. Taken together, these data indicate that under fed conditions, the extent of absorption is the same for the tablet and capsule and the rate of absorption is slightly slower for the tablet. An effect of food on the pharmacokinetics of the tablet formulation cannot be excluded, since the 90% CI for AUClast, AUCinf and Cmax fell outside the no-effect boundaries of 80.00% to 125.00%. The GMRs amounted to 111.01%; (90% CI: 96.78%, 127.33%), 110.64%; (90% CI: 96.59%, 126.74%) and 79.18%; (90% CI: 68.58%, 91.43%) for AUClast, AUCinf and Cmax, respectively, for fed vs fasted conditions. The median tmax under fed conditions (3.000 hours; range: 0.500 to 8.03 hours) occurred approximately 1 hour later than the median tmax under fasted conditions (2.000 hours; range: 0.500 to 6.02 hours). Safety At total of 26 (44.1%) of subjects experienced at least 1 TEAE. The most common TEAEs were headache (11 [18.6%] subjects), nasopharyngitis (3 [5.1%] patients), back pain, diarrhea, rhinitis and toothache (2 [3.4%] patients). There were no deaths, SAEs or AEs leading to permanent discontinuation of study drug during this clinical study. Data cutoff date 05 May 2015 (Final CSR) AE: adverse event; BMI: body mass index; CI: confidence interval; CSR: clinical study report; CYP: cytochrome P450; GMR: geometric mean ratio; SAE: serious adverse event; TEAE: treatment-emergent adverse event

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7.2 Phase 1 Studies in Prostate Cancer Patients 7.2.1 S-3100-1-01 Study title A Phase 1, Open-label, Dose-escalation Safety and Pharmacokinetic Study of MDV3100 in Patients With Castration-resistant Prostate Cancer Clinical Status Ongoing (enrollment complete) Study design Phase 1, first-in-man, open-label, dose escalation Indication Prostate cancer Key eligibility criteria Histologically or cytologically confirmed adenocarcinoma of the prostate; ongoing ADT with a GnRH analogue or orchiectomy; serum testosterone < 50 ng/dL; disease progression per RECIST, 2 or more new lesions on bone scan or rising PSA ≥ 2 ng/mL (most recent value in a series of at least 3 rising values at ≥ 1-week intervals). Metastatic disease was allowed only if chemotherapy was not planned, if patient was ineligible for/intolerant of/declined chemotherapy or if progressive disease was documented despite chemotherapy. No more than 2 prior chemotherapy regimens with at least 1 containing docetaxel were allowed. Enrollment (planned) Approximately 186 patients Primary objective Safety and tolerability including dose-limiting toxicities and maximum tolerated dose Secondary objectives Define a dose or doses to be further studied; pharmacokinetics following single-dose and multiple-dose administration; effect on serum PSA, PSA response, PSA response duration; circulating tumor cell counts; bone turnover markers (serum bone-specific alkaline phosphatase and urinary N-telopeptide); disease progression during treatment Drug administration Enzalutamide Dose 30, 60, 150, 240, 360, 480 and 600 mg/day. Patients remaining on study were assigned to 160 mg/day Enrolled/treated 140 enrolled/140 treated (65 patients without previous chemotherapy and 75 patients with previous chemotherapy). Demographics Median age 68 years (20.0% of patients  75 years); 96.4% white, 2.9% black or African American; median baseline PSA 49 ng/mL; all patients had distant metastases at initial diagnosis (77.9% with soft tissue metastases and 52.1% with bone metastases); all patients had at least 1 prior hormonal therapy for prostate cancer. Efficacy At 12 weeks, 69.8% of patients without previous chemotherapy and 54.0% of patients with previous chemotherapy had a ≥ 50% decrease from baseline in PSA and 26.4% of patients without previous chemotherapy and 12.0% of patients with previous chemotherapy had a ≥ 90% decrease from baseline in PSA; median time to PSA progression was not reached in patients without previous chemotherapy and was 316 days (10.4 months) in patients with previous chemotherapy. Table continued on next page

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S-3100-1-01 (continued) Safety Of 140 patients, 138 (98.6%) had 1 or more AE; the most common were fatigue (70.0%), nausea (40.0%), constipation (32.1%), back pain (30.0%), arthralgia (29.3%), dyspnea (25.7%) and diarrhea (24.3%); nausea appeared to be dose- dependent. Potential enzalutamide-associated toxicities included fatigue, rash and seizure. Grade 3 or higher AEs were reported in 70 patients (29 patients without previous chemotherapy and 41 with previous chemotherapy); fatigue was a dose-dependent grade 3 or higher toxicity. Thirty-six patients experienced SAEs (17 patients without previous chemotherapy and 19 with previous chemotherapy) including fatigue in 4 patients and convulsions in 3 patients; no other SAEs were reported in more than 2 patients. No deaths were reported. Four patients ( 360 mg) had 5 dose-limiting toxicities (at both 360 mg and 480 mg, 1 patient had seizure; at 600 mg, 1 patient had seizure and confusion and 1 patient had a rash). A dose-dependent increase was apparent in events of fatigue leading to dose reduction, with incidences of 2.9% at 240 mg, 7.5% at 360 mg daily and 20.0% at 480 mg. The maximum tolerated dose was 240 mg daily, based on the occurrence of dose-limiting toxicities as well as events of fatigue leading to dose reductions at higher doses.

Pharmacokinetics Enzalutamide was absorbed rapidly after oral administration, with a median tmax of 1.00 h (range: 0.42 - 4.00 h postdose) after a single dose; pharmacokinetics of enzalutamide was essentially linear in the dose range of 30 to 600 mg after single or multiple doses. After a single dose, the mean terminal t1/2 was 5.82 days (range: 2.77 - 10.23 days) and did not appear to be affected by the dose size. It took approximately 1 month to reach steady state. The mean accumulation index was 8.33 and the mean peak-to-trough ratio was 1.25. Interpatient variability in

steady-state Cmax, Cmin and AUC0-τ values was low ( 29% CV). Data cutoff date 01 Sep 2010 (CSR) 30 Aug 2017 (clinical status) ADT: androgen deprivation therapy; AE: adverse event; CSR: clinical study report; CV: coefficient of variation; GnRH: gonadotropin-releasing hormone; PSA: prostate-specific antigen; RECIST: Response Evaluation Criteria in Solid Tumors; SAE: serious adverse event

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7.2.2 9785-CL-0007 Study title A Phase I Open-label Study to Evaluate the Effect of Multiple Doses of MDV3100 (ASP9785) on the Pharmacokinetics of Substrates for CYP2C8, CYP2C9, CYP2C19 and CYP3A4 in Patients with Castration-resistant Prostate Cancer Clinical Status Completed Study design Open-label, nonrandomized, single sequence crossover DDI study Indication Prostate cancer Key eligibility criteria Male patient aged 18 years old or above, with histologically or cytologically confirmed adenocarcinoma of the prostate without neuroendocrine differentiation or small cell features, with ongoing androgen deprivation therapy with a GnRH analogue or orchiectomy (i.e., medical or surgical castration). Progressive disease by PSA or imaging; estimated life expectancy of ≥ 6 months. BMI of at least 18.5 kg/m2 and no greater than 32.0 kg/m2. Enrollment (Planned) 14 Patients Primary objective To determine the effect of multiple once daily administration of enzalutamide on the pharmacokinetics of a single dose of pioglitazone (CYP2C8 substrate), S-warfarin (CYP2C9 substrate), omeprazole (CYP2C19 substrate) and midazolam (CYP3A4 substrate) in patients with CRPC. Secondary objective To evaluate the safety and tolerability of multiple once daily administration of enzalutamide alone and in combination with a single dose of pioglitazone, warfarin, omeprazole and midazolam in patients with CRPC Drug administration Enzalutamide, pioglitazone, warfarin, omeprazole and midazolam Dose All patients received once daily oral doses of 160 mg enzalutamide (four 40 mg capsules) from day 13 onwards up to day 97 (± 3 days). All patients received a single oral dose of 30 mg pioglitazone (CYP2C8 substrate) on day 1, followed by a 4-day washout. On day 5, a single oral cocktail of 10 mg warfarin (S-warfarin = CYP2C9 substrate), 20 mg omeprazole (CYP2C19 substrate) and 2 mg midazolam (CYP3A4 substrate) was administered, followed by a washout period of 8 days. On days 1 and 5, a single oral dose of enzalutamide PTM (4 capsules) was coadministered. A single oral dose of 30 mg pioglitazone was administered on day 55, followed by a 7-day washout. A single oral drug cocktail of 10 mg warfarin, 20 mg omeprazole and 2 mg midazolam was administered on day 62, followed by a 10-day washout. Enrolled/treated 14 enrolled/14 treated Demographics Eleven of the 14 male patients enrolled in this study were white, 3 of the 14 were other (mixed race); none were Hispanic or Latino. The mean age was 70.4 years and the mean BMI was 27.09 kg/m2.

Pharmacokinetics Enzalutamide (160 mg once daily to steady state) increased the AUCinf for pioglitazone (CYP2C8 substrate) by 20% and decreased the AUCinf of S-warfarin (CYP2C9 substrate), omeprazole (CYP2C19 substrate) and midazolam (CYP3A4 substrate) by 56%, 70% and 86%, respectively. Taken together, the results indicate that enzalutamide does not have a clinically important impact on CYP2C8 substrates and enzalutamide is a strong inducer of CYP3A4 and a moderate inducer of CYP2C9 and CYP2C19. Safety The most frequently reported (i.e., in ≥ 3/14[21.4%] patients) TEAEs were nausea, constipation, dizziness, arthropod bite, fatigue and hot flush. The majority of the reported TEAEs were NCI-CTCAE grade 1 or 2 in intensity. One patient experienced a single and transient episode of generalized tonic-clonic seizure which was assessed as probably related to enzalutamide and led to discontinuation of study treatment with enzalutamide. No clinically significant changes were noted for the safety laboratory tests or ECGs Data cutoff date 31 May 2012 (Final CSR) BMI: body mass index; CRPC: castration-resistant prostate cancer; CSR: clinical study report; CYP: cytochrome P450; DDI: drug-drug interaction; ECG: electrocardiogram; GnRH: gonadotropin-releasing hormone; NCI-CTCAE: National Cancer Institute-Common Terminology Criteria for Adverse Events; PSA: prostate-specific antigen; PTM: placebo to match; TEAE: treatment-emergent adverse event

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7.2.3 9785-CL-0003 Study title A Phase I, Open-label, Randomized, Parallel, Relative Bioavailability Study Comparing a Capsule and a Tablet Formulation of Enzalutamide Following Multiple Once Daily Doses of 160 mg Enzalutamide in Male Subjects with Prostate Cancer Clinical Status Completed Study design Open-label, randomized, parallel group Indication Prostate cancer Key eligibility criteria Male patient aged 18 years old or above with histologically confirmed prostate cancer (all stages) for whom ADT was indicated (except when indicated in a neoadjuvant/adjuvant setting) and had no more than 2 rounds of prior chemotherapy. Patients had evidence of progressive disease at study entry (rising PSA [2 consecutive levels], RECIST criteria for soft tissue progression or 2 or more new bone lesions). Enrollment (planned) 26 Patients Primary objective To evaluate the relative bioavailability of 2 oral formulations of enzalutamide following multiple 160 mg doses under fasted conditions in male subjects with prostate cancer. Secondary objective To evaluate the relative bioavailability of 2 oral formulations of enzalutamide following multiple 160 mg doses under fed conditions in male subjects with prostate cancer. To assess the effects of food on the relative bioavailability of each of the 2 oral formulations of enzalutamide following multiple 160 mg doses in male subjects with prostate cancer. To evaluate the safety and tolerability of 2 oral formulations of enzalutamide in male subjects with prostate cancer. Drug administration Enzalutamide Dose Patients were randomly assigned in a 1:1 ratio to 1 of 2 treatment arms (13 patients per arm). Patients assigned to Treatment Arm A received multiple doses of 160 mg enzalutamide formulated as four 40 mg soft gelatin capsules and patients assigned to Treatment Arm B received multiple doses of 160 mg enzalutamide formulated as a solid tablet. All received 160 mg enzalutamide daily under fasted conditions on days 1 and 56 and under fed conditions (after a standard high-fat, high-calorie meal) on day 57. On other study days, enzalutamide was taken with or without food. Enrolled/treated 27 enrolled/27 treated (13 in Arm A and 14 in Arm B) Demographics All subjects were male and the majority of subjects were white (100% in the Capsule Group and 78.6% in the Tablet Group). Median age was comparable for the 2 groups (70.0 years in the Capsule Group and 69.0 years in the Tablet Group). The median weight in the Capsule Group was 84.70 kg and the median weight in the Tablet Group was 90.80 kg. Median BMI was comparable for the 2 groups (27.60 kg/m2 Capsule Group and 28.70 kg/m2 Tablet Group). Pharmacokinetics In the food-effects comparison with the capsule formulation, after a high-fat, high-calorie meal, enzalutamide Cmax and AUCtau of the capsule formulation were comparable to under fasted conditions with GMRs of 0.9990 (90% CI: 0.9606, 1.0390) and 0.9929 (90% CI: 0.9574, 1.0298), respectively. Safety Across all treatment groups, a total of 24/27 (88.9%) subjects experienced at least 1 TEAE; all 13 (100%) subjects in the Capsule Group and 11/14 subjects (78.6%) in the Tablet Group. Nineteen (70.4%) subjects experienced at least 1 study drug-related TEAE: 10/13 (76.9%) subjects in the Capsule Group and 9/14 (81.8%) subjects in the Tablet Group. A total of 19/27 (70.4%) subjects experienced at least 1 NCI-CTCAE graded TEAE that was considered by the investigator to be related to study drug (possible or probable). The 17 NCI-CTCAE grade 1 TEAEs were evenly distributed across the 2 treatment groups; however, 2 subjects in the Capsule Group experienced at least 1 NCI-CTCAE grade 2 TEAE compared to 0 subjects in the Tablet Group. The investigator considered the study drug-related abnormal laboratory values reported as TEAEs (experienced by 2 subjects in the Capsule Group and 2 subjects in the Tablet Groups) to be mild (NCI-CTCAE grade 1). Data cutoff date 25 Oct 2013 (Final CSR) ADT: androgen deprivation therapy; BMI: body mass index; CI: confidence interval; CSR: clinical study report; GMR: geometric mean ratio; NCI-CTCAE: National Cancer Institute-Common Terminology Criteria for Adverse Events; PSA: prostate-specific antigen; RECIST: Response Evaluation Criteria in Solid Tumors; TEAE: treatment-emergent adverse event

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7.2.4 9785-CL-0111 Study title A Phase 1-2, Open-label, Uncontrolled, Dose-escalation Study of MDV3100 in Patients with Castration-resistant Prostate Cancer Clinical Status Completed Study design Multicenter, open-label, uncontrolled, dose-escalation study Indication CRPC Key eligibility criteria CRPC with metastases to the bone with progressive disease receiving ADT (surgical or medical castration). Patients participating in the dose-expansion cohort had to have measurable metastatic lesions and no more than 2 prior chemotherapy regimens, with 1 regimen containing docetaxel. Enrollment (Planned) Dose escalation: 9; Dose expansion: 37 Primary objective Dose-escalation Cohort: To determine the safety, tolerability and pharmacokinetics of enzalutamide when administered orally to Japanese patients with CRPC Expansion Cohort: To determine the efficacy, safety and pharmacokinetics of enzalutamide when administered orally to patients with CRPC who have previously been treated with chemotherapy including docetaxel (postchemo CRPC patients). Drug administration Enzalutamide Dose Single-dose Period: Subjects received the study drug at a dose of 80 mg, 160 mg or 240 mg on day S1 and were followed up for 7 days (inclusive of the day of administration). Multiple-dose Period: Subjects received the study treatment for 84 days. The subjects in each group of the Dose-escalation Cohort entered this period following the Single-dose Period and received the study drug at the dose assigned to their treatment group. However, subjects in the 240 mg group continued the study treatment at a reduced dose of 160 mg in the subsequent periods starting from the Multiple-dose Period. Subjects in the Expansion Cohort started to receive the study treatment in the Multiple-Dose Period. Long-term Dosing Period: after the Multiple-dose Period, all subjects in each group generally received the study drug at the same dose as that in the Multiple-dose Period. Subjects in the 80 mg group, however, were allowed to receive an increased dose of 160 mg at the discretion of the investigator or subinvestigator once the first subject in the Expansion Cohort started study treatment at 160 mg. Enrolled/treated 47 enrolled/47 treated Demographics Of the 38 patients in the dose-expansion cohort included in efficacy analyses, the median age was 71.5 years (range, 50-85 years) and all were of Japanese descent. Twenty-five (65.8%) patients entered the study with an ECOG performance status of 0 and 13 (34.2%) patients had an ECOG performance status of 1. Twenty-nine (76.3%) patients had Gleason scores at diagnosis of 8 to 10 and median PSA at baseline was 65.8 ng/dL. A major difference in this small study population compared with the CRPC2 study population was that most patients received prior treatment with estramustine in addition to prior treatment with docetaxel and had a greater number of prior hormonal treatments. Pharmacokinetics The pharmacokinetic results for enzalutamide after single- and multiple-dose administrations in Study 9785-CL-0111 (Japanese patients) were consistent with those in Study S-3100-1-01 (non-Japanese subjects). Table continued on next page

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Study 9785-CL-0111 (continued) Efficacy The radiographic objective response rate (CR or PR) at day 85 was 5.3% as assessed by the independent RECIST evaluation committee and 7.9% as assessed by the investigator. When evaluating best overall radiographic response rates during long-term dosing (final analysis), the values were 11.5% by the RECIST committee and 11.5% by the investigator. Radiographic disease control rate (CR, PR or stable disease) at day 85 was 47.4% as assessed by the RECIST committee and 50% as assessed by the investigator. Best overall radiographic disease control rate during long-term dosing (final analysis) was 73.1% as assessed by the RECIST committee and 73.1% by the investigator. Eleven of 38 patients (28.9%) had a ≥ 50% decrease in PSA at the time of nadir; 4 of 38 patients (10.5%) had a ≥ 90% decrease in PSA at the time of nadir. Safety One TEAE resulting in death was reported. A patient died due to disseminated intravascular coagulation. This event was considered unrelated to the study drug. Serious TEAES were reported in 3 (33.3%) patients in the Dose-escalation Cohort when analyzed during both the Single-dose Period and subsequent Multiple-dose Period and in 13 (34.2%) patients in the Expansion Cohort. Overall, TEAEs of the SOC Investigations were the most common (63.8% of patients). Drug-related serious TEAEs were reported only in the Expansion Cohort; the incidence was 10.5%. TEAEs occurred in all 9 patients in the Dose-escalation Cohort when analyzed during both the Single-Dose Period and subsequent Multiple-Dose Period and in 36 (94.7%) patients in the Expansion Cohort. The most common TEAEs (incidence ≥ 10%) in the Expansion Cohort were weight decreased (47.4%); decreased appetite (28.9%); constipation (26.3%); cancer pain (21.1%); hypertension (18.4%); ECG QT prolonged, hypertension (15.8%); nausea, nasopharyngitis, somnolence, hematuria, rash (13.2%); anemia, fatigue, pyrexia, blood potassium decreased, tumor pain and hydronephrosis (10.5%). The incidence of grade 3 or higher TEAEs was 66.7% in the Dose-escalation Cohort and 63.2% in the Expansion Cohort. The incidence of drug-related grade 3 or higher TEAEs was 55.6% in the Dose-escalation Cohort and 36.8% in the Expansion Cohort. The incidence of TEAEs leading to permanent discontinuation in the Dose-escalation Cohort was 11.1% and in the Expansion Cohort the incidence was 26.3%. Seizure did not occur in the patients in any cohort or group. Data cutoff date 12 Jul 2012 (CSR Revised Version) 01 Jul 2013 (CSR Amendment 1, 1-year safety follow up) 02 Jul 2014 (CSR Amendment 2, study completion) ADT: androgen deprivation therapy; CR: complete response; CRPC: castration-resistant prostate cancer; CSR: clinical study report; ECG: electrocardiogram; ECOG: Eastern Cooperative Oncology Group; PR: partial response; PSA: prostate specific antigen; RECIST: Response Evaluation Criteria in Solid Tumors; TEAE: treatment-emergent adverse event

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7.2.5 9785-CL-0406 Study title A Phase 1 Open-label Study to Evaluate the Effect of Multiple Doses of Enzalutamide on the Pharmacokinetics of Substrates for CYP1A2 and CYP2D6 in Male Subjects with Prostate Cancer Clinical Status Completed Study design Open-label, fixed-sequence, crossover DDI study Indication Prostate cancer Key eligibility criteria Histologically confirmed prostate cancer (all stages) with progressive disease; androgen deprivation therapy is indicated (except when indicated in a neoadjuvant/adjuvant setting); and no more than 2 prior chemotherapy regimens. Subjects may be on ongoing androgen deprivation therapy with a GnRH analogue or have undergone prior bilateral orchiectomy (i.e., medical or surgical castration) at screening. Enrollment (Planned) 14 Patients Primary objective To determine the effect of multiple once daily administration of enzalutamide on the pharmacokinetics of a single dose of caffeine (CYP1A2 substrate) and dextromethorphan (CYP2D6 substrate) in subjects with prostate cancer. Secondary objective To evaluate the safety and tolerability of multiple once daily administration of enzalutamide alone and in combination with a single dose of caffeine and dextromethorphan in subjects with prostate cancer. Drug administration Enzalutamide, caffeine, dextromethorphan Dose Day 1: 100 mg caffeine (CYP1A2 substrate), 30 mg dextromethorphan (CYP2D6 substrate) and enzalutamide placebo. Day 4 to 54 (or day 55 for extension study): 160 mg enzalutamide, taken once daily Day 53: 100 mg caffeine and 30 mg dextromethorphan. Enrolled/treated 14 enrolled/14 treated Demographics All patients were white males. The mean age was 64.5 years and the mean BMI was 28.5 kg/m2. Seven of the 14 (50%) patients had an ECOG performance grade of 0 and the remaining 7 (50%) had an ECOG performance grade of 1. Pharmacokinetics  The pharmacokinetic data for caffeine suggest that enzalutamide does not have a clinically meaningful effect on CYP1A2.  Based on changes in the pharmacokinetics of dextromethorphan (CYP2D6 substrate), enzalutamide (160 mg once daily to steady state) appeared to be a weak inducer of CYP2D6; however, induction of CYP3A4 (which also metabolizes dextromethorphan) possibly contributed to the observed effects (the combination of dextromethorphan with enzalutamide decreased the AUC0-t, AUC0-inf and Cmax for dextromethorphan by 49%, 31% and 38%, respectively).

 Mean (SD) steady-state Cmax values for enzalutamide, M1, M2 and the sum of enzalutamide plus M2 were 17.6 (3.59) µg/mL, 8.14 (6.33) µg/mL, 11.7 (2.70) µg/mL and 28.2 (4.55) µg/mL, respectively. Fluctuations in the steady state plasma concentrations for enzalutamide, M1, M2 and for the sum of enzalutamide plus M2 during a dosing interval were low. Safety Four (28.6%) patients reported 11 TEAEs, 7 of the TEAEs were experienced by 1 patient and the other 4 TEAEs by 3 patients. No cases of seizure or death were reported. The patient who experienced 7 TEAEs withdrew from the study prematurely on day 37 due to 4 interrelated SAEs associated with spinal fracture, all of which were considered by the investigator as unrelated to study drug. A single and transient, potentially clinically significant increase in GGT was noted in 1 patient following administration of substrates and prior to treatment initiation with enzalutamide. The GGT levels in this patient returned to normal during the subsequent enzalutamide treatment period. Data cutoff date 10 Nov 2014 (Final CSR) AE: adverse event; BMI: body mass index; CSR: clinical study report; CYP: cytochrome P450; DDI: drug-drug interaction; ECOG: Eastern Cooperative Oncology Group; GGT: gamma-glutamyltransferase; GnRH: gonadotropin-releasing hormone; M1: MDPC0001; M2: MDPC0002 (N-desmethyl enzalutamide); TEAE: treatment-emergent adverse event; SAE: serious adverse event

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7.2.6 MDV3100-06 Study title A Phase 1b, Open-label, Safety and Tolerability Study of Oral MDV3100 in Combination With Docetaxel in Men With Advanced Prostate Cancer Clinical Status Ongoing (enrollment complete) Study design Phase 1b, uncontrolled, open-label Indication Advanced prostate cancer Key eligibility criteria Adults 18 years or older with histologically or cytologically confirmed adenocarcinoma of the prostate without neuroendocrine differentiation or small cell features; ongoing androgen deprivation therapy with a GnRH analogue or prior bilateral orchiectomy; serum testosterone < 1.73 nmol/L; ECOG 0 or 1; and life expectancy  6 months. Recommended by medical oncologist for treatment with docetaxel-based chemotherapy (no prior docetaxel-based chemotherapy allowed). Enrollment (planned) Approximately 18 patients Primary objective Safety, tolerability and pharmacokinetics of docetaxel in combination with enzalutamide Secondary objective Pharmacokinetic parameters of docetaxel with and without concomitant enzalutamide Drug administration Docetaxel by constant-rate 1 h intravenous infusion once every 21 days, dexamethasone by mouth 12 h, 3 h and 1 h before the start of each docetaxel infusion and prednisone by mouth twice daily during docetaxel treatment. Enzalutamide by mouth once daily starting the day after the first docetaxel infusion. Enzalutamide treatment could continue after discontinuation of docetaxel. Dose Docetaxel 75 mg/m2, dexamethasone 8 mg, prednisone 5 mg, enzalutamide 160 mg Enrolled/treated 22 enrolled/22 treated (21 docetaxel + enzalutamide, 1 received docetaxel only) Demographics Median age 70.5 years (90.9% of patients  55 years); 86.4% white and 13.6% black or African American; median baseline PSA 57.9 µg/L; all patients had distant metastases at initial diagnosis (81.8% with soft tissue metastases and 90.9% with bone metastases). Most patients (15 of 22 [68.2%]) with bone metastases at screening had ≥ 5 bone lesions. All patients had at least 1 prior hormonal therapy for prostate cancer.

Pharmacokinetics Docetaxel AUC decreased by 11.8% and Cmax decreased by 3.7% when docetaxel was administered concomitantly with enzalutamide relative to when docetaxel was administered without enzalutamide. These small changes in exposure to docetaxel are not clinically relevant. Efficacy Exploratory analyses of PSA response rates and duration of PSA response were performed. Mean (SD) percentage reduction in PSA from baseline was 89.0% (17.27); 95% of patients had  50% PSA reduction from baseline; 65% of patients had  90% PSA reduction from baseline; median duration of PSA response was 226.0 days (approximately 7.4 months). Table continued on next page

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MDV3100-06 (continued) Safety All 22 patients had 1 or more TEAE; the most common ( 5 [22.7%] patients) were neutropenia (86.4%); fatigue (77.3%); constipation (54.5%), back pain, nausea and peripheral neuropathy (45.5% each); decreased appetite (40.9%); peripheral sensory neuropathy (36.4%); arthralgia and dyspnea (31.8% each); alopecia, diarrhea, dysgeusia, musculoskeletal pain and pain in extremity (27.3% each); abdominal pain, anemia, dizziness, dyspepsia, increased lacrimation, insomnia, peripheral edema and rash (22.7% each). Twenty-one (95.5%) patients had 1 or more grade 3 or higher AEs and those occurring in  2 (9.1%) patients were neutropenia (86.4%), febrile neutropenia and WBC count decreased (18.2% each), ECG QT prolonged, hyperkalemia, flank pain and sepsis (9.1% each). Thirteen (59.1%) patients had 1 or more SAEs and those occurring in  2 patients were febrile neutropenia and atrial fibrillation (3 [13.5%] patients each) and acute coronary syndrome, pyrexia and sepsis (2 [9.1%] patients each). Two (9.1%) patients permanently discontinued study drug due to AEs; both with acute coronary syndrome and 1 each with chest pain and fatigue. One patient died of an unknown cause during the treatment period and a second patient died of disease progression approximately 3 weeks after discontinuing enzalutamide treatment and approximately 2 months after discontinuing docetaxel. Repeated cycles of docetaxel were associated with decreasing neutrophil counts from day 1 to 15 of each cycle. Data cutoff date 01 Jul 2013 (CSR) 30 Aug 2017 (clinical status) AE: adverse event; CSR: clinical study report; ECG: electrocardiogram; ECOG: Eastern Cooperative Oncology Group; GnRH: gonadotrophin-releasing hormone; PSA: prostate-specific antigen; SAE: serious adverse event; TEAE: treatment-emergent adverse event; WBC: white blood cell

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7.3 Phase 2 Studies in Prostate Cancer Patients 7.3.1 CRPC-MDA-1 Study title A Study of Continuous Oral Dosing of a Novel Antiandrogen MDV3100, in Castration-resistant Bone Metastatic Prostate Cancer Patients Evaluating the Tumor Micro-environment Clinical Status Completed Study design Phase 2, nonrandomized, single arm, open-label Indication Bone metastatic CRPC Key eligibility criteria Histologically or cytologically confirmed adenocarcinoma of the prostate without neuroendocrine differentiation or small cell features; metastatic disease to the bone; ongoing ADT with a GnRH analogue or orchiectomy; serum testosterone < 50 ng/dL; progressive disease defined by rising PSA (3 rising PSA tests with ≥ 1-week interval between each determination), soft tissue (per RECIST 1.1) or bone (2 or more new lesions on bone scan); ECOG 0-2; no more than 2 prior chemotherapy regimens; and life expectancy ≥ 6 months. Enrollment (planned) 60 patients Primary objective Correlation of androgen signaling and expression of survival/escape pathways in bone marrow with measures of antitumor activity to identify predictors of response or resistance to therapy Secondary objectives Antitumor activity as assessed by serum PSA, imaging of soft tissue and bone metastases and markers of bone metabolism; safety and tolerability Drug administration Enzalutamide Dose 160 mg once daily Enrolled/treated 60 enrolled/60 treated. Demographics Median age 69.5 years (90.0% of patients  55 years); 88.3% white, 6.7% black or African American; median baseline PSA 57.1 ng/mL. All patients had distant metastases at initial diagnosis (31.7% with soft tissue metastases and 100% with bone metastases); 59 of 60 patients had at least 1 prior hormonal therapy and 48 of 60 patients had at least 1 previous chemotherapy regimen. All patients had at least 1 prior hormonal therapy and/or previous chemotherapy regimen. Efficacy Of the 58 patients treated with 160 mg daily (safety population) who had both a baseline and postbaseline PSA, 74.1% had a reduction from baseline on therapy (46.6% had a  50% maximum reduction and 22.4% had a ≥ 90% maximum reduction). PSA responses (safety population) for patients who did not receive prior docetaxel and had both a baseline and postbaseline PSA (n = 16) was 43.8% with a  50% maximum reduction and 31.3% with a ≥ 90% maximum reduction. Of the patients who received prior docetaxel and had both a baseline and postbaseline PSA (n = 42), 47.6% had a  50% maximum reduction and 19.0% had a  90% maximum reduction. Table continued on next page

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CRPC-MDA-1 (continued) Safety Initial data cutoff: At least 1 AE was reported in 98.3% of patients. The most common AEs ( 15%) were fatigue (71.7%), anorexia (28.3%), constipation (28.3%), arthralgia (26.7%), back pain (23.3%), peripheral edema (23.3%), nausea (18.3%), dyspnea (16.7%) and hot flush (15.0%). Enzalutamide treatment was associated with increases in systolic and diastolic blood pressures. An elevation in at least 1 systolic blood pressure ≥ 140 mm Hg with an increase from baseline of ≥ 20 mm Hg was observed in 36.7% of patients. Grade 3 or higher AEs were reported in 29 patients (48.3%). Grade 3 or higher AEs reported in 2 or more patients included fatigue (6 patients), back pain (6), blood alkaline phosphatase increased (5), arthralgia (4), anemia (2), nausea (2), urinary tract infection (2), urosepsis (2), compression fracture (2), bone pain (2), hematuria (2) and urinary retention (2). The grade 4 events were lymphocyte percentage decreased and anemia (both in the same patient), neutropenia in 1 patient and hyperuricemia in 1 patient. Of the 23 SAEs reported, only 2 were reported in more than 1 patient: urinary tract infection and urosepsis (2 patients each). AEs that may be related to the known pharmacology of androgen receptor signaling inhibition by enzalutamide may include hot flush, dry skin and gynecomastia. Nausea, vomiting and dyspepsia may also be related to study drug treatment. No deaths were reported. Remainder of study: All 13 (100%) patients who continued in the study after the 26 Aug 2011 data cutoff through the end of the study reported at least 1 TEAE. The most common (reported in > 20% of patients) TEAEs were fatigue (11 [84.6%] patients); diarrhea, edema peripheral and arthralgia (4 [30.8%] patients each); and constipation, anorexia and hot flush (3 [23.1%] patients each). Nine (69.2%) patients reported a grade 3 or higher TEAE. The most common grade 3 event was fatigue (4 [30.8%] patients). All other grade 3 or higher TEAEs were reported in 1 patient each. One (7.7%) patient had an SAE of pathological fracture and the same patient permanently discontinued enzalutamide due to the event. None of the patients died. Data cutoff date 26 Aug 2011 (CSR) 27 Aug 2013 (CSR addendum) ADT: androgen deprivation therapy; AE: adverse event; CRPC: castration-resistant prostate cancer; CSR: clinical study report; ECOG: Eastern Cooperative Oncology Group; GnRH: gonadotropin-releasing hormone; PSA: prostate specific antigen; RECIST: Response Evaluation Criteria in Solid Tumors; SAE: serious adverse event; TEAE: treatment-emergent adverse event

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7.3.2 9785-CL-0011 Study title A Phase 2 Study Determining Safety and Tolerability of Enzalutamide (formerly MDV3100 ) in Combination with Abiraterone Acetate in Bone Metastatic Castration-Resistant Prostate Cancer Patients Clinical Status Ongoing (enrollment complete) Study design Open-label Indication Bone metastatic CRPC Key eligibility criteria CRPC with metastases to the bone with progressive disease receiving ADT (surgical or medical castration). Patients who received an antiandrogen must demonstrate disease progression following discontinuation of the antiandrogen. Enrollment (Planned) 60 Patients Primary objective To explore the safety and tolerability of enzalutamide in combination with abiraterone acetate plus prednisone. Secondary objective  To explore the effect of enzalutamide in combination with abiraterone acetate plus prednisone on androgen receptor signaling and androgen levels.  To explore the antitumor activity of enzalutamide in combination with abiraterone acetate plus prednisone as assessed by serum PSA, imaging of soft tissue and bone metastases and markers of bone metabolism. Drug administration Enzalutamide, abiraterone and prednisone Dose Enzalutamide 160 mg once daily and abiraterone acetate 1000 mg once daily, prednisone 5 mg twice daily Enrolled/treated 60 enrolled/60 treated Demographics Mean age 65.4 years (85.4% of patients  55 years); 85.0% white, 10.0% black or African American; mean BMI was 31.1 kg/m2. At initial diagnosis, the most frequently recorded Gleason score was 9 (46.7% of patients) and the majority of patients had unknown regional lymph node and distant metastasis assessment. At total of 13.3% of patients received prior prostate cancer therapy with docetaxel, 46.7% received 2 or more prior hormonal prostate cancer therapies and 13.3% received other therapies. Fifty percent of patients received prior radiation therapy, 48.3% had a previous prostatectomy and 3.3% had a transurethral resection of the prostate. Efficacy Clinical efficacy of enzalutamide in combination with abiraterone and prednisone was noted both radiographically and by PSA response. Of the 16 patients with measurable soft tissue disease, 11 (68.8%) had PR, 3 (18.8%) had stable disease and 2 (12.5%) had PD as best overall response per RECIST 1.1. Of the 43 patients who had results for best overall response at the end-of-treatment visit, 3 had PR, 18 had PD and 22 had non-CR and non-PD. Over the entire study period, 52 patients (86.7%) had a ≥ 30% reduction in PSA from baseline and 29 patients (48.3%) had a ≥ 90% reduction. Median PFS was 8.4 months. Safety All 60 (100%) patients experienced at least 1 TEAE. The highest incidence of TEAEs during the study were categorized in the SOC of Investigations (55 [91.7%] patients), Metabolism and nutrition disorders (49 [81.7%] patients), Musculoskeletal and connective tissue disorders (48 [80.0%] patients) and General disorders and administration site conditions (46 [76.7%] patients). The most frequently reported TEAEs (> 20 patients) were fatigue (43 [71.7%] patients), hyperglycemia (40 [66.7%] patients), blood alkaline phosphatase increased (32 [53.3%] patients), hot flush (26 [43.3%] patients), AST increased (22 [36.7%] patients) and anemia (21 [35.0%] patients). The most frequently reported enzalutamide-related TEAEs (> 15 patients) were fatigue (35 [58.3%] patients), hot flush (23 [38.3%] patients), hypertension and AST increased (17 [28.3%] patients each). In total, 10 treatment-emergent SAEs were reported in 8 (13.3%) patients; all events were singular occurrences. Three (5.0%) patients were permanently discontinued from study drug due to a TEAE (none were related to study drug), including an event of spinal compression fracture, ALT increased, AST increased and spinal cord compression. No fatal cases and no cases of seizure were reported. Data cutoff date 30 Aug 2015 (CSR) 30 Aug 2017 (clinical status) Footnotes appear on next page

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ADT: androgen deprivation therapy; ALT: alanine aminotransferase; AST: aspartate aminotransferase; BMI: body mass index; CR: complete response; CRPC: castration –resistant prostate cancer; CSR: clinical study report; PD: progressive disease; PFS: progression-free survival; PR: partial response; PSA: prostate specific antigen; RECIST: Response Evaluation Criteria in Solid Tumors; SAE: serious adverse event; TEAE: treatment-emergent adverse event

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7.3.3 9785-CL-0121 Study title A Phase 2 Open-label Extension Study to Assess the Safety of Continued Administration of MDV3100 in Subjects with Prostate Cancer Who Showed Benefit from Prior Exposure to MDV3100 Clinical Status Completed Study design Open-label extension study Indication CRPC Key eligibility criteria Patients who were actively enrolled and have completed enzalutamide treatment in a previous study with enzalutamide could be eligible to participate in this study when continuation of enzalutamide was deemed by the investigator in the best interest of the subjects. Enrollment Prostate cancer patients Primary objective To follow up the long-term safety of continued administration of enzalutamide in prostate cancer subjects who were enrolled and completed enzalutamide treatment period in a prior study with enzalutamide. Drug administration Enzalutamide Dose Subjects took 160 mg (4 capsules) enzalutamide once daily oral dose at the same time each day. Enrolled/treated 52 enrolled/52 treated Demographics Mean age 68.6 years; 90.4% white, 3.8% black or African American, 5.8% other; mean BMI was 28.1 kg/m2. At initial diagnosis, the most frequently recorded Gleason score was 7 (30.8% of patients; 32.7% unknown) and the majority of patients had unknown primary tumor, pathologic tumor state, regional lymph node or distant metastasis assessment. Safety Overall, 43 (82.7%) patients experienced at least 1 TEAE. Of TEAEs starting on day 1 or later, the highest incidence of TEAEs during the study were categorized in the SOC of Gastrointestinal disorders (22 [42.3%] patients), Musculoskeletal and connective tissue disorders (20 [38.5%] patients), General disorders and administration site conditions (17 [32.7%] patients) and Metabolism and nutrition disorders (13 [25.0%] patients). The most frequently reported TEAEs (> 10% of patients) were fatigue (14 [26.9%] patients), arthralgia and back pain (7 [13.5%] patients each), decreased appetite, diarrhea and hot flush (6 [11.5%] patients each). In total, 17 (32.7%) patients experienced a treatment-emergent SAE. All events were single occurrences, with the exception of malignant neoplasm progression (4 [7.7%] patients), asthenia and spinal cord compression (2 [3.8%] patients each). Twelve (23.1%) patients were permanently discontinued from study drug due to a TEAE including events of malignant neoplasm progression (3 [5.8%] patients), dysphagia (2 [3.8%] patients) and pancreatic carcinoma, tonsil cancer, pancreatitis acute, rectal hemorrhage, asthenia, fatigue, cardiac arrest, acute myocardial infarction, amnesia and hypercalcemia (1 [1.9%] patient each). Five (9.6%) patients experienced TEAEs leading to death including 4 (7.7%) events of malignant neoplasm progression and an event of acute myocardial infarction (1.9%). No seizure cases were reported. Data cutoff date 18 Apr 2017 (Final CSR) BMI: body mass index; CRPC: castration-resistant prostate cancer; CSR: clinical study report; SAE: serious adverse event; TEAE: treatment-emergent adverse event

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7.3.4 9785-CL-0321 Study title A Phase 2, Open-label, Single-arm, Efficacy and Safety Study of Enzalutamide (MDV3100) in Patients with Hormone-naïve Prostate Cancer Clinical Status Completed Study design Open-label, single-arm, multicenter study Indication Hormone-naïve prostate cancer Key eligibility criteria Patients with prostate cancer who had noncastrate levels of testosterone at study entry. Patients must not have been previously treated or currently receiving hormonal therapy with the intent to treat prostate cancer (surgical castration or other hormonal manipulation, e.g., GnRH or antagonists, anti-androgens or ). Enrollment (Planned) 60 Patients Primary objective  To evaluate the effect of enzalutamide on PSA Secondary objective  To evaluate the safety and tolerability of enzalutamide in patients who have not previously received hormone treatment for prostate cancer;  To evaluate the pharmacodynamic effects of enzalutamide on circulating testosterone, DHT, SHBG , DHEA, LH, FSH, estradiol and  To evaluate the pharmacokinetics of enzalutamide and the human metabolite N-desmethyl enzalutamide Drug administration Enzalutamide Dose 160 mg (4 capsules), given orally once daily Enrolled/treated 67 enrolled/67 treated Pharmacokinetics The pharmacokinetic profile was generally consistent with those in other studies of enzalutamide. Demographics Of the 67 patients enrolled and treated, 66 (98.5%) patients were white and 1 (1.5%) was black or African American. The median age was 73 years (range, 48-86 years) and the mean duration of prostate cancer was 2.8 years. Tumor was confined to the prostate in 31 (46.3%) patients and Gleason score was 8 to 10 at initial diagnosis in 16 (23.9%) patients. Efficacy Overall, 62 (92.5%) patients had a PSA response ≥ 80% at week 25. Of the 5 patients categorized as nonresponders, 4 patients did not complete 25 weeks of treatment; and 1 patient with a 57.0% PSA decline at week 25 had a 90.7% PSA decline at week 9. Of the 63 patients who completed 25 weeks of treatment, 62 (98.4%) patients had a ≥ 80% decline in PSA. The mean maximum PSA decline was 98.3% through week 25. At week 49 (1 year of treatment), 54 of 67 (80.6%) patients had a PSA response ≥ 80%; the 13 patients considered nonresponders were those who did not complete 49 weeks of treatment. At week 97 (2 years of treatment), 45 of 67 (67.2%) patients had a PSA response ≥ 80%; the 22 patients who were nonresponders did not complete 97 weeks of treatment. All 45 (100%) patients who were on treatment for 2 years had a ≥ 80% decline in PSA from baseline. The mean maximum PSA decline was 99.1% through the cutoff date of 28 Dec 2013. At 3 years (week 169), 38 of 67 (56.7%) patients had a PSA response ≥ 80%. Among the 29 nonresponders, 4 (13.8%) had completed 169 weeks of treatment. Of the 42 patients who were on treatment up to the 3-year visit, 38 (90.5%) had a ≥ 80% decline in PSA from baseline. The mean PSA decline was 91.74% at the 3-year analysis. Table continued on next page

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9785-CL-0321 (continued) Efficacy (continued) From baseline to end of study, on average, mean PSA decreased by -0.7% (-28.49 ng/mL) (n = 27); this mean decrease was lower that seen from baseline to 3 years (week 169). Based on all PSA measurements available by the last evaluation date (27 Apr 2017), the mean PSA maximum decline (i.e., the largest reduction from baseline in PSA level that occurred at any point after start of treatment and up to and including the assessment made at the safety follow-up visit) was 99.10%. During the entire study, 49 of 67 (73.1%) patients reached an undetectable PSA level (≤ 0.1 ng/mL) before discontinuing treatment. Safety At the end of study final analysis, all (100%) patients reported at least 1 TEAE, with the highest incidence of TEAEs occurring in the SOC of Reproductive system and breast disorders (50 [74.6%] patients), Gastrointestinal disorders (37 [55.2%] patients), Musculoskeletal and connective tissue disorders (36 [53.7%] patients) General disorders and administration site conditions (33 [49.3%] patients) and Infections and infestations (30 [44.8%] patients). The most frequently reported TEAEs (> 7 patients) were gynecomastia (36 [53.7%] patients), fatigue (28 [41.8%] patients), hypertension (17 [25.4%] patients), hot flush (15 [22.4%] patients), nipple pain (13 [19.4%] patients), diarrhea and nausea (11 [16.4%] patients each), back pain (10 [14.9%] patients), constipation (9 [13.4%] patients), edema peripheral and pain in extremity (8 [11.9%] patients each), dry skin and osteoporosis (7 [10.4%] patients each). Twenty-four (35.8%) patients experienced an SAE, all of which were single occurrences with the exception of atrial fibrillation (4 [6.0%] patients), angina pectoris, syncope, urinary retention and pneumonia (2 [3.0%] patients each). Anoxic seizure was reported in 1 patient following a cardiac arrest. Thirteen (19.4%) patients experienced a TEAE that led to permanent discontinuation of study drug; all were single occurrences with the exception of fatigue and depression (2 [3.0%] patients each). Five (7.5%) patients experienced a TEAE that led to death including cardiac arrest, acute myocardial infarction, cardio-respiratory arrest, colon cancer metastatic and hypercalcemia (1 [1.5%] patient each). Data cutoff date 29 Jul 2012 (week 25) and 28 Dec 2012 ( 1 year/week 49) (CSR, week 25 and 1 year [week 49] analyses) 28 Dec 2013 (CSR, 2 year [week 97] analysis) 16 Apr 2015 (CSR, 3 year [week 169] analysis) 27 Apr 2017 (Final CSR) BMI: body mass index; CSR: clinical study report; DHEA: ; DHT: dihydrotestosterone; FSH: follicle-stimulating hormone; GnRH: gonadotropin-releasing hormone; LH: luteinizing hormone; PSA: prostate specific antigen; SAE: serious adverse event; SHBG: -binding globulin; TEAE: treatment-emergent adverse event

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7.3.5 MDV3100-07 Study title A Randomized, Open-label, Phase 2 Study of MDV3100 as Neoadjuvant Therapy for Patients Undergoing Prostatectomy for Localized Prostate Cancer Clinical Status Completed Study design Phase 2, randomized, open-label Indication Localized intermediate or high-risk prostate cancer Key eligibility criteria Adults 18 years or older with histologically confirmed adenocarcinoma of the prostate without neuroendocrine differentiation or small cell features and a minimum of 3 cores positive for tumor; candidates for radical prostatectomy (surgically resectable by urologic evaluation); PSA > 10 ng/mL or Gleason score  7 (4+3) at study entry; ECOG 0 or 1. Clinical stage T4 disease was not allowed. Prior ADT, chemotherapy, surgery or radiation for prostate cancer was not permitted. Enrollment (planned) Approximately 50 patients randomly assigned 1:1 to triple therapy (enzalutamide, leuprolide, dutasteride) or single-agent enzalutamide stratified by baseline risk category (intermediate risk vs high risk) Primary objective pCR rate at 6 months Secondary objectives Effects on PSA reduction, surgical endpoints, near pCR rate, serum hormones and HRQoL; safety and tolerability Drug administration Enzalutamide once daily by mouth (all patients); dutasteride once daily by mouth and leuprolide once every 3 months by intramuscular injection (patients assigned to triple therapy). Treatment continued for 6 months (until the day before prostatectomy). Dose Enzalutamide 160 mg; dutasteride 0.5 mg; leuprolide 22.5 mg Enrolled/treated 52 enrolled/52 treated (25 triple therapy and 27 single-agent enzalutamide) Demographics The median age was 60 years (range, 46-74 years) in the triple therapy group and 61 years (range, 47-75 years) in the enzalutamide group. Most (88.5%) patients were white; race was generally balanced between treatment groups. Median baseline PSA was 12.8 μg/L in the triple therapy group and 10.9 μg/L in the enzalutamide group. Median baseline Gleason score was 8.0 for both treatment groups. Efficacy pCR and near pCR: pCR rate by the local pathologist was 8.7% triple therapy (95% CI: 1.1%, 28.0%) and 0% enzalutamide (95% CI: 0, 13.7%). pCR rate by the central pathologist (sensitivity analysis) was 4.3% triple therapy (95% CI: 0.1%, 21.9%) and 0% enzalutamide (95% CI: 0, 13.7%). Near pCR rate by the local pathologist was 13.0% triple therapy and 0% enzalutamide. Surgical endpoints (local pathologist): positive surgical margins (4.3% triple therapy and 12.0% enzalutamide); extracapsular extension (26.1% triple therapy and 36.0% enzalutamide, different staging criteria used among study sites); positive seminal vesicles (30.4% triple therapy and 36.0% enzalutamide); positive lymph nodes (26.1% triple therapy and 4.0% enzalutamide. PSA response: Mean (SD) PSA decreased from 16.17 (13.86) µg/L at baseline to 1.81 (2.08) µg/L for the triple therapy group and from 16.22 (16.47) µg/L to 3.50 (3.40) µg/L for the enzalutamide group by day 30. Mean (SD) PSA nadir was 0.08 (0.11) µg/L for the triple therapy group and 1.40 (2.16) µg/L for the enzalutamide group. Mean (SD) time to PSA nadir was 5.06 (1.10) months for the triple therapy group and 5.58 (1.05) months for the enzalutamide group. PSA < 0.2 µg/L was 92.0% in the triple therapy group and 29.6% in the enzalutamide group. All patients in both treatment groups had a 50% decrease in PSA from baseline. All (100.0%) patients in the triple therapy group and 63.0% of patients in the enzalutamide group had a 90% decrease in PSA from baseline. Table continued on next page

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MDV3100-07 (continued) Efficacy (continued) HRQoL: Sexual domain summary scores worsened from baseline for most patients; however, a slightly higher proportion of patients in the enzalutamide group (37.5%) had a stable sexual domain summary score from baseline compared with the triple therapy group (25.0%). Hormonal domain summary scores worsened for most patients; however, a higher proportion of patients in the enzalutamide group (38.9%) had a stable hormonal domain summary score from baseline compared with the triple therapy group (18.8%). Serum hormones: Serum testosterone and DHT increased for patients in the enzalutamide group and decreased for patients in the triple therapy group. Safety All 52 patients in the safety population experienced 1 or more TEAEs; the most common ( 24% in either treatment group) were fatigue (60.0% triple therapy and 70.4% enzalutamide), hot flush (96.0% and 25.9%), gynecomastia (12.0% and 63.0%), insomnia (36.0% and 22.2%), libido decreased (32.0% and 14.8%), breast tenderness (8.0% and 33.3%), diarrhea (24.0% and 18.5%) and pollakiuria (24.0% and 14.8%). Nine patients (6 triple therapy and 3 enzalutamide) had 1 or more grade 3 or higher AEs. Diarrhea, medical device pain, clostridial infection, pelvic abscess, procedural pain, hyperglycemia, hyponatremia and hot flush occurred in 1 patient each. Lymphocele was the only grade 3 or higher AE that occurred in more than 1 patient. One patient had a grade 4 AE (pelvic abscess). SAEs were lymphocele (2 patients), postoperative ileus, pelvic abscess and clostridial infection (1 patient each); all occurred after radical prostatectomy. No patient died and no patient permanently discontinued study treatment due to an AE. Data cutoff date 31 Jan 2014 (Final CSR) ADT: androgen-deprivation therapy; AE: adverse event; CI: confidence interval; CSR: clinical study report; DHT: dihydrotestosterone; ECG: electrocardiogram; ECOG: Eastern Cooperative Oncology Group; HRQoL: health-related quality of life; pCR: pathologic complete response; PSA: prostate-specific antigen; SAE: serious adverse event; TEAE: treatment-emergent adverse event

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7.3.6 9785-CL-0222 (TERRAIN) Study title TERRAIN: A Randomized, Double-blind, Phase II, Efficacy and Safety Study of MDV3100 (ASP9785) vs. Bicalutamide in Castrate Men with Metastatic Prostate Cancer Clinical Status Ongoing (enrollment complete) Study design Randomized, double-blind, parallel group, active control study Indication CRPC Key eligibility Metastatic CRPC with progressive disease; ongoing ADT (surgical or medical castration). criteria Enrollment 370 (1:1 enzalutamide: bicalutamide) (Planned) Primary To determine the PFS of enzalutamide as compared to bicalutamide objective Secondary  To determine the safety of treatment with enzalutamide as compared to bicalutamide objective  To determine the PSA response of enzalutamide at week 13 as compared to bicalutamide  To determine the time to PSA progression of enzalutamide as compared to bicalutamide Drug Enzalutamide or bicalutamide administration Dose Enzalutamide arm: 160 mg (4 capsules) of enzalutamide and 1 placebo tablet orally once daily at the same time each day. Bicalutamide arm: 50 mg (1 tablet) of bicalutamide and 4 placebo capsules orally once daily at the same time each day. Enrolled/treated 375 enrolled/372 treated (183 enzalutamide, 189 bicalutamide) Demographics Demographic and baseline characteristics were generally similar between the enzalutamide and bicalutamide treatment groups. The overall median age was 71.0 years, with approximately 24% of patients aged < 65 years in both groups, 46.2% (enzalutamide) and 41.9% (bicalutamide) aged 65-75 years and 29.3% (enzalutamide) and 33.5% (bicalutamide) aged > 75 years. Overall, the population was predominantly white (92.8%), with 4.8% black or African American and 1.3% Asian patients. A small percentage was Native Hawaiian/Other Pacific Islander or Other (0.5% each). Baseline pain assessment by BPI question 3 (worst pain in the last 24 hours) was 0 in 44.0% of enzalutamide-treated patients vs 53.4% of bicalutamide-treated patients, 1 in 10.9% vs 7.9% of patients, 2 in 14.7% vs 14.7% of patients and 3 in 22.8% vs 20.4% of patients. The remainder of patients had baseline pain scores > 3. The majority of patients had a baseline ECOG performance score of 0 (70.7% of enzalutamide-treated patients vs 76.4% of bicalutamide-treated patients). In general, demographic and baseline characteristics were balanced between both treatment groups for a particular stratum (i.e., bilateral orchiectomy or receipt of LHRH agonist/antagonist therapy started before or after the diagnosis of metastases). Efficacy Ninety-nine (53.8%) patients in the enzalutamide group and 141 (73.8%) patients in the bicalutamide group experienced a PFS event in the FAS. Median (95% CI) PFS was 15.7 (11.5, 19.4) months in the enzalutamide group and 5.8 (4.8, 8.1) months in the bicalutamide group (P < 0.0001). Treatment with enzalutamide vs bicalutamide was associated with a 56% reduction in the risk of progression based on Independent Central Review (hazard ratio: 0.44; 95% CI: 0.34, 0.57; P < 0.0001). Among enzalutamide-treated patients, median PFS was similar regardless whether orchiectomy/LHRH was started before or after the diagnosis of metastases (15.9 vs 15.3 months). Among bicalutamide-treated patients, median PFS was shorter in patients who started orchiectomy/LHRH before the diagnosis of metastases (5.5 months) than in those who started orchiectomy/LHRH after the diagnosis of metastases (6.6 months) Table continued on next page

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9785-CL-0222 (TERRAIN) (continued) Efficacy In the enzalutamide group vs the bicalutamide group in the FAS, the proportion of patients (continued) experiencing a first progression event was highest for radiographic progression based on Independent Central Review (25.0% vs 33.0%), followed by new antineoplastic therapy (13.6% vs 28.3%), skeletal-related event (11.4% vs 10.5%) and death (3.8% vs 2.1%). Treatment with enzalutamide vs bicalutamide was associated with a 58% reduction in the risk of progression in PFS based on investigator assessment (hazard ratio: 0.42; 95% CI: 0.33, 0.55; P < 0.0001).In the FAS, mean values of the best PSA response were -75.9% in the enzalutamide group (n = 174) and 207.3% in the bicalutamide group (n = 168). In the FAS at the data cutoff date, 65 (35.3%) patients in the enzalutamide group and 98 (51.3%) patients in the bicalutamide group experienced PSA progression (hazard ratio: 0.28; 95% CI: 0.20, 0.39; P < 0.0001). Median (95% CI) time to PSA progression was 19.4 (16.6, estimate not met) months in the enzalutamide group and 5.8 (5.6, 8.3) months in the bicalutamide group (P < 0.0001) Safety A total of 173 (94.5%) patients in the enzalutamide group and 178 (94.2%) patients in the bicalutamide group had 1 or more TEAEs. The highest incidences of TEAEs were in the SOC of Musculoskeletal and connective tissue disorders (203 [54.6%] patients), Gastrointestinal disorders (165 [44.4%] patients), General disorders and administration site conditions (154 [41.4%] patients) and Nervous system disorders (116 [31.2%] patients). The most common ( 10% of patients in the enzalutamide group and  2% higher than the bicalutamide group) were fatigue (28.4% enzalutamide vs 20.1% bicalutamide), hot flush (14.8% vs 11.1%), hypertension (14.8% vs 7.4%), diarrhea (11.5% vs 9.0%), pain in extremity (10.9% vs 5.3%) and weight decreased (10.9% vs 7.9%). SAEs occurred in 61 patients (33.3%) in the enzalutamide group and 45 patients (23.8%) in the bicalutamide group; those occurring in  2.0% of patients in either treatment group were anemia (3.3% enzalutamide vs 0% bicalutamide), cardiac failure congestive (2.7% vs 1.6%), pathological fracture (2.7% vs 1.1%) and myocardial infarction (2.2% vs 0%). AEs were the primary reason for discontinuation of study drug in 53 (29.0%) patients in the enzalutamide group and 45 patients (23.8%) in the bicalutamide group. Thirteen patients had an AE resulting in death (10 in the enzalutamide group and 3 in the bicalutamide group). Data cutoff date 19 Oct 2014 (CSR) 30 Aug 2017 (clinical status) ADT: androgen deprivation therapy; BPI: Brief Pain Inventory-Short Form; CI: confidence interval; CRPC: castration-resistant prostate cancer; CSR: clinical study report; ECOG: Eastern Cooperative Oncology Group; FAS: full analysis set; LHRH: luteinizing hormone-releasing hormone; PFS: progression free survival; PSA: prostate specific antigen; SAE: serious adverse event; TEAE: treatment-emergent adverse event

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7.3.7 MDV3100-09 (STRIVE) Study title STRIVE: A Multicenter Phase 2, Randomized, Double-Blind, Efficacy and Safety Study of Enzalutamide vs. Bicalutamide in Men With Prostate Cancer Who Have Failed Primary Androgen Deprivation Therapy Clinical status Ongoing (enrollment complete) Study design Phase 2, randomized, double-blind, active control; open-label extension Indication CRPC Key eligibility criteria Inclusion: Ongoing androgen deprivation therapy with a GnRH analog or bilateral orchiectomy; rising PSA or radiographic progression; M0 or M1 disease; ECOG 0 or 1. Exclusion: History of seizure or any condition that may predispose to seizure; prior radiation or radionuclide therapy for treatment of distant metastases; prior , abiraterone or cytotoxic chemotherapy for prostate cancer; prior disease progression while receiving bicalutamide. Primary objective PFS Secondary objectives Time to PSA progression; PSA response; rPFS; quality of life assessed by FACT-P; safety Drug administration Enzalutamide or bicalutamide Dose Enzalutamide 160 mg once daily or bicalutamide 50 mg once daily Enrolled/treated 396 enrolled/395 treated (197 enzalutamide, 198 bicalutamide) Demographics Median age was 72.0 years (range, 46.0-92.0 years) in the enzalutamide group and 74.0 years (range, 50.0-91.0 years) in the bicalutamide group. Disease stage at study entry was M0 (35.4% enzalutamide, 34.8% bicalutamide) or M1 (64.6% enzalutamide, 65.2% bicalutamide). Baseline ECOG performance status was 0 (74.7% enzalutamide vs 73.2% bicalutamide) or 1 (25.3% enzalutamide vs 26.8% bicalutamide). Median baseline PSA was 11.0 g/L for the enzalutamide group and 13.2 g/L for the bicalutamide group. Efficacy The results from this study demonstrated a clinically meaningful and statistically significant improvement in PFS in patients with metastatic or nonmetastatic CRPC (ITT population) randomized to enzalutamide as compared with bicalutamide (HR: 0.240; 95% CI: 0.181, 0.320; P < 0.0001) and in the subset of patients with nonmetastatic disease (HR: 0.243; 95% CI: 0.142, 0.416; P < 0.0001). The superiority of enzalutamide was observed across all sensitivity analyses performed on the primary PFS endpoint for the ITT population. The beneficial effects of enzalutamide compared with bicalutamide in the ITT population were seen across multiple other efficacy endpoints tested, in all prespecified subgroups, including patients with nonmetastatic disease. In particular, treatment with enzalutamide resulted in a statistically significant reduction in risk of rPFS, which is analogous to MFS, compared with treatment with bicalutamide in patients with nonmetastatic disease (HR: 0.238; 95% CI: 0.102, 0.558, P = 0.003). In addition, treatment with enzalutamide was associated with a statistically significant reduction in the risk of a PFS event and PSA progression, in addition to a statistically significant difference in the ≥ 50% PSA response rates compared with bicalutamide treatment in patients with nonmetastatic disease. Safety A total of 365 (92.4%) patients had ≥ 1 TEAE; the most common ( 10% of patients in the enzalutamide group and  2% higher than the bicalutamide group) were fatigue (39.6% enzalutamide vs 28.8% bicalutamide), fall and hot flush (16.2% vs 9.6% each), dizziness (12.7% vs 7.6%), hypertension (12.7% vs 5.1%) and decreased appetite (12.2% vs 8.6%). A total of 152 patients (38.5%) had ≥ 1 grade 3 or higher AE (39.1% enzalutamide vs 37.9% bicalutamide); those occurring in  2.0% of patients in either treatment group were hypertension (6.1% vs 1.5%), anemia (4.1% vs 5.1%), fatigue (4.6% vs 2.5%), hematuria (3.6% vs 2.0%), syncope (2.5% vs 2.5%), UTI (1.0% vs 3.5%), fall (2.5% vs 1.5%), hydronephrosis (3.0% vs 1.0%), pneumonia (2.0% vs 2.0%), arthralgia (2.0% vs 1.0%), cardiac failure congestive (2.0% vs 1.0%), hypokalemia (1.0% vs 2.0%), urinary retention (0.5% vs 2.0%) and decreased appetite (0% vs 2.0%). Table continued on next page

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MDV3100-09 (STRIVE) (continued) Safety (continued) SAEs occurred in 64 (32.5%) patients in the enzalutamide group and 59 (29.8%) patients in the bicalutamide group; those occurring in  2.0% of patients in either treatment group were hematuria (2.5% enzalutamide vs 2.0% bicalutamide), pneumonia (2.5% vs 2.0%), anemia (1.5% vs 2.0%), UTI (0.5% vs 3.0%), hydronephrosis (2.0% vs 0.5%), transient ischemic attack (2.0% vs 0.5%) and fall (2.0% vs 0.0%). AEs were the primary reason for discontinuation of study drug in 16 patients (8.1%) in the enzalutamide group and 13 patients (6.6%) in the bicalutamide group. Fourteen patients had an AE resulting in death (8 in the enzalutamide group and 6 in the bicalutamide group). Data cutoff date 09 Feb 2015 (CSR) 30 Aug 2017 (clinical status) AE: adverse event; CI: confidence interval; CRPC: castration-resistant prostate cancer; CSR: clinical study report; ECOG: Eastern Cooperative Oncology Group; FACT-P: Functional Assessment of Cancer Therapy-Prostate; GnRH: gonadotropin-releasing hormone; HR: hazard ratio; INR: international normalized ratio; ITT: intent-to-treat; M0: no distant or bone metastasis; M1: distant or bone metastasis; MFS: metastasis free survival; PFS: progression-free survival; PSA: prostate-specific antigen; rPFS: radiographic progression-free survival; SAE: serious adverse event; TEAE: treatment-emergent adverse event; UTI: urinary tract infection

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7.3.8 9785-CL-0122 Study title A Phase 2, Multicenter, Single-arm, Open-label Study to Monitor the Safety of Enzalutamide in Patients with Progressive Castration-resistant Prostate Cancer Previously Treated with Docetaxel-based Chemotherapy Clinical Status Completed Study design Phase 2, open-label, single-arm Indication Progressive CRPC previously treated with docetaxel Key eligibility criteria Age 18 years or older with histologically or cytologically confirmed adenocarcinoma of the prostate and had ongoing ADT with a GnRH agonist/antagonist and planned to maintain the therapy throughout the study period or had a prior orchiectomy. In addition, the patient must have had at least 1 prior chemotherapy regimen for metastatic CRPC with at least 1 regimen containing docetaxel, progressive disease per investigator, no known or suspected brain metastasis and ECOG 0 to 2. No prior abiraterone use was allowed. Enrollment (planned) Approximately 30 Primary objective Safety in Eastern European population Drug administration Enzalutamide Dose 160 mg/day once daily Enrolled/treated 30 enrolled/30 treated Demographics All 30 patients were white males. The mean age was 67.5 years, mean BMI was 28.5 kg/m2 and the majority of patients (25/30 [83.3%]) had an ECOG performance status of 1 at study entry. Results of metastases assessment at screening showed that all patients had metastatic disease and the majority of patients (27/30 [90.0%]) had bone metastases. A total of 10/30 (33.3%) patients had previous radiation therapy for their primary cancer. A total of 18/30 (60.0%) patients had surgical treatment of their primary cancer: 9/18 (50.0%) patients had a prostatectomy, 7/18 (38.9%) patients had an orchiectomy, 3/18 (16.7%) patients had transurethral resection of the prostate and 2/18 (11.1%) patients had other procedures (prostate biopsy and ureteral stenting. Safety A total of 20 of 30 treated patients (66.7%) had 1 or more TEAE. The most frequently reported TEAEs (reported in ≥ 10% of patients) were asthenia (6 [20.0%] patients), fatigue (6 [20.0%] patients), increased PSA (4 [13.3%] patients), bone pain (4 [13.3%] patients) and increased AST (3 [10/0%] patients). A total of 6 (20%) patients had 1 or more SAE: malignant neoplasm progression (3 [10.0%] patients) and general physical health deterioration and metastases to skin, anemia, cardiopulmonary failure, hematemesis, fatigue, hepatic failure, AST increased and hematuria (1 [3.3%] patient each). AEs led to permanent discontinuation of study drug in 9 (30.0%) patients. The 3 most common TEAEs leading to discontinuation of study drug were increased PSA (4 patients) and increased AST and malignant neoplasm progression (2 patients each); all other events were single occurrences. Three patients died due to a TEAE during the study: 2 patients due to prostate cancer progression and 1 patient due to cardiopulmonary failure and liver failure. None of these events were considered related to study drug. By the end of the study, no patients experienced an enzalutamide-related grade 3 or higher TEAE, an enzalutamide-related SAE or an enzalutamide-related TEAE leading to permanent discontinuation. Data cutoff date 18 Oct 2015 (CSR) 25 May 2017 (Final CSR) ADT: androgen-deprivation therapy; AST: aspartate aminotransferase; BMI: body mass index; CRPC: castration-resistant prostate cancer; CSR: clinical study report; ECOG: Eastern Cooperative Oncology Group; GnRH: gonadotropin-releasing hormone; PSA: prostate-specific antigen; SAE: serious adverse event; TEAE: treatment-emergent adverse event

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7.3.9 9785-CL-0123 Study title A Phase 2 Open-label Extension Study for Subjects with Prostate Cancer Who Previously Participated in an Enzalutamide Clinical Study Clinical Status Ongoing (enrolling) Study design Patients who were actively enrolled and have completed enzalutamide treatment in a previous study with enzalutamide could be eligible to participate in this study when continuation of enzalutamide was deemed by the investigator in the best interest of the subjects. Indication Prostate cancer patients Key eligibility criteria Patients who were actively enrolled and have completed enzalutamide treatment in a previous study with enzalutamide could be eligible to participate in this study when continuation of enzalutamide was deemed by the investigator in the best interest of the subjects. Enrollment (planned) Approximately 470 Primary objective To follow up the long-term safety of continued administration of enzalutamide in prostate cancer subjects who were enrolled and completed enzalutamide treatment period in a prior study with enzalutamide which has completed, at a minimum, the primary analysis or the study specified evaluation period Drug administration Enzalutamide Dose 160 mg enzalutamide once daily Enrolled/treated 0 enrolled/0 treated Demographics Not yet available Safety Not yet available Data cutoff date 30 Aug 2017 (clinical status)

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7.3.10 MDV3100-18 Study title A Phase 2, Open-Label, Single-Arm Study of 18F-Sodium Fluoride PET/CT Bone Imaging in Enzalutamide-Treated Chemotherapy-Naïve Patients With Bone-Metastatic Castration-Resistant Prostate Cancer Clinical status Ongoing (enrollment complete) Study design Phase 2, single arm, open-label Indication Bone metastatic CRPC Key eligibility criteria Inclusion: Patients  18 years of age with bone-metastatic CRPC as assessed by at least 2 lesions on conventional whole-body 99mTc-MDP radionuclide bone scintigraphy that did not show a superscan. Progressive disease on ADT at screening demonstrated by rising PSA with most recent PSA ≥ 2 µg/L. Ongoing ADT with an LHRH analog or bilateral orchiectomy. Testosterone ≤ 1.73 nmol/L at screening. Asymptomatic/minimally symptomatic prostate cancer; ECOG 0 or 1; 1ife expectancy ≥ 12 months. Exclusion: Visceral metastatic disease; prior enzalutamide, abiraterone acetate, , ketoconazole, radium Ra 223 dichloride or other bone-targeting radionuclides; cytotoxic chemotherapy in the CRPC setting for the treatment of prostate cancer; participation in a of an investigational agent that inhibits the androgen receptor or androgen synthesis (unless treatment was placebo); history of seizure or any condition that may predispose to seizure. Enrollment (Planned) 40 Primary objective Evaluate 18F-NaF PET/CT imaging as a method for determining treatment response in metastatic bone lesions at the time of disease progression (PSA, bone or soft tissue or other clinically relevant progression) or at 2 years without progression after treatment initiation in patients who are chemotherapy-naïve in the castration-resistant setting with progressive bone-metastatic CRPC treated with enzalutamide. Secondary objectives Evaluate heterogeneity of response in metastatic bone lesions at the time the primary objective is assessed. Drug administration Enzalutamide Dose Enzalutamide 160 mg once daily Enrolled/treated 0 enrolled/0 treated Demographics Not yet available Safety Not yet available Data cutoff date 30 Aug 2017 (clinical status) 18F-NaF: 18F-sodium fluoride; ADT: androgen deprivation therapy; CRPC: castration-resistant prostate cancer; ECOG: Eastern Cooperative Oncology Group; LHRH: luteinizing hormone-releasing hormone; PET/CT: positron-emission tomography / computed tomography; PSA: prostate-specific antigen; 99mTc-MDP: Tc 99m medronate.

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7.3.11 9785-MA-1010 (ENACT) Study title A Randomized Study of Enzalutamide in Patients with Localized Prostate Cancer Undergoing Active Surveillance (ENACT) Clinical Status Ongoing (enrolling) Study design Open-label, 2-arm study Indication Localized prostate cancer Key eligibility criteria Male patients, at least 18 years of age, who have histologically proven adenocarcinoma of the prostate diagnosed (with ≥ 10 core biopsy) within 6 months of screening. Prostate cancer categorized (as determined by central pathology review) as low risk is defined as T1c-T2a, PSA < 10, N0, M0 (or presumed N0, M0 if CT/bone scan not done due to low risk of metastases), Gleason score ≤ 6, ECOG status ≤ 2 and estimated life expectancy > 5 years or intermediate risk is defined as T2b-T2c, PSA < 20, N0, M0 (or presumed N0, M0 if CT/bone scan not done), Gleason score ≤ 7 (3+4 pattern only), ECOG status ≤ 2 and estimated life expectancy > 5 years. Enrollment (Planned) 222 Patients To compare the time to prostate cancer progression (pathological or therapeutic Primary objective progression) between patients treated with enzalutamide vs patients undergoing active surveillance To evaluate: safety, proportion of patients with negative biopsy for cancer at 1 year and 2 years, percent of cancer positive cores at 1 year and 2 years, time to PSA progression (secondary rise in serum PSA ≥ 25% above baseline or ≥ 25% above nadir or absolute increase ≥ 2 ng/mL), proportion of patients with Secondary objectives secondary rise in serum PSA≥ 25% above baseline or ≥ 25% above nadir or absolute increase ≥ 2 ng/mL at 1 year and 2 years, brief fatigue index, medical outcomes study 12-item short form survey, Expanded Prostate Cancer Index Composite questionnaire - urinary, sexual and hormonal domains, Memorial Anxiety Scale for Prostate Cancer questionnaire Drug administration Enzalutamide Dose 160 mg once daily (4 x 40 mg capsules) Enrolled/treated 0 enrolled/0 treated Demographics Not yet available Efficacy Not yet available Safety Not yet available Data cutoff date 30 Aug 2017 (clinical status) CT: computed tomography; ECOG: Eastern Cooperative Oncology Group; PSA: prostate-specific antigen

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7.4 Phase 3 Studies in Prostate Cancer Patients 7.4.1 MDV3100-03 (PREVAIL) Study title PREVAIL: A Multinational Phase 3, Randomized, Double-Blind, Placebo-Controlled Efficacy and Safety Study of Oral MDV3100 in Chemotherapy-Naïve Patients With Progressive Metastatic Prostate Cancer Who Have Failed Androgen Deprivation Therapy Clinical status Ongoing (enrollment complete) Study design Phase 3, randomized, double-blind, placebo-controlled Indication Chemotherapy-naïve metastatic castration-resistant prostate cancer after failure of ADT Key eligibility criteria Age 18 years or older with histologically or cytologically confirmed adenocarcinoma of the prostate without neuroendocrine differentiation or small cell features; ongoing ADT with a GnRH analogue or bilateral orchiectomy (i.e., surgical or medical castration); serum testosterone ≤ 1.73 nmol/L; progressive disease documented by at least 1 of the following while the patient was on ADT: PSA progression (defined as a minimum of 2 rising PSA levels at ≥ 1-week intervals between each determination with progression documented after withdrawal from antiandrogen therapy and PSA ≥ 2 ng/mL at screening), soft tissue disease progression defined by RECIST 1.1 or bone disease progression defined by PCWG2; asymptomatic or mildly symptomatic from prostate cancer (i.e., < 4 on BPI question 3); ECOG 0 or 1; life expectancy of ≥ 6 months. No prior cytotoxic chemotherapy allowed. Primary objective OS and rPFS Secondary objectives Time to first skeletal related event, time to initiation of cytotoxic chemotherapy, time to PSA progression, PSA response rate ≥ 50% and best overall soft tissue response Drug administration Enzalutamide or placebo Dose 160 mg once daily Enrolled/treated 1717 enrolled/1715 treated (871 enzalutamide, 844 placebo) Demographics The median age at randomization was 72.0 years in the enzalutamide group and 71.0 years in the placebo group and the majority (approximately 77%) of patients in both groups were white. In both groups, the baseline ECOG performance score was 0 in approximately 68% of patients and 1 in approximately 32% of patients. In both groups, the baseline mean pain score (BPI question 3) was 0 to 1 (asymptomatic) in approximately 67% of patients and 2 to 3 (mildly symptomatic) in approximately 31% of patients. Approximately 43% of patients in both groups entered the study with PSA progression only (rising PSA), and approximately 40% of patients in both groups entered the study with radiographic and PSA progression. Efficacy Treatment with enzalutamide was associated with a statistically significant benefit on both coprimary endpoints and all secondary endpoints. Treatment with enzalutamide was shown to decrease the risk of death by 29% (HR: 0.706; P < 0.0001). As described through the Kaplan Meier curve of OS, the OS benefit was observed early, approximately 3 to 4 months after randomization, and was maintained over the duration of the study. It is also noteworthy that the survival benefit was observed despite substantially higher and earlier use in the placebo group (70.3%) compared with the enzalutamide group (40.3%) of subsequent therapies with a demonstrated survival benefit in patients with prostate cancer. A consistent relative OS benefit was observed across all prespecified subgroups. Treatment with enzalutamide also conferred an important benefit on the Table continued on next page

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MDV3100-03 (continued) Efficacy (continued) coprimary endpoint, rPFS, as measured by blinded central review. Patients receiving enzalutamide had an 81% decreased risk of radiographic progression or death (HR: 0.186; P < 0.0001). The results of the rPFS analysis were robust as confirmed by all prespecified sensitivity analyses as well as consistent with the investigator-assessed rPFS analysis. The effect on rPFS was observed at the first postbaseline imaging time point as demonstrated by the early separation of the Kaplan-Meier curves and increased over time. The data integrity for the rPFS endpoint was high; more than 98% of imaging scans were received for central review and a high degree of concordance (87.6%) was observed between central and investigator assessments of radiographic progression using the same 06 May 2012 data cutoff date. Other clinically important findings included a 17.2-month delay in the median time to initiation of cytotoxic chemotherapy in the enzalutamide group vs placebo (28.0 vs 10.8 months), which also delayed chemotherapy treatment-associated morbidities. Additionally, the absolute difference in objective soft tissue response between the enzalutamide-treated patients and placebo-treated patients was 53.9% (95% CI: 48.5%, 59.2%; P < 0.0001). In patients with measurable soft tissue disease, CR was reported in 19.7% of enzalutamide-treated patients compared to 1.0% of placebo-treated patients and PR was reported in 39.1% of enzalutamide-treated patients vs 3.9% of placebo-treated patients. A decrease in risk of a skeletal-related event (HR: 0.718; 95% CI: 0.610, 0.844; P < 0.0001) and PSA progression (HR: 0.169; 95% CI: 0.147, 0.195; P < 0.0001) with substantial and statistically significant PSA response rates (78.0% had PSA response ≥ 50% and 46.8% had PSA response ≥ 90%, P < 0.0001 for both) in enzalutamide-treated patients provide additional evidence of clinical benefit. Furthermore, the benefit on time to degradation of FACT-P total scores (HR: 0.625; 95% CI: 0.542, 0.720; P < 0.0001) suggests that treatment with enzalutamide may prolong quality of life. Safety TEAEs were reported in the majority of patients in the enzalutamide and placebo groups (96.9% vs 92.3%). Enzalutamide-treated patients had a higher incidence of grade 3 or higher TEAEs (42.9% enzalutamide vs 37.1% placebo) and SAEs (32.0% vs 26.8%); however, the time to first grade 3 or higher event and time to first SAE were longer in the enzalutamide group compared with the placebo group. The overall incidence of AEs that were the primary reason for treatment discontinuation (approximately 6%) and AEs leading to death (approximately 4%) was similar between treatment groups. AEs reported in at least 5% of patients in either treatment group with at least a 2% absolute increased incidence in the enzalutamide group compared with the placebo group included fatigue, back pain, constipation, arthralgia, decreased appetite, diarrhea, hot flush, asthenia, weight decreased, peripheral edema, hypertension, headache, fall, dizziness, hematuria, insomnia, nasopharyngitis, dysgeusia and upper respiratory tract infection. The AEs with an event rate higher in the enzalutamide group compared with the placebo group when adjusted for length of exposure were hot flush, hypertension, fall and dysgeusia (increase in event rate of dysgeusia was marginal). Grade 3 or higher AEs reported in at least 1% of patients in either treatment group and with at least a 0.5% absolute increased incidence in the enzalutamide group compared with the placebo group include cataract, nausea, general physical health deterioration, pneumonia, fall, spinal cord compression, syncope and hypertension. After adjustment for length of exposure, cataract and hypertension were the only events with a higher event rate per 100 patient-years in the enzalutamide group. Table continued on next page

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MDV3100-03 (continued) Safety (continued) SAEs with at least 0.5% absolute higher incidence in the enzalutamide group compared with the placebo group included anemia, coronary artery disease, fatigue, femoral neck facture, pathological fracture, syncope, cauda equina syndrome and hypertension. During the study, 27.6% of enzalutamide-treated patients and 35.4% of placebo-treated patients died as of the data cutoff date. Overall, deaths due to disease progression, deaths due to other causes and deaths due to unknown causes were lower in the enzalutamide group than the placebo group. Treatment-emergent deaths due to causes assessed as unrelated to prostate cancer occurred in 1.8% of enzalutamide-treated patients and 1.5% of placebo-treated patients. On average, these deaths occurred twice as late after randomization in the enzalutamide group compared with the placebo group (333 days vs 165 days). With respect to previously identified risks associated with enzalutamide and AEs of clinical interest, treatment with enzalutamide was associated with a higher incidence of fatigue, hot flush, hypertension, falls, nonpathological fractures, mental impairment and neutropenia; and was not associated with a higher incidence of seizure, or infections leading to death. Data cutoff date 16 Sep 2013 (CSR) 30 Aug 2017 (clinical status) ADT: androgen deprivation therapy; AE: adverse event; BPI: Brief Pain Inventory-Short Form; CI: confidence interval; CR: complete response; CSR: clinical study report; ECOG: Eastern Cooperative Oncology Group; FACT-P: Functional Assessment of Cancer Therapy-Prostate; GnRH: gonadotropin-releasing hormone; HR: hazard ratio; OS: overall survival; PCWG2: Prostate Cancer Clinical Trials Working Group 2; PR: partial response; PSA: prostate-specific antigen; RECIST: Response Evaluation Criteria in Solid Tumors; rPFS: radiographic progression-free survival; SAE: serious adverse event; TEAE: treatment-emergent adverse event

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7.4.2 CRPC2 (AFFIRM) Study title AFFIRM: A Multinational Phase 3, Randomized, Double-blind, Placebo- controlled Efficacy and Safety Study of Oral MDV3100 in Patients with Progressive Castration-resistant Prostate Cancer Previously Treated with Docetaxel-based Chemotherapy Clinical Status Ongoing (enrollment complete) Study design Phase 3, randomized, double-blind, placebo-controlled Indication Metastatic castration-resistant prostate cancer after failure of docetaxel therapy Key eligibility criteria Men with histologically or cytologically confirmed adenocarcinoma of the prostate without neuroendocrine differentiation or small cell features; ongoing ADT with a GnRH analogue or orchiectomy (i.e., surgical or medical castration); serum testosterone ≤ 1.7 nmol/L; progressive disease by PSA or imaging after docetaxel-based chemotherapy in the setting of medical or surgical castration and defined by 1 or more of the following: PSA progression a minimum of 3 rising PSA levels at ≥ 1-week intervals between each determination, with PSA ≥ 2 ng/mL at screening), soft tissue disease progression defined by RECIST 1.1 or bone disease progression defined by 2 or more new lesions on bone scan; ECOG 0 to 2; life expectancy of ≥ 6 months. No more than 2 prior chemotherapy regimens with at least 1 regimen containing docetaxel. Primary objective OS Secondary objectives rPFS; time to first skeletal related event; QoL; time to PSA progression; pain palliation; and circulating tumor cell count conversion rate Drug administration Enzalutamide and placebo Dose 160 mg once daily Enrolled/treated 1199 enrolled/1199 treated (800 enzalutamide, 399 placebo) Demographics The median age was 69.0 years in both treatment groups, with approximately 25% of patients in both arms ≥ 75 years old. Over 90% of patients in both treatment groups were White. Approximately 90% of patients in both arms had a baseline ECOG performance status of 0 or 1. Greater than 90% of patients in both treatment groups entered the study with bone metastases and greater than 60% of patients in both treatment groups entered the study with both bone and soft tissue metastases. The median number of cycles of prior docetaxel received was 8.5 in the enzalutamide group and 8.0 in the placebo group. Less than 5% of patients in both the enzalutamide- and placebo-treated groups received less than 225 mg/m2 (or 3 cycles) of prior docetaxel. Efficacy This study demonstrated that enzalutamide treatment decreased the risk of death by 37% (HR: 0.631; P < 0.0001) compared with placebo treatment. The statistically significant and clinically meaningful benefit of enzalutamide treatment as measured by OS was seen in all prespecified patient subgroups and observed despite 42.0% of enzalutamide-treated and 61.4% of placebo-treated patients receiving subsequent therapies to treat prostate cancer, including abiraterone (20.9% vs 24.3%) and cabazitaxel (9.8% vs 13.8%), both shown to improve OS following docetaxel treatment. Enzalutamide treatment also resulted in significant improvements over placebo treatment in all key secondary efficacy endpoints that were rank-prioritized in the statistical analysis plan including: time to PSA progression, rPFS and time to first skeletal-related event. Enzalutamide treatment resulted in statistically significant improvements over placebo treatment in the other secondary and exploratory efficacy endpoints of PSA response, radiographic response, QoL as assessed by FACT-P, pain palliation rate at week 13, pain progression at week 13 and time to pain progression based on FACT-P. Table continued on next page

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CRPC2 (continued) Safety The number of patients reporting any AE was similar in the enzalutamide and placebo arms (98.1% vs 97.7%, respectively). AEs leading to death (2.9% vs 3.5%), AEs leading to dose reduction (2.1% vs 2.8%), dose interruption (12.8% vs 15.3%), discontinuation of study drug (7.6% vs 9.8%), SAEs (33.5% vs 38.6%) and grade 3 or higher AEs (45.3% vs 53.1%) all occurred less frequently in the enzalutamide group than in the placebo group. The causes of death were similar in both treatment groups. AEs that occurred more frequently in the enzalutamide group with at least a 2% increase over the rate observed in the placebo group included: fatigue (33.6% vs 29.1%), diarrhea (21.4% vs 17.5%), hot flush (20.3% vs 10.3%), musculoskeletal pain (13.6% vs 10.0%), headache (11.6% vs 5.5%), insomnia (8.6% vs 6.0%), (6.5% vs 4.5%), hematuria (6.5% vs 4.5%), anxiety (6.4% vs 4.0%), hypertension (6.1% vs 2.8%), nasopharyngitis (5.1% vs 3.0%), pollakiuria (4.6% vs 2.5%), fall (4.0% vs 1.3%), pruritus (3.6% vs 1.3%), dry skin (3.5% vs 1.3%) and musculoskeletal stiffness (2.5% vs 0.3%). When event rates were analyzed by the event rate per 100 patient-years of treatment, hot flush (27.4 vs 24.6), headache (17.8 vs 14.4), hypertension (8.4 vs 7.2), fall (5.9 vs 3.0), pruritus (5.3 vs 3.0) and dry skin (4.6 vs 3.0) remained more frequent in the enzalutamide group. Overall, there were fewer patients reporting SAEs in the enzalutamide group than in the placebo group. SAEs other than seizure that occurred more frequently in the enzalutamide group than the placebo group included: spinal cord compression (6.0% vs 3.8%), metastatic pain (1.5% vs 0.8%), pathological fracture (1.5% vs 0.5%), urinary tract obstruction (0.9% vs 0.3%) and cauda equina syndrome (0.8% vs 0.0%). These SAEs are consistent with prostate cancer disease progression. Overall, there were fewer patients reporting grade 3 or higher AEs in the enzalutamide group than in the placebo group. Grade 3 or higher AEs that occurred more frequently in the enzalutamide group than the placebo group included: spinal cord compression (5.8% vs 3.8%), anorexia (2.1% vs 1.0%), metastatic pain (1.9% vs 0.8%) and pathological fracture (1.5% vs 0.5%). These grade 3 or higher AEs are consistent with prostate cancer disease progression. A smaller proportion of patients in the enzalutamide group discontinued treatment due to AEs (7.6% vs 9.8%) as compared with patients in the placebo group. Except for 5 patients with seizures, who discontinued treatment (as per protocol), the AE preferred terms for events leading to treatment discontinuation were varied and balanced between the 2 treatment groups. This study identified the following adverse drug reactions associated with enzalutamide treatment: seizure, fatigue, hot flush, headache, hypertension, falls, hallucinations, cognitive and memory impairment, pruritus and dry skin. Data cutoff date 25 Sep 2011 (CSR) 30 Aug 2017 (clinical status) ADT: androgen deprivation therapy; AE: adverse event; CSR: clinical study report; ECOG: Eastern Cooperative Oncology Group; FACT-P: Functional Assessment of Cancer Therapy-Prostate; GnRH: gonadotropin-releasing hormone; HR: hazard ratio; OS: overall survival; PSA: prostate-specific antigen; QoL: quality of life; RECIST: Response Evaluation Criteria in Solid Tumors; rPFS: radiographic progression-free survival; SAE: serious adverse event; TEAE: treatment-emergent adverse event

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7.4.3 MDV3100-13 (EMBARK) Study title EMBARK: A Phase 3, Randomized, Efficacy and Safety Study of Enzalutamide Plus Leuprolide, Enzalutamide Monotherapy and Placebo Plus Leuprolide in Men With High-Risk Nonmetastatic Prostate Cancer Progressing After Definitive Therapy Clinical status Ongoing (enrolling) Study design Phase 3, randomized Indication High-risk nonmetastatic prostate cancer Key eligibility criteria Patients  18 years of age with prostate cancer initially treated with curative intent by radical prostatectomy or radiotherapy or both, followed by disease recurrence (rising PSA). No evidence of distant metastatic disease, no prior hormonal therapy other than neoadjuvant/adjuvant therapy to treat prostate cancer ≤ 36 months in duration and ≥ 9 months before randomization and no prior cytotoxic chemotherapy or systemic biologic therapy, including immunotherapy, for prostate cancer. Enrollment (Planned) Approximately 1860 Primary objective Metastasis-free survival Secondary objectives Primary: Overall survival, proportion of patients per group who remain treatment-free 2 years after suspension of study drug treatment at week 37 due to undetectable PSA and time to castration resistance Secondary: Proportion of patients per group with undetectable PSA 2 years after suspension of study drug treatment at week 37 due to undetectable PSA; proportion of patients per group with undetectable PSA at 36 weeks on study drug; prostate cancer-specific survival; time to resumption of any hormonal therapy following suspension at week 37 due to undetectable PSA; time to first symptomatic skeletal event; time to metastasis; time to clinically relevant pain; quality of life; and safety. Drug administration Random assignment to 1 of the following: Enzalutamide (blinded) plus leuprolide Placebo (blinded) plus leuprolide Enzalutamide monotherapy (open-label) Dose Enzalutamide: four 40-mg soft gelatin capsules by mouth once daily (160 mg/day) Placebo: identical in appearance to enzalutamide capsules and administered in the same manner as enzalutamide Leuprolide acetate: 22.5 mg administered as a single intramuscular or subcutaneous injection once every 12 weeks (minimum of 3 doses, providing 36 weeks of treatment) Enrolled/treated 0 enrolled/0 treated Demographics Not yet available Efficacy Not yet available Safety Not yet available Data cutoff date 30 Aug 2017 (clinical status) PSA: prostate-specific antigen

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7.4.4 MDV3100-14 (PROSPER) Study title PROSPER: A Multinational, Phase 3, Randomized, Double-blind, Placebo-controlled, Efficacy and Safety Study of Enzalutamide in Patients With Nonmetastatic Castration-resistant Prostate Cancer Clinical Status Ongoing (enrollment complete) Study design Phase 3, randomized, placebo-controlled, double-blind Indication Nonmetastatic castration-resistant prostate cancer Key eligibility criteria Age 18 years or older with histologically or cytologically confirmed adenocarcinoma of the prostate without neuroendocrine differentiation, signet cell or small cell features; no prior or present evidence of metastatic disease by whole body radionuclide bone scan for bone disease and CT/MRI for soft tissue disease; ongoing ADT with a GnRH agonist/antagonist or prior bilateral orchiectomy; progressive disease based on rising PSA ≥ 2 ng/mL (most recent value in a series of at least 3 tests at ≥ 1-week intervals); PSA doubling time ≤ 10 months; testosterone ≤ 1.73 nmol/L; ECOG 0 or 1; life expectancy of ≥ 12 months. No prior cytotoxic chemotherapy allowed. Enrollment (planned) Approximately 1440 patients (960 enzalutamide and 480 placebo) Primary objective MFS Secondary objectives OS; time to pain progression; time to opiate use for prostate cancer pain; time to pain progression or opiate use for prostate cancer pain; time to first use of cytotoxic chemotherapy; time to first use of new antineoplastic therapy; time to PSA progression; PSA response rates; time to functional status deterioration assessed by FACT-P; quality of life (EQ-5D-5L, QLQ-PR25); safety Drug administration Enzalutamide or placebo Dose 160 mg/day once daily Enrolled/treated 1401 enrolled/1395 treated (930 enzalutamide, 465 placebo) Demographics The median age at randomization was 74.0 years in the enzalutamide group and 73.0 years in the placebo group and the majority (70.7%) of all patients were white. The majority (76.8%) of all patients had a PSA doubling time < 6 months and the median PSA doubling time was 3.7 months. Efficacy The study met the primary objective demonstrating that enzalutamide improved MFS in patients with nonmetastatic CRPC when compared with placebo. As of the data cutoff date (28 Jun 2017), treatment with enzalutamide in men with nonmetastatic CRPC and rapidly rising PSA level resulted in substantial improvement over placebo as demonstrated by a clinically meaningful and statistically significant 70.8% decrease in the risk of an MFS event assessed by BICR, with an HR of 0.292 (95% CI: 0.241, 0.352; P < 0.0001). The median (95% CI) time to a MFS event was 36.6 (33.1, not reached) months in the enzalutamide group vs 14.7 (14.2, 15.0) months in the placebo group, for a difference of 21.9 months. The improvement in MFS was robust and consistent across all prespecified sensitivity and subgroup analyses. Improvement observed in the primary MFS endpoint was supported by clinically meaningful and statistically significant improvements in 2 key secondary endpoints: time to PSA progression and time to first use of new antineoplastic therapy. Treatment with enzalutamide was associated with a 93.4% decrease in the risk of a PSA progression event compared with treatment with placebo, with an HR of 0.066 (95% CI: 0.054, 0.081; P < 0.0001). The median (95% CI) time to PSA progression was 37.2 (33.1, not reached) months in patients receiving enzalutamide compared with 3.9 (3.8, 4.0) months in patients receiving placebo. Treatment with enzalutamide was associated with a 79.2% reduction in the risk of initiating a new antineoplastic therapy compared with treatment with placebo, with an HR of 0.208 (95% CI: 0.168, 0.258; P < 0.0001). The median (95% CI) time to first use of new antineoplastic therapy was 39.6 (37.7, not reached) months in the enzalutamide group vs 17.7 (16.2, 19.7) months in the placebo group. With only 11.8% of deaths needed for the planned analysis, the OS data are not yet mature. However, at the time of the primary MFS analysis, the first interim analysis of OS showed a favorable trend, with an HR of 0.795 (95% CI: 0.580, 1.089; P = 0.1519). Table continued on next page

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MDV3100-14 (PROSPER) (continued) Efficacy (continued) Treatment with enzalutamide resulted in a clinically meaningful and statistically significant improvement over placebo in most other secondary endpoints as well. However, for time to pain progression, treatment with enzalutamide compared with placebo resulted in an HR of 0.959 (95% CI: 0.801, 1.149; P = 0.6534). The median (95% CI) time to pain progression was 18.5 (17.0, 22.1) months in the enzalutamide group vs 18.4 (14.8, 22.1) months in the placebo group. Treatment with enzalutamide did not show a significant difference in quality of life compared with placebo as measured by the time to degradation of the global FACT-P score, with an HR of 0.922 (95% CI: 0.787, 1.080; P = 0.3128). Safety A total of 1168 of 1395 (83.7%) treated patients had 1 or more TEAE. TEAEs reported in ≥ 5% of patients in the enzalutamide group and with a ≥ 2% higher incidence than the placebo group were fatigue (32.6% enzalutamide vs 13.8% placebo), hot flush (13.0% vs 7.7%), hypertension (11.9% vs 5.2%), nausea (11.4% vs 8.6%), fall (11.4% vs 4.1%), dizziness (9.8% vs 4.3%), decreased appetite (9.6% vs 3.9%), constipation (9.1% vs 6.9%), headache (9.1% vs 4.5%), asthenia (8.8% vs 6.0%) and weight decreased (5.9% vs 1.5%). When adjusted for duration of treatment, the differences between the enzalutamide group vs placebo group for these TEAEs were reduced; the event rates per 100 patient- years of treatment were as follows: fatigue (22.9 enzalutamide vs 13.1 placebo), hot flush (8.8 vs 7.4), hypertension (8.4 vs 5.1), nausea (9.0 vs 8.6), fall (9.5 vs 4.1), dizziness (7.2 vs 4.9), decreased appetite (7.1 vs 3.5), constipation (6.9 vs 6.8), headache (6.5 vs 4.9), asthenia (6.9 vs 5.7) and weight decreased (4.0 vs 1.4). Overall, the incidence of grade 3 or higher TEAEs reported in the enzalutamide group was higher than in the placebo group (31.4% vs 23.4%). Grade 3 or higher TEAEs occurring in ≥ 1% of patients in the enzalutamide group and with ≥ 0.5% higher incidence than the placebo group were hypertension (4.6% enzalutamide vs 2.2% placebo), fatigue (2.9% vs 0.6%), syncope (1.1% vs. 0.4%), fall (1.3% vs 0.6%), asthenia (1.2% vs 0.2%) and pneumonia (1.1% vs 0.4%). The proportion of patients with TEAEs leading to death was higher in the enzalutamide group compared with the placebo group (32 [3.4%] patients vs 3 [0.6%] patients). Of the 32 patients who had TEAEs leading to death, 2 patients had TEAEs that were considered by the investigator to be related to the study drug (general physical health deterioration and duodenal ulcer hemorrhage). The majority of deaths (19 patients in the enzalutamide group vs 2 patients in the placebo group) occurred > 365 days after initiating study drug. The most frequently reported preferred terms leading to death were myocardial infarction (0.4%), general physical health deterioration (0.2%) and acute myocardial infarction (0.2%). The proportion of study-drug-related treatment-emergent SAEs in the enzalutamide group was higher compared with the placebo group (3.4% vs 2.6%). The only SAE in ≥ 1% patients that was ≥ 0.5% higher in the enzalutamide group compared with placebo was pneumonia (1.0% vs 0.2%). The proportion of patients with TEAEs reported as the primary reason for permanent discontinuation of study drug was higher in the enzalutamide group compared with placebo (9.4% enzalutamide vs 6.0% placebo). The most frequent TEAEs reported as the primary reason for permanent discontinuation of study drug included fatigue (1.6%) followed by myocardial infarction (0.4%), cardiac failure (0.3%), cerebrovascular accident (0.3%) and nausea (0.3%). Data cutoff date 28 Jun 2017 (CSR) 30 Aug 2017 (clinical status) ADT: androgen deprivation therapy; AE: adverse event; BICR: blinded independent central review; CI: confidence interval; CSR: clinical study report; CT: computed tomography; ECOG: Eastern Cooperative Oncology Group; EQ-5D-5L: European Quality of Life-Five Domain Five Level Scale; FACT-P: Functional Assessment of Cancer Therapy-Prostate; GnRH: gonadotropin-releasing hormone; HR: hazard ratio; MFS: metastasis free survival; MRI: magnetic resonance imaging; OS: overall survival; PSA: prostate-specific antigen; QLQ-PR25: Quality of Life Questionnaire Patient-reported 25 Questions; SAE: serious adverse event; TEAE: treatment-emergent adverse event

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7.4.5 9785-CL-0232 (Asian PREVAIL) Study title Asian Multinational Phase 3, Randomized, Double-Blind, Placebo Controlled Efficacy and Safety Study of Oral Enzalutamide in Chemotherapy Naive Subjects with Progressive Metastatic Prostate Cancer Who Have Failed Androgen Deprivation Therapy Clinical Status Ongoing (enrollment complete) Study design Phase 3, randomized, placebo-controlled, double-blind Indication Chemotherapy-naïve patients with progressive metastatic castration resistant prostate cancer who failed ADT Key eligibility criteria Male ≥ 18 years of age with histologically or cytologically confirmed adenocarcinoma of the prostate without neuroendocrine differentiation or small cell histology; ongoing ADT with a GnRH analogue or bilateral orchiectomy; serum testosterone level ≤ 1.73 nmol/L (50 ng/dL) and progressive, metastatic disease at screening. The patient must have an ECOG 0 or 1 and a life expectancy of ≥ 6 months. No prior chemotherapy for prostate cancer is permitted. Enrollment (planned) Approximately 400 evaluable patients (200 per treatment arm) Objectives Time to PSA progression, pharmacokinetics of enzalutamide and its major metabolites, exposure of enzalutamide and its major metabolite and safety Drug administration Enzalutamide or placebo in combination with ADT (either bilateral orchiectomy or GnRH agonist/antagonist) Dose Enzalutamide: 160 mg/day once daily Placebo: matching capsules Enrolled/treated 388 enrolled/388 treated (198 enzalutamide and 190 placebo; data from Site 105 were excluded from the analyses due to data quality concerns) Demographics Demographic characteristics for the ITT population were generally similar between the 2 treatment groups. The median age at randomization was 71.0 years in both groups, with overall 30.4% of patients aged 75 to 84 years and 5.7% of patients ≥ 85 years. All patients were Asian. Overall, 61.1% of patients had a baseline ECOG performance status of 0 and 38.9% had a baseline ECOG performance status of 1. Approximately 66% of patients had a high-risk Gleason score of 8 to 10. Most patients received at least 3 prostate cancer therapies before entering the study (29.9% received 3 prior prostate cancer therapies and 36.9% received 4 or more prior prostate cancer therapies). Approximately 55% of patients received at least 3 hormonal therapies before entering the study (31.2% received 3 hormonal therapies and 23.7% received 4 or more hormonal therapies). Overall, 88.1% of patients received prior antiandrogen therapies and 23.7% were receiving bisphosphonate or denosumab therapy at baseline. Only 1.8% of patients received prior ketoconazole therapy at baseline. Overall, 14.7% of patients had prior radiotherapy as treatment for prostate cancer and 37.4% of patients had a prior surgical procedure to treat prostate cancer. Efficacy Treatment with enzalutamide resulted in a statistically significant improvement in the primary efficacy endpoint, time to PSA progression (P < 0.0001). The median time to PSA progression was 8.31 months in the enzalutamide group versus 2.86 months in the placebo group (median follow-up time based on reverse Kaplan-Meier estimation of 6.47 months for the enzalutamide group and 2.99 months for the placebo group). The separation of Kaplan-Meier curves was noted as early as 3 to 4 months after randomization and was maintained throughout the study. Table continued on next page

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9785-CL-0232 (continued) Efficacy (continued) Treatment with enzalutamide resulted in statistically significant improvements in almost all secondary endpoints evaluating OS (P = 0.0015), rPFS (P < 0.0001), time to initiation of cytotoxic chemotherapy (P = 0.0020), PSA response ≥ 50% (P < 0.0001) and best overall soft tissue response (P < 0.0001), and a nonstatistically significant numerical benefit in time to the first SRE (44% reduction in risk of a first SRE [HR 0.56; 95% CI: 0.21, 1.52; P = 0.2501]). Treatment with enzalutamide resulted in a statistically significant improvement in the exploratory endpoints of time to the first subsequent antineoplastic therapy (cytotoxic or hormonal) and PSA response ≥ 90% and a trend toward benefit in improving QoL. Pharmacokinetics Plasma concentration of enzalutamide plus M2 (sum of active moieties) achieved at steady state by day 57. For enzalutamide plus M2, the mean accumulation ratio was 17.9 and the mean peak trough ratio was 1.08 on day 85. The variability of steady-state Cmin was low for enzalutamide plus M2 (sum of active moieties). Safety A total of 167 (84.3%) and 153 (80.5%) patients had 1 or more TEAE in the enzalutamide and placebo groups, respectively; the most common (≥ 5% of patients) with > 2% absolute higher incidence in the enzalutamide group compared to placebo included fatigue (12.6% enzalutamide vs 6.3% placebo), decreased appetite (12.1% vs 8.9%), dizziness (8.6% vs 3.7%), hypertension (8.1% vs 1.1%), nausea (7.1% vs 4.7%), nasopharyngitis (6.6% vs 3.2%), musculoskeletal pain (5.1% vs 2.6%) and insomnia (5.1% vs 2.6%). A total of 34 (17.2%) and 47 (24.7%) patients had 1 or more SAE, in the enzalutamide and placebo groups, respectively. The only SAE with more than a 1% absolute higher incidence in the enzalutamide group compared with the placebo group was lung infection (2.0% enzalutamide vs none placebo). AEs led to permanent discontinuation of study drug in 26 (13.1%) and 34 (17.9%) patients in the enzalutamide and placebo groups, respectively. No individual AE preferred terms leading to study drug discontinuation had more than a 1% absolute higher incidence in the enzalutamide group compared with the placebo group. AEs leading to study drug discontinuation reported in ≥ 2 patients overall included asthenia (2 [1.0%] patients enzalutamide vs none placebo), arthralgia (none vs 2 [1.1%] patients) and thrombocytopenia (none vs 2 [1.1%] patients). SAEs resulting in death occurred in 7 (3.5%) patients in the enzalutamide group and 6 (3.2%) patients in the placebo group, without any imbalances between the treatment groups. Overall, the most common SAEs resulting in death (2 or more patients in either treatment group) were death (none vs 2 [1.1%] patients) and respiratory failure (none vs 2 [1.1%] patients). No drug-related SAEs resulting in death occurred in either treatment group. Data cutoff date 20 Sep 2015 (efficacy and safety) and 20 Jan 2016 (pharmacokinetics) (CSR) 30 Aug 2017 (clinical status) AE: adverse event; ADT: androgen deprivation therapy; CI: confidence interval; CSR: clinical study report; ECOG: Eastern Cooperative Oncology Group; GnRH: gonadotropin-releasing hormone; HR: hazard ratio; ITT: intent-to-treat; M2: MDPC0002 (N-desmethyl enzalutamide); OS: overall survival; PSA: prostate-specific antigen; QoL: quality of life; rPFS: radiographic progression-free survival; SAE: serious adverse event; SRE: time to first skeletal-related event; TEAE: treatment-emergent adverse event

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7.4.6 9785-CL-0335 (ARCHES) Study title A Multinational, Phase 3, Randomized, Double-blind, Placebo-controlled Efficacy and Safety Study of Enzalutamide Plus Androgen Deprivation Therapy (ADT) Versus Placebo Plus ADT in Patients with Metastatic Hormone Sensitive Prostate Cancer (mHSPC) Clinical Status Ongoing (enrollment complete) Study design Phase 3, randomized, placebo-controlled, double-blind Indication Patients with mHSPC Key eligibility criteria Adult male with histologically or cytologically confirmed adenocarcinoma of the prostate without neuroendocrine differentiation, signet cell or small cell histology; metastatic disease documented by positive bone scan or metastatic lesions on CT or MRI scan and must maintain ADT with an LHRH agonist or antagonist during study treatment or have a history of bilateral orchiectomy (i.e., medical or surgical castration). The patient must have an ECOG 0 or 1 and a life expectancy of ≥ 12 months. No prior pharmacotherapy, radiation therapy or surgery for metastatic prostate cancer (with some exceptions) are permitted. Enrollment (planned) Approximately 1100 patients (550 per treatment arm) Primary objective Efficacy as assessed by rPFS based on central review Secondary objectives OS; time to first SSE, castration resistance, deterioration of QoL, initiation of new antineoplastic therapy and PSA progression; PSA undetectable rate (< 0.2 ng/mL); ORR, worsening of pain and safety Drug administration Enzalutamide or placebo in combination with ADT, either bilateral orchiectomy or an LHRH agonist or antagonist, which must be maintained during study treatment, as per standard of care. Dose Enzalutamide: 160 mg/day once daily Placebo: matching Enrolled/treated 0 enrolled/0 treated Demographics Not yet available. Efficacy Not yet available. Safety Not yet available. Data cutoff date 30 Aug 2017 (clinical status) ADT: androgen deprivation therapy; CT: computed tomography; ECOG: Eastern Cooperative Oncology Group; LHRH: luteinizing hormone-releasing hormone; mHSPC: metastatic hormone-sensitive prostate cancer; MRI: magnetic resonance imaging; ORR: objective response rate; OS: overall survival; PSA: prostate-specific antigen; QoL: quality of life; rPFS: radiographic progression-free survival; SSE: symptomatic skeletal event

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7.4.7 9785-MA-1001 Study title A Randomized, Double-Blind, Placebo-Controlled, Phase IIIb Study of the Efficacy and Safety of Continuing Enzalutamide in Chemotherapy Naïve Metastatic Castration Resistant Prostate Cancer Patients Treated with Docetaxel plus Prednisolone Who Have Progressed on Enzalutamide Alone Clinical Status Ongoing (enrolling) Study design Phase 3b, randomized, placebo-controlled, double-blind Indication Progressive metastatic prostate cancer patients who have failed ADT but are naïve to chemotherapy Key eligibility criteria Age 18 years or older with histologically confirmed adenocarcinoma of the prostate without neuroendocrine differentiation or small cell features; metastatic disease documented by at least 2 bone lesions on bone scan or soft tissue disease documented by CT/MRI; ongoing ADT with a LHRH agonist/antagonist or prior bilateral orchiectomy; progressive disease based on PSA progression (defined by a minimum of 3 rising PSA levels) and a PSA value ≥ 2 µg/L; serum testosterone ≤ 1.73 nmol/L; ECOG 0 or 1; life expectancy of ≥ 12 months. No prior cytotoxic chemotherapy allowed. Enrollment (planned) Approximately 650 patients (approximately 274 from period 1 will be randomized to treatment in period 2) Primary objective Efficacy as measured by PFS Secondary objectives Time to PSA progression, PSA response, objective response rate, time to pain progression, time to opiate use for cancer-related pain, time to first skeletal- related event and QoL. Drug administration Period 1: enzalutamide; Period 2: enzalutamide in combination with docetaxel and prednisolone or placebo in combination with docetaxel and prednisolone Dose Enzalutamide: 160 mg/day once daily; docetaxel: 75 mg/m2 every 3 weeks; prednisolone: 10 mg daily Enrolled/treated 0 enrolled/0 treated Demographics Not yet available. Efficacy Not yet available. Safety Not yet available. Data cutoff date 30 Aug 2017 (clinical status) ADT: androgen deprivation therapy; CT: computed tomography; ECOG: Eastern Cooperative Oncology Group; LHRH: luteinizing hormone-releasing hormone; MRI: magnetic resonance imaging; PFS: progression-free survival; PSA: prostate-specific antigen; QoL: quality of life

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7.5 Phase 4 Studies in Prostate Cancer Patients 7.5.1 MDV3100-10 (PLATO) Study title A Phase 4, Randomized, Double-blind, Placebo-controlled Study of Continued Enzalutamide Treatment Beyond Progression in Patients With Chemotherapy-naïve Metastatic Castration Resistant Prostate Cancer Clinical Status Ongoing (enrollment complete) Study design Phase 4, 2-stage (open-label followed by randomized, double-blind, placebo-controlled) Indication Prostate cancer Key eligibility criteria Metastatic CRPC by whole body radionuclide bone scan for bone disease or CT/MRI for soft tissue disease; progressive disease on ADT (at least 3 rising PSA values with an interval of  1 week between each determination with both the most recent local PSA and the central PSA value ≥ 2 µg/L. Must continue ADT with a GnRH agonist/antagonist throughout study or by prior bilateral orchiectomy; testosterone  1.73 nmol/L ( 50 ng/dL), ECOG performance status  1, asymptomatic or minimally symptomatic prostate cancer (BPI question 3 < 4); and life expectancy  12 months. No prior cytotoxic chemotherapy, aminoglutethimide, ketoconazole, abiraterone acetate, enzalutamide or androgen receptor inhibitors allowed. Enrollment (planned) Approximately 500 patients Primary objective PFS after PSA progression on enzalutamide plus abiraterone and prednisone (or prednisolone) compared with placebo plus abiraterone and prednisone Secondary objectives Time to PSA progression; PSA response; objective response rate; rate of pain progression; time to first use of a subsequent antineoplastic therapy for prostate cancer; quality of life; safety Drug administration Period 1: Enzalutamide (open-label) Period 2: Enzalutamide OR placebo (double-blind) plus abiraterone and prednisone Dose Enzalutamide 160 mg or placebo once daily, abiraterone 1000 mg once daily; prednisone 10 mg (5 mg twice daily) Enrolled/treated Period 1: 509 enrolled/509 treated (enzalutamide) Period 2: 251 randomized/249 treated (125 enzalutamide, abiraterone and prednisone; 124 placebo, abiraterone and prednisone) Demographics Period 1: The median age was 72.0 years (range: 40.0-95.0). Overall, the population was predominantly white (87.0%). At initial diagnosis, ECOG performance score was 0 for 70.7% and 1 for 29.3% of patients; the most frequently recorded pain score (BPI question 3) was 0 to 1 (64.4% of patients); median total Gleason score was 8.0 (range, 3.0-10.0) with 54.4% of patients in the high total Gleason score category (8-10). The majority of patients (68.2%) had 4 or more unique prior therapies for prostate cancer. Period 2: The median age of all patients was 72.0 years (range: 56.0-90.0). ECOG performance score was 0 for 64.9% and 1 for 35.1% of patients; the most frequently recorded pain score was 0-1 (57.8% of patients); median total Gleason score was 8.0 (range, 5.0-10.0) for both treatment groups, with 55.0% of patients overall in the high total Gleason score category (8-10). The majority of patients overall (72.1%) had 4 or more unique prior therapies for prostate cancer. In double-blind period 2 (data collected prior to enrollment in period 1), the median (range) time from initial diagnosis or first treatment of prostate cancer to enrollment was similar between treatment groups: 58.3 (0.4-271.4) months for the enzalutamide group and 57.8 (0.2-218.7) months for the placebo group. Table continued on next page

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MDV3100-10 (PLATO) (continued) Efficacy Primary and secondary study objectives evaluated data from patients in period 2 only. Treatment with enzalutamide plus abiraterone and prednisone following PSA progression on enzalutamide alone did not result in a statistically significant difference in duration of PFS compared with patients receiving placebo plus abiraterone and prednisone (HR: 0.828; 95% CI: 0.612, 1.119). The median (95% CI) duration of PFS was similar between treatment groups (5.7 [4.6, 8.1] months enzalutamide vs 5.6 [4.5, 7.3] months placebo). Results of PFS subgroup analyses were generally consistent with the primary PFS analysis. Time to PSA progression did not differ between the treatment groups (HR: 0.874; 95% CI: 0.617, 1.239; P = 0.4500) and the median was 2.8 months for both treatment groups. Confirmed PSA response ≥ 50% was low in both groups (enzalutamide 1 [0.8%] patient vs placebo 3 [2.5%] patients) and the difference between treatment groups was not statistically significant. No statistically significant differences were observed between treatment groups for the other secondary efficacy endpoints: confirmed PSA response ≥ 30% and ≥ 90%, pain progression rate (≥ 30% increase in pain intensity score from baseline to month 6 and to worst postbaseline measurement), best objective response rate (CR, PR and stable disease) by investigators per RECIST 1.1 and time to degradation of FACT-P. No statistically significant difference was observed between the treatment groups in time to first use of subsequent antineoplastic therapy (HR: 0.861; 95% CI: 0.616, 1.204). The median time to initiation of subsequent antineoplastic therapy was 10.3 months for the enzalutamide group vs 8.6 months for the placebo group. Additionally, while not statistically significant, the best objective response rate of CR, PR and stable disease was higher in the enzalutamide group (68.4% vs 57.5% in the placebo group) in patients with measureable disease at screening. Best overall responses of stable disease were observed for more patients in the enzalutamide group (68.4% vs 52.5% in the placebo group) and responses of disease progression were observed for more patients in the placebo group (35.0% vs 21.1% in the enzalutamide group). The same findings (though not statistically significant) were confirmed in a supportive analysis conducted in patients with at least 1 target lesion or nontarget lesion per RECIST 1.1 at screening. Safety Period 1: 475 of 509 (93.3%) patients had 1 or more TEAE. The most common (≥ 10% of patients) TEAEs were fatigue (39.3%), back pain (20.6%), nausea (19.3%), hot flush (17.7%), decreased appetite (16.1%), constipation (15.5%), arthralgia (14.7%) and diarrhea (13.2%). A total of 180 (35.4%) patients had at least 1 grade 3 or higher AE; the most common (≥ 2% of patients) grade 3 or higher AEs were fatigue (3.9%), hypertension (2.4%), anemia (2.2%) and hematuria (2.0%). SAEs occurred in 142 of 509 (27.9%) patients . The most common SAE in the open-label period was hematuria (10[2.0%] patients), followed by disease progression, fall, pneumonia, syncope and urinary tract infection (5 [1.0%] patients each). All other SAEs occurred in 4 or fewer patients each. Table continued on next page

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MDV3100-10 (PLATO) (continued) Safety (continued) AEs led to permanent discontinuation of enzalutamide in 35 (6.9%) patients; the most common events were fatigue in 4 patients, followed by confusional state, dizziness, general physical health deterioration and vertigo in 2 patients each. All other AEs leading to permanent discontinuation of enzalutamide were reported in 1 patient each. Twenty-four (4.7%) patients had 1 or more AEs resulting in death. The most common was disease progression (4 [0.8%] patients), followed by general physical health deteriorations (2 [0.4%] patients) and metastases to the central nervous system (2 [0.4%] patients). All other AEs resulting in death occurred in 1 patient each. Most AEs were related to metastatic prostate cancer. One AE (cardiorespiratory arrest, day 18) was considered possibly related to enzalutamide. Period 2: The percentage of patients with at least 1 TEAE was similar between treatment groups (89.6% [112/125 patients] enzalutamide vs 91.1% [113/124 patients] placebo). The most common ( 10% patients in either treatment group) TEAEs were back pain (20.8% enzalutamide vs 22.6% placebo), fatigue (13.6 % vs 14.5% ), hypertension (20.0% vs 7.3%), arthralgia (14.4% vs 11.3%) and nausea (16.8% vs 8.9%), constipation (13.6% vs 9.7%), decreased appetite (10.4% vs 8.1%) and edema peripheral (5.6% vs 12.9%) and musculoskeletal chest pain (10.4% vs 5.6%). The percentage of patients with at least 1 grade 3 or higher AE was higher in the enzalutamide group than in the placebo group (44.8% [56/125 patients] vs 37.1% [46/124 patients]). The most common ( 2% of patients in either treatment group) grade 3 or higher AEs were hypertension (9.6% enzalutamide vs 1.6% placebo), ALT increased (5.6% vs 2.4%), hypokalemia (1.6% vs 2.4%), metastatic pain (2.4% vs 1.6%), spinal cord compression (2.4% vs 1.6%), back pain (2.4% vs 0.8%) and AST increased (2.4% vs 0). The percentage of patients with at least 1 SAE was similar between treatment groups (30.4% [38/125 patients] enzalutamide and 28.2% [35/124 patients] placebo). The most common SAEs were spinal cord compression (3.2% enzalutamide vs 1.6% placebo) and metastatic pain (2.4% vs 1.6%). All other SAEs occurred in 3 or fewer patients in each treatment group. AEs led to permanent discontinuation of study drug in more patients in the enzalutamide group (11 [8.8%] patients) than in the placebo group (5 [4.0%] patients). All AEs leading to study drug discontinuation occurred in 1 patient each. Four (3.2%) patients in the enzalutamide group and 3 (2.4%) patients in the placebo group had an AE resulting in death. The most common AE resulting in death was disease progression (enzalutamide 2 [1.6%] patients vs placebo 1 [0.8%] patient). All other AEs occurred in 1 (0.8%) patient each: bronchitis and general physical health deterioration in the enzalutamide group and cardiac failure, myocardial infarction and pneumonia in the placebo group. None of the fatal events were considered related to study drug. Data cutoff date 07 Oct 2016 (CSR) 30 Aug 2017 (clinical status) ADT: androgen deprivation therapy; AE: adverse event; ALT: alanine aminotransferase; AST: aspartate aminotransferase; BPI: Brief Pain Inventory-Short Form; CI: confidence interval; CR: complete response; CRPC: castration-resistant prostate cancer; CSR: clinical study report; CT: computed tomography; ECOG: Eastern Cooperative Oncology Group; FACT-P: Functional Assessment of Cancer Therapy-Prostate; GnRH: gonadotropin-releasing hormone; HR: hazard ratio; MRI: magnetic resonance imaging; PFS: progression-free survival; PR: partial response; PSA: prostate-specific antigen; RECIST: Response Evaluation Criteria in Solid Tumors; SAE: serious adverse event; TEAE: treatment-emergent adverse event

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7.5.2 9785-CL-0403 (UPWARD) Study title A Multicenter, Single-Arm, Open-Label, Post-Marketing Safety Study to Evaluate the Risk of Seizure Among Subjects with Metastatic Castration-Resistant Prostate Cancer (mCRPC) Treated with Enzalutamide Who Are at Potential Increased Risk of Seizure Status Ongoing (enrollment complete) Study design Open-label, single-arm study Indication Metastatic CRPC Key eligibility criteria Metastatic CRPC with progressive disease; ongoing androgen deprivation therapy with a GnRH analogue (agonist or antagonist) or bilateral orchiectomy (i.e., surgical or medical castration) and an ECOG performance status of 0 to 2. Patient has been evaluated by a local neurologist prior to study entry who has determined the subject has at least 1 risk factor for seizure (as defined by the protocol). Enrollment (Planned) 400 Patients Primary objective To evaluate the seizure rate and monitor the safety of enzalutamide treatment in subjects with metastatic CRPC known to have risk factor(s) for seizure. Drug administration Enzalutamide Dose 160 mg once daily (4 x 40 mg capsules) Enrolled/treated 424 enrolled/423 treated Demographics The median age was 74.0 years, with 15.6% of patients aged < 65 years. Overall, the population was predominantly white (90.1%). ECOG performance score was 0 for 44.4%, 1 for 44.9% and 2 for 10.6% of patients. At initial diagnosis, the most frequently recorded Gleason score was 7 (32.9% of patients). Overall, the main seizure risk categories were current use of a medication that may lower (57.2%), history of traumatic brain or head injury with loss of consciousness (26.5%) and history of CVA or TIA (22.2%). Safety Overall, 357 (84.4%) patients experienced at least 1 TEAE. The highest incidence of TEAEs during the study were categorized in the SOC of General disorders and administration site conditions (189 [44.7%] patients), Musculoskeletal and connective tissue disorders (160 [37.8%] patients), Gastrointestinal disorders (145 [34.3%] patients), Nervous system disorders (114 [27.0%] patients) and Metabolism and nutrition disorders (105 [24.8%] patients). The most frequently reported TEAEs were fatigue (87 [20.6%] patients), asthenia (80 [18.9%] patients), decreased appetite (70 [16.5%] patients), anemia (53 [12.5%] patients), back pain (53 [12.5%] patients) and nausea (48 [11.3%] patients). In total, 139 (32.9%) patients experienced a treatment-emergent SAE. The most common SAEs (≥ 2% of patients) were malignant neoplasm progression (19 [4.5%] patients), general physical health deterioration (10 [2.4%] patients), pneumonia (10 [2.4%] patients) and anemia (9 [2.1%] patients). Sixty-six (15.6%) patients were permanently discontinued from study drug due to a TEAE. Thirty-eight (9.0%) patients experienced TEAEs leading to death. Four patients experienced a seizure event within 4 months of treatment, while a total of 7 patients experienced a seizure event during the study period (IAC-confirmed). Data cutoff date 01 Feb 2016 (CSR) 30 Aug 2017 (clinical status) CRPC: castration-resistant prostate cancer; CSR: clinical study report; CVA: cerebrovascular accident; ECOG: Eastern Cooperative Oncology Group; GnRH: gonadotropin-releasing hormone; IAC: Independent Adjudication Committee; SAE: serious adverse event; TEAE: treatment-emergent adverse event; TIA: transient ischemic attack

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7.5.3 9785-CL-0410 Study title A Multi-center, Single-arm Study of Enzalutamide in Patients with Progressive Metastatic Castration-resistant Prostate Cancer Previously Treated with Abiraterone Acetate Clinical Status Completed Study design Open-label, single-arm study Indication Metastatic CRPC Key eligibility criteria Male patients, at least 18 years of age, who have histological confirmation of adenocarcinoma of the prostate without neuro-endocrine differentiation or small cell features and had received a minimum of 24 weeks of treatment with abiraterone acetate within its approved label indication for which treatment was discontinued at least 4 weeks prior to the start of the study. Enrollment (Planned) 200 Patients To evaluate radiographic progression-free survival, defined as the time from first Primary objective dose to the first objective evidence of radiographic disease progression or death from any cause, whichever occurred first. Drug administration Enzalutamide Dose 160 mg once daily (4 x 40 mg capsules) Enrolled/treated 215 enrolled/214 treated. Patients were grouped according to whether or not they had received previous chemotherapy treatment for prostate cancer (no more than 1 prior line of docetaxel and must have been used prior to abiraterone acetate therapy). Demographics The median age was 73.0 years and the majority of the 214 patients were white (76.6%). At baseline, ECOG performance score was 1 for 52.8% of patients. The median duration of previous abiraterone acetate therapy was 54.21 weeks (60.0 weeks in the previous chemotherapy group and 51.6 weeks in the no previous chemotherapy group). Patients’ total Gleason score at initial diagnosis was widely distributed, with the more common overall scores being 7 (86 [40.2%] patients), 8 (42 [19.6%] patients) and 9 (46 [21.5%] patients); the scores were similarly distributed for the previous chemotherapy group and the no previous chemotherapy group. Efficacy As of the last evaluation date of 29 Sep 2017, 47 (22.0%) patients had a PSA response of ≥ 50% decrease in PSA from baseline (95% CI: 16.61%, 28.11%). For patients in the previous chemotherapy group (n = 69), 15 (21.7%) patients had a PSA response of ≥ 50% decrease in PSA from baseline (95% CI: 12.71%, 33.31%). For patients in the no previous chemotherapy group (n = 145), 32 (22.1%) patients had a PSA response of ≥ 50% decrease in PSA from baseline (95% CI: 15.61%, 29.70%). The median maximal PSA reduction from baseline was -10.60% (range: -99.7%, 458.8%). A total of 66 (36.7%) patients experienced a PSA reduction from baseline of ≥ 30%, 47 (26.1%) patients experienced a PSA reduction from baseline of ≥ 50% and 10 (5.6%) patients experienced a PSA reduction from baseline of ≥ 90%. These results were comparable for PSA reduction ≥ 30% and ≥ 50% for the previous chemotherapy group and the no previous chemotherapy group; whereas PSA reduction ≥ 90% was higher in the no previous chemotherapy group (9 [7.3%] patients) compared to the previous chemotherapy group (1 [1.8%] patient). The PSA median percent change from baseline increased by 132.20% (range: -91.0%, 10169.2%) at the 30-day safety follow-up visit. In the previous chemotherapy group, the PSA median percent change from baseline increased by 107.30% (range: -91.0%, 600.6%) at the 30-day safety follow-up visit. In the no previous chemotherapy group, the PSA median percent change from baseline increased by 144.90% (range: -63.3%, 10169.2%) at the 30-day safety follow-up visit. Overall, the efficacy results show that the patients enrolled in this study obtained clinical benefit with enzalutamide treatment regardless of whether or not they had received previous chemotherapy. Table continued on next page

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9785-CL-0410 (continued) Safety A total of 63 (91.3%) patients in the previous chemotherapy group and 136 (93.8%) patients in the no previous chemotherapy group experienced TEAEs from the start of the study until the last evaluation date (29 Sep 2017). The most common (≥ 10% overall) TEAEs were fatigue (24.6% in the previous chemotherapy group vs 37.9% in the no previous chemotherapy group), decreased appetite (30.4% vs 22.8%), asthenia (29.0% vs 13.8%), back pain (21.7% vs 15.9%), arthralgia (14.5% vs 17.2%), nausea (14.5% vs 15.2%), constipation (15.9% vs 12.4%), diarrhea (20.3% vs 10.3%), bone pain (14.5% vs 17.2%), weight decreased (11.6% vs 12.4%), anemia (15.9% vs 9.7%), pain in extremity (11.6% vs 11.7%) and musculoskeletal pain (8.7% vs 11.7%). The percentage of patients with TEAEs considered to be study drug-related was similar between the previous chemotherapy group and the no previous chemotherapy group (59.4% vs 59.3%). The percentage of patients with TEAEs of NCI-CTCAE grade 3 or higher was lower in the previous chemotherapy group than in the no previous chemotherapy group (23 [33.3%] patients vs 72 [49.7%] patients). The more frequently (≥ 2% in any group) reported grade 3 or higher TEAEs were malignant neoplasm progression (4.3% in the previous chemotherapy group vs 6.2% in the no previous chemotherapy group), anemia (5.8% vs 3.4), spinal cord compression (4.3% vs 4.1%), bone pain (4.3% vs 3.4%), general physical health deterioration (1.4% vs 4.8%), hematuria (2.9% vs 3.4%), asthenia (0 vs 4.1%), fatigue (2.9% vs 2.1%), hypertension (1.4% vs 2.8%), pain in extremity (2.9% vs 2.1%), pulmonary embolism (2.9% vs 2.1%), back pain (2.9% vs 2.1%), anemia of malignant disease (0 vs 2.1%), pneumonia (2.9% vs 1.4%) and renal failure (2.9% vs 0). The percentage of patients with SAEs was lower in the previous chemotherapy group than in the no previous chemotherapy group (18 [26.1%] patients vs 64 [44.1%] patients). The more frequently (≥ 2.0% overall) reported SAEs were malignant neoplasm progression (3 [4.3%] patients in the previous chemotherapy group vs 10 [6.9%] patients in the no previous chemotherapy group), general physical health deterioration (2 [2.9%] patients vs 8 [5.5%] patients), spinal cord compression and hematuria (each 2 [2.9%] patients vs 5 [3.4%] patients) and anemia and pulmonary embolism (each 1 [1.4%] patient vs 4 [2.8%] patients) and renal failure acute (0 vs 5 [3.4%] patients). For all other types of TEAEs, the percentage of patients was similar between the previous chemotherapy group and the no previous chemotherapy group. Eight patients (3.7%) experienced 12 study drug-related SAEs. Twenty-two (10.3%) patients experienced a TEAE that led to death. One of these deaths (cerebral infarction) was considered to be possibly related to study drug. Seventy-six (35.5%) patients experienced a TEAE that led to permanent discontinuation of study drug; 23 (10.7%) patients experienced a study drug-related TEAE that led to permanent discontinuation of study drug. During the study, the following cardiac TEAEs were reported in 1 (0.5%) patient each: arrhythmia, atrial fibrillation, left ventricular dysfunction, mitral valve incompetence and tachycardia. The safety profile observed in this study is consistent with what has been seen in prior enzalutamide trials in similar populations. Data cutoff date 29 Sep 2017 (Final CSR) CI: confidence interval; CRPC: castration-resistant prostate cancer; CSR: clinical study report; NCI-CTCAE: National Cancer Institute-Common Terminology Criteria for Adverse Events; ECOG: Eastern Cooperative Oncology Group; PSA: prostate-specific antigen; SAE: serious adverse event; TEAE: treatment-emergent adverse event

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7.5.4 9785-MA-1008 Study title A Multicenter, Open-label, Single-arm Study of Enzalutamide Re-Treatment in Metastatic Castration-Resistant Prostate Cancer, As First Treatment Post-Chemotherapy in Patients who Have Previously Received Enzalutamide in the Pre-Chemotherapy Setting Clinical Status Terminated Study design Open-label, single-arm study Indication Metastatic CRPC Key eligibility criteria Male patients, at least 18 years of age, who have metastatic CRPC, who had previously been treated with enzalutamide for at least 8 months and stopped enzalutamide due to progressive disease (not due to AEs), followed by at least 4 cycles of docetaxel and/or cabazitaxel chemotherapy, with or without other intervening anticancer therapies prior to receiving chemotherapy. Patients must have had ongoing androgen deprivation therapy with a gonadotropin-releasing hormone analogue or prior bilateral orchiectomy (medical or surgical castration) and testosterone levels ≤ 1.73 nmol/L (≤ 50 ng/dL) at screening. Enrollment (Planned) 40 Patients Primary objective To evaluate rPFS of re-treatment with enzalutamide + GnRH analogue. To assess OS rate, PSA response rate, time to PSA progression, ORR, time to Secondary objectives first use of a subsequent antineoplastic therapy and safety of enzalutamide re-treatment in the postchemotherapy setting Drug administration Enzalutamide Dose 160 mg once daily (4 x 40 mg capsules) Enrolled/treated 4 enrolled/4 treated Demographics All patients were male; 1 was 71 years of age, 2 were 72 years of age and 1 was 79 years of age. Two patients were white (not Hispanic or Latino), 1 was white Hispanic or Latino and 1 was Asian. One patient had undergone a radical prostatectomy without radiation therapy, 1 patient had undergone a radical prostatectomy with radiation therapy and a bilateral orchiectomy, 1 patient had radiation therapy and primary/salvage brachytherapy of the prostate gland and 1 patient had no previous surgery or radiation therapy for treatment of the primary cancer. Efficacy As of the date of last evaluation (15 Mar 2017), all patients had experienced a progression event. The time of rPFS ranged from 52+ days to 173 days. No patient had died from any cause and OS ranged from more than 85 to more than 331 days. Two patients had a PSA response of ≥ 50% decrease in PSA from baseline. No patient had a PSA response of ≥ 90% decrease in PSA from baseline. The maximal PSA reduction from baseline was -70% (range: -70%, 345%). PSA progression was observed in all 4 patients. The time to PSA progression ranged from 1 to 142 days. Overall, the efficacy results show that some patients enrolled in this study obtained clinical benefit with enzalutamide re-treatment. Table continued on next page

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9785-MA-1008 (continued) Safety All patients experienced at least 1 TEAE; overall, 33 TEAEs were reported by the 4 patients from the start of the study until the study completion date of 15 Mar 2017. Overall, the more frequently reported TEAEs were in the SOCs Musculoskeletal and connective tissue disorder, General disorders and administration site conditions and Gastrointestinal disorders. The most frequently reported study drug related TEAE was fatigue. All TEAEs were NCI-CTCAE grade 1 or 2. There were no reported SAEs or deaths or TEAEs that led to permanent discontinuation of study drug. The safety profile observed in this study is consistent with what has been seen in prior enzalutamide trials in similar populations. Data cutoff date 15 Mar 2017 (Final CSR) AE: adverse event; CRPC: castration-resistant prostate cancer; CSR: clinical study report; GnRH: gonadotropin releasing hormone; NCI-CTCAE: National Cancer Institute-Common Terminology Criteria for Adverse Events; ORR: objective response rate; OS: overall survival; PSA: prostate-specific antigen; rPFS: radiographic progression-free survival; SAE: serious adverse event; TEAE: treatment-emergent adverse event

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7.5.5 9785-MA-3051 Study title A Randomized Phase IV Study Comparing Enzalutamide versus Flutamide in CRPC Patients Who Have Failed Combined Androgen Blockade Therapy with Bicalutamide plus ADT Clinical Status Ongoing (enrolling) Study design Open-label, 2-arm study Indication CRPC Key eligibility criteria Male patients, at least 20 years of age, who have histologically or cytologically confirmed adenocarcinoma of the prostate without neuroendocrine differentiation or small-cell histology, are on continuous ADT with GnRH agonist/antagonist or bilateral orchiectomy (surgical or chemical castration), have serum testosterone level ≤ 1.73 nmol/L (50 ng/dL or 0.5 ng/mL) at screening visit, have asymptomatic or mildly symptomatic prostate cancer (Brief Pain Inventory-Short Form score is < 4 to Question 3 “the worst pain within 24 hours”), have an ECOG performance status of 0 or 1 and have an estimated life expectancy of ≥ 12 months. Patients must have progression of the disease that falls under at least 1 of the following 3 criteria during CAB therapy in combination of bicalutamide and ADT: PSA increase should be confirmed at least 2 timepoints with an interval of ≥ 1 week (in at least 6 weeks after the last dose of bicalutamide, PSA should be confirmed higher than the highest PSA measured after the nadir was confirmed during administration of bicalutamide and PSA at screening visit should be ≥ 2 ng/mL); soft tissue disease progression defined by RECIST 1.1; or progression of ≥ 2 bone lesions defined as new lesions in bone scintigraphy by PCWG2. Enrollment (Planned) 200 Patients To determine the benefit of enzalutamide + ADT as compared to flutamide + ADT as Primary objective assessed by time to PSA progression with 1st line AAT (TTPP1). To determine: the order of AAT treatment as assessed by time to PSA progression with 1st line AAT + 2nd line AAT (TTPP2); the benefit of enzalutamide + ADT as compared to flutamide + ADT as assessed by PSA response rate to 1st line AAT (proportion of subjects with a decrease by at least 50% or 90% from baseline irrespective of the timing); the benefit of enzalutamide + ADT as compared to flutamide + ADT as assessed by PSA response rate to 1st line AAT at week 13 Secondary objectives (proportion of subjects with a decrease by at least 50% or 90% from baseline); the benefit of enzalutamide + ADT as compared to flutamide + ADT as assessed by time to PSA decrease by 50% from baseline with 1st line AAT; the benefit of enzalutamide + ADT as compared to flutamide + ADT as assessed by time to discontinuation of 1st line AAT (TTF1); the order of AAT treatment as assessed by time to discontinuation of 2nd line AAT (TTF2); the benefit of enzalutamide + ADT as compared to flutamide + ADT as assessed by rPFS. Drug administration Random assignment to 1 of the following: Enzalutamide Flutamide Dose Enzalutamide: 160 mg once daily (4 x 40 mg capsules) Flutamide: 125 mg 3 times daily (125 mg tablets) Enrolled/treated 0 enrolled/0 treated Demographics Not yet available Efficacy Not yet available Safety Not yet available Data cutoff date 30 Aug 2017 (clinical status) AAT: alternative antiandrogen therapy; ADT: androgen deprivation therapy; CAB: combined androgen blockade; CRPC: castration-resistant prostate cancer; ECOG: Eastern Cooperative Oncology Group; GnRH: gonadotropin-releasing hormone; PCWG2: Prostate Cancer Clinical Trials Working Group 2; PSA: prostate-specific antigen; RECIST: Response Evaluation Criteria in Solid Tumors; rPFS: radiographic progression-free survival; TTF: time to treatment failure; TTPP: time to PSA progression

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7.6 Compassionate Use and Expanded Access Programs in Prostate Cancer Patients 7.6.1 9785-CL-0401 Study title A Multicenter, Single-arm, Open-label Treatment Protocol to Provide Expanded Access to Enzalutamide (MDV3100) and Monitor Its Safety in Patients with Progressive Castration-resistant Prostate Cancer Previously Treated with Docetaxel-Based Chemotherapy Clinical Status Completed Study design Open-label Indication CRPC Key eligibility criteria Metastatic CRPC with at least 1 prior chemotherapy regimen containing docetaxel. Patients received ongoing ADT with a GnRH analogue (agonist or antagonist) or orchiectomy (i.e., surgical or medical castration). Enrollment (Planned) 500 Patients Primary objective To provide expanded access to enzalutamide and monitor its safety in patients with progressive CRPC previously treated with docetaxel-based chemotherapy. Drug administration Enzalutamide Dose 160 mg once daily (4 x 40 mg capsules) Demographics The median patient age was 71.0 years; with 200 (39.4%) patients between 65 and 74 years of age (inclusive). The majority of patients were white (448 [88.2%] patients) and had a baseline ECOG performance status of 1 (285 [56.1%] patients). The median (range) duration of disease at baseline was 88.9 (9.5–301.8) months. The median (range) number of prior unique anti-neoplastic therapies per patient was 5 (1–18) therapies and the median (range) number of prior unique chemotherapies per patient was 1 (0–10) therapy. The majority of patients had prior abiraterone exposure (386 [76.0%] patients) and 126 (24.8%) patients had prior abiraterone and cabazitaxel exposure. The median (range) number of cycles of prior docetaxel exposure per patient was 8 (1–76) cycles. Enrolled/treated 508 enrolled/507 treated, including 1 patient who previously participated in study CRPC2 and 8 patients who previously participated in the Named Patient Program. Efficacy Not applicable Safety A total of 447 (88.2%) out of 507 patients reported TEAEs. The most frequently reported TEAEs (reported in ≥ 10% of patients) were fatigue (198 [39.1%] patients), nausea (115 [22.7%] patients), anorexia (75 [14.8%] patients), anemia (60 [11.8%] patients), edema peripheral (58 [11.4%] patients), back pain (52 [10.3%] patients), vomiting (52 [10.3%] patients) and arthralgia (51 [10.1%] patients). One-hundred and forty-three of 507 (28.2%) patients experienced an SAE and 50 (9.9%) patients died during the study. Seventy-one (14.0%) patients experienced a TEAE resulting in permanent discontinuation of study drug. Three AEs with a fatal outcome were considered by the investigator as possibly related to study drug; cerebrovascular accident, acute myocardial infarction and myocardial infarction. In addition, 1 AE with a fatal outcome was reported as “death”; relatedness to study drug for this event was not reported. Data cutoff date 07 Oct 2013 (Final CSR) ADT: androgen deprivation therapy; AE: adverse event; CRPC: castration-resistant prostate cancer; CSR: clinical study report; ECOG: Eastern Cooperative Oncology Group; GnRH: gonadotropin-releasing hormone; SAE: serious adverse event; TEAE: treatment-emergent adverse event

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7.6.2 Named Patient Program A NPP is offered to provide expanded access to enzalutamide and monitor its safety in patients with progressive CRPC previously treated with docetaxel-based chemotherapy in several European countries, South Africa, Russia, Australia and New Zealand. The NPP was also offered in Canada prior to approval. Patients are receiving enzalutamide 160 mg/day until the patient is no longer deriving a benefit in the judgment of the investigator, initiates treatment with another anticancer therapy or meets 1 of the discontinuation criteria. 7.6.3 9785-CL-0402 (Cohort Authorisation Temporaire d’Utilisation) The Cohort Authorisation Temporaire d’Utilisation (cATU) allowed for an early provision of enzalutamide when there was no marketing authorization in France yet. Adult males with metastatic CRPC which had progressed following at least 1 previous course of chemotherapy using docetaxel and for whom there was no appropriate alternative treatment available were eligible to be included in this program. The cATU program was closed on 31 October 2013 with 600 patients treated, following commercial launch in France and the transition of the patients to commercially available enzalutamide. Overall, data from this completed compassionate use program are consistent with the known safety profile of enzalutamide and no new safety signals were identified.

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7.7 Phase 1 Studies in Breast Cancer Patients 7.7.1 MDV3100-08 Study title A Phase 1 Open-Label, Dose Escalation Study Evaluating the Safety, Tolerability and Pharmacokinetics of Enzalutamide (Formerly MDV3100) in Patients With Incurable Breast Cancer Addendum: Safety, Tolerability and Pharmacokinetic Study of Anastrozole, Exemestane, or Fulvestrant in Combination With Enzalutamide at the Recommended Phase 2 Dose in Patients With Hormone Receptor-Positive Breast Cancer Clinical status Ongoing (enrollment complete) Study design Phase 1, open-label, dose escalation (stage 1), dose expansion (stage 2) Indication Incurable breast cancer Key eligibility criteria 18 years of age or older; histologically confirmed breast cancer with pathology report;  2 lines of prior systemic therapy in the advanced disease setting (stage 1 and stage 2 cohort 1 only); eligibility for stage 2 Cohort 1 and Cohort 4 requires AR+ breast cancer; eligibility for stage 2 Cohorts 2, 3, 3B and 4 required ER/PgR+ disease and able to start or continue therapy with anastrozole (1 mg/day) for Cohort 2, exemestane (25 mg/day) for Cohort 3, exemestane (50 mg/day) for Cohort 3B and fulvestrant (500 mg IM every 28 days) for Cohort 4. All patients must have had adequate organ and bone marrow function and ECOG 0 or 1 (stable ECOG 2 considered). Patients with a history of seizure or using medications that may reduce the seizure threshold, known or suspected brain metastasis or leptomeningeal disease were excluded. Enrollment (planned) Approximately 100 patients, including approximately 85 patients in the addendum Primary objective  Safety, tolerability and dose-limiting toxicities of enzalutamide in patients with incurable (stage IV or locally advanced unresectable) breast cancer  Safety and tolerability of daily enzalutamide at the recommended phase 2 dose in patients with incurable AR+ breast cancer  Safety, tolerability and pharmacokinetics of combined treatment with enzalutamide and anastrozole, or exemestane or fulvestrant in patients with hormone receptor-positive breast cancer Secondary objective Pharmacokinetics Drug administration Stage 1: Enzalutamide Stage 2: Enzalutamide alone or in combination with anastrozole, exemestane or fulvestrant Dose Stage 1: Enzalutamide 80 mg or 160 mg once daily with or without food Stage 2: - Cohort 1: Enzalutamide 160 mg once daily with or without food - Cohort 2: Enzalutamide 160 mg once daily with or without food plus anastrozole 1 mg once daily after breakfast - Cohort 3 and 3B: Enzalutamide 160 mg with or without food plus exemestane (25 or 50 mg) once daily after breakfast. (For Cohort 2, 3 and 3B, patients were to fast before receiving enzalutamide on pharmacokinetic evaluation days.) - Cohort 4: Enzalutamide 160 mg once daily with or without food plus fulvestrant 500 mg IM every 28 days Table continued on next page

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MDV3100-08 (continued) Enrolled/treated Stage 1: 15 enrolled/15 treated Stage 2 total: 86 enrolled/84 treated Stage 2 cohort 1: 14 enrolled/14 treated Stage 2 cohort 2: 21 enrolled/20 treated Stage 2 cohort 3: 16 enrolled/16 treated Stage 2 cohort 3B: 24 enrolled/23 treated Stage 2 cohort 4: 11 enrolled/11 treated Demographics Median age of patients in both stages treated with enzalutamide only (n = 29) was 57 years (range, 37 - 78) and treated with enzalutamide plus any hormonal therapy (n = 70) was 62 years (range, 30 - 84). Most patients were white (93.1% enzalutamide only and 78.6% enzalutamide plus any hormonal therapy) followed by black or African American (6.9% enzalutamide only and 17.1% enzalutamide plus any hormonal therapy). ECOG score was 0 for 20.7%, 1 for 75.9% and 2 for 3.4% enzalutamide only and 0 for 58.6%, 1 for 40.0% and 2 for 1.4% enzalutamide plus any hormonal therapy. Efficacy The efficacy endpoints in this phase 1 study were exploratory. No patient had an objective response (CR or PR). The determination of clinical benefit rate included patients with stable disease only. Clinical benefit rate at 16 weeks was 6.9% for the enzalutamide monotherapy group and 20.0% for the combination therapy group. Clinical benefit rate at 16 weeks was highest for patients who received enzalutamide plus fulvestrant (45.5%). Clinical benefit rate at 24 weeks was 3.4% for the monotherapy group and 8.6% for the combination therapy group. Clinical benefit rate at 24 weeks was highest for patients who received enzalutamide plus fulvestrant (18.2%). Pharmacokinetics Enzalutamide was rapidly absorbed after single and multiple oral doses of enzalutamide in patients with advanced breast cancer. Following a single dose, exposure increased approximately dose proportionally from 80 mg to 160 mg. At steady state following multiple daily doses, Cmin, Cmax and exposure appeared slightly less than dose proportional from 80 mg to 160 mg. Plasma concentrations of enzalutamide reached steady state after about 22 days. Administration of enzalutamide 160 mg/day with other hormonal therapies (anastrozole, exemestane or fulvestrant) did not appear to affect plasma concentrations of enzalutamide compared with administration of enzalutamide alone. Enzalutamide 160 mg/day administered with anastrozole or exemestane decreased exposure and peak plasma concentrations and increased clearance of these hormonal agents compared with administration of anastrozole and exemestane alone. The pharmacokinetics of fulvestrant did not appear to be affected by coadministration with enzalutamide. Safety The overall incidence of AEs was 100% for the monotherapy group and 95.7% for the combination therapy group. The most common (≥ 15% of patients) AEs in the monotherapy group were nausea (41.4%); fatigue (34.5%); back pain, cough, diarrhea, dizziness, hypertension and vomiting (20.7% each); and anemia, AST increased, dyspnea, headache and musculoskeletal pain (17.2% each). The most common (≥ 15% of patients) AEs in the combination therapy group were fatigue (57.1%), nausea (51.4%), decreased appetite (30.0%), back pain and diarrhea (22.9% each), vomiting (21.4%), hot flush (20.0%), musculoskeletal pain (18.6%), constipation (17.1%) and cough and weight decreased (15.7% each). Table continued on next page

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MDV3100-08 (continued) Safety (continued) Common (≥ 15% of patients) AEs that were at least 5% higher in monotherapy- treated patients compared with combination therapy-treated patients were anemia (17.2% monotherapy vs 10.0% combination therapy), AST increased (13.8% vs 4.3%), cough (20.7% vs 15.7%), dizziness (20.7% vs 14.3%) and hypertension (20.7% vs 11.4%). Common AEs that were at least 5% higher in combination therapy-treated patients compared with monotherapy-treated patients were nausea (41.4% monotherapy vs 51.4% combination therapy), fatigue (34.5% vs 57.1%), decreased appetite (10.3% vs 30.0%), hot flush (13.8% vs 20.0%) and weight decreased (6.9% vs 15.7%). The incidence of grade 3 or higher AEs (27.6% monotherapy vs 35.7% combination therapy) and enzalutamide-related AEs (82.8% vs 88.6%) was similar between treatment groups; however, the incidence of grade 3 or higher AEs considered related to enzalutamide was more than twice as high in the combination therapy group (17.1%) compared with the monotherapy group (6.9%). Six patients died during the study (1 [3.4%] patient who received monotherapy died due to AE of urosepsis on day 72; and 5 [7.1%] patients who received combination therapy, died due to disease progression). All deaths were associated with disease progression and none was considered related to enzalutamide treatment. The incidence of SAEs was similar between treatment groups (17.2% monotherapy and 14.3% combination therapy) and 1 patient in each treatment group had an SAE considered related to enzalutamide: 1 patient enzalutamide 80 mg (adrenal insufficiency) and 1 patient exemestane 25 mg (hypercalcemia). The incidence of AEs associated with discontinuation of enzalutamide or that led to enzalutamide dose interruption or reduction was higher in the combination therapy group compared with the monotherapy group. One (3.4%) patient in the monotherapy group and 5 (7.1%) patients in the combination therapy group had 1 or more AEs associated with permanent discontinuation of study drug. Four patients (13.8%) in the monotherapy group and 17 patients (24.3%) in the combination therapy group had 1 or more dose interruption of study drug due to an AE. Ten (14.3%) patients in the combination therapy group had a dose reduction of enzalutamide due to an AE. No patients in the monotherapy group had a dose reduction due to an AE. Shifts in hematology laboratory parameters from baseline to worst postbaseline value were similar between monotherapy and combination therapy groups except for neutrophils (low): 3.4% monotherapy vs 22.9% combination therapy. Data cutoff date 08 Jan 2016 (CSR) 30 Aug 2017 (clinical status) AE: adverse event; AR+: androgen receptor positive; AST: aspartate aminotransferase; CR: complete response; CSR: clinical study report; ECOG: Eastern Cooperative Oncology Group; ER: estrogen receptor; IM: intramuscular; PgR+: progesterone receptor positive; PR: partial response; SAE: serious adverse event; TEAE: treatment-emergent adverse event.

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7.8 Phase 2 Studies in Breast Cancer Patients 7.8.1 MDV3100-11 Study title A Phase 2, Single-Arm, Open-Label, Multicenter Study of the Clinical Activity and Safety of Enzalutamide in Patients With Advanced Androgen Receptor-Positive, Triple-Negative Breast Cancer Clinical status Ongoing (enrollment complete) Study design Phase 2, single arm, open-label Indication Triple-negative advanced breast cancer Key eligibility criteria Adult females with advanced AR+ TNBC whose disease is not amenable to curative surgery or radiotherapy. Patients must provide tissue for central assessment of AR. Bone-only nonmeasurable disease is allowed. Adequate organ and bone marrow function required; ECOG 0-1. Patients with current or previously treated brain metastases are excluded. Enrollment (planned) 95 patients (62 evaluable) Primary objective CBR16, defined as the proportion of evaluable patients with a best response of CR, PR, or stable disease ≥ 16 weeks Secondary objectives CBR24 (proportion of evaluable patients with a best response of CR, PR or stable disease ≥ 24 weeks); best ORR (patients with measurable disease with CR or PR); duration and time to response; PFS, pharmacokinetics of enzalutamide; safety and tolerability Drug administration Enzalutamide Dose 160 mg once daily Enrolled/treated 118 enrolled/118 treated Demographics Median age of all treated patients was 57 years (range, 32 - 85). Race was white for 77.1%, black or African American for 16.9%, Asian for 5.1% and American Indian or Alaskan Native for 0.8% of patients. ECOG performance score was 0 for 58.5% and 1 for 41.5%. Most patients were postmenopausal (80.5%). Efficacy The primary efficacy endpoint, CBR16, was achieved in 33% (26 of 78 patients) in the evaluable population and 25% (29 of 118) in the ITT population; CBR24 was 28% (22 of 78) in the evaluable and 20% (24 of 118) in the ITT population. Seven of the 118 patients in the ITT population had a confirmed best overall response of CR or PR; 6 of whom met the criteria for the evaluable subgroup. Median PFS was also similar between the evaluable subgroup and ITT population (14.3 weeks and 12.6 weeks, respectively). The median overall survival (exploratory endpoint) after a median follow-up of 72 weeks was 75.6 weeks for the evaluable subgroup and 54.7 weeks for the ITT population. Best objective response rate was 6.2% for the ITT population and 8.5% in the evaluable population. Pharmacokinetics Mean (SD) circulating estrone decreased from baseline (30.7 [16.01] pg/mL) to week 9 (23.7 [12.01] pg/mL) and mean (SD) circulating testosterone increased from baseline (177.1 [119.10] pg/mL) to week 9 (267.2 [262.15] pg/mL), consistent with the mechanism of action of enzalutamide. The increase in testosterone was more pronounced in the gene expression-positive subgroup compared with the gene expression-negative-subgroup. Circulating mean (SD) androstenedione increased slightly from baseline (548.4 [316.23] pg/mL) to week 9 (644.0 [374.18] pg/mL). Circulating tumor biomarkers CA 15.3 and CA 27.29 decreased from baseline to week 9 and remained low throughout the study. The Ctrough of enzalutamide and M2 was similar at weeks 9 and 17. Table continued on next page

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MDV3100-11 (continued) Safety Overall, 109 treated (92.4%) patients had 1 or more TEAEs; the most common TEAEs (≥ 10%) were fatigue (41.5%), followed by nausea (33.1%), decreased appetite (18.6%), constipation (16.9%), diarrhea (15.3%), headache and insomnia (13.6% each), arthralgia and back pain (12.7% each), dyspnea (11.0%) and hot flush (10.2%). Thirty-six (30.5%) patients had 1 or more grade 3 or higher AE and those occurring in ≥ 2 patients (1.7%) were fatigue (5.1%); pleural effusion (3.4%); disease progression, dyspnea, malignant pleural effusion and metastatic pain (2.5% each); and anemia, breast cancer metastatic, pain, pericardial effusion, sepsis and vomiting (1.7% each). All other grade 3 or higher AEs occurred in 1 patient each. Twenty-nine (24.6%) patients had 1 or more SAE including disease progression, malignant pleural effusion, pleural effusion and metastatic pain (3 [2.5%] patients each); constipation, lung infection, metastatic breast cancer, pericardial effusion, sepsis and spinal cord compression (2 [1.7%] patients each); all other SAEs occurred in 1 patient each. Eight (6.8%) patients discontinued enzalutamide due to an AE. The AEs that led to discontinuation of enzalutamide (i.e., metastases to CNS, malignant pleural effusion, metastatic pain, CNS lesion, headache, muscular weakness, back pain, anxiety and general physical health deterioration) were experienced by 1 [0.8%] patient each, with 1 patient experiencing both back pain and general physical health deterioration. Twelve (10.2%) patients had an AE with fatal outcome: disease progression (3 [2.5%] patients); metastatic breast cancer, pericardial effusion and pleural effusion (2 [1.7%] patients each); and general physical health deterioration, malignant neoplasm progression, malignant pleural effusion and sepsis (1 [0.8%] patient each); no event that resulted in death was considered by the investigator to be related to enzalutamide. Data cutoff date 15 Sep 2015 (CSR) 30 Aug 2017 (clinical status) AE: adverse event; AR+: androgen receptor positive; CBR16: clinical benefit rate at 16 weeks; CBR24: clinical benefit rate at 24 weeks; CNS: central nervous system; CR: complete response; CSR: clinical study report; ECOG: Eastern Cooperative Oncology Group; ITT: intent-to-treat; M2: MDPC0002 (N-desmethyl enzalutamide); ORR: objective response rate; PFS: progression-free survival; PR: partial response; SAE: serious adverse event; TEAE: treatment-emergent adverse event; TNBC: triple-negative breast cancer

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7.8.2 MDV3100-12 Study title A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study of Efficacy and Safety of Enzalutamide in Combination With Exemestane in Patients With Advanced Breast Cancer That Is Estrogen or Progesterone Receptor-Positive and HER2-Normal Clinical status Ongoing (enrollment complete) Study design Phase 2, randomized, double-blind, placebo-controlled Indication Hormone receptor-positive advanced breast cancer Key eligibility criteria Adult postmenopausal females with advanced breast cancer that is hormone receptor- positive (ER+ and/or PgR+) and HER2-normal, whose disease is not amenable to curative surgery or radiotherapy. Nonmeasurable bone and skin disease is allowed; must have had  1 prior hormone;  1 prior chemotherapy agent for advanced breast cancer is allowed. Adequate organ and bone marrow function; ECOG 0-1. Patients with current or previously treated brain metastases are excluded. Enrollment (planned) Approximately 240 patients (120 in each cohort) Primary objective PFS as follows in each cohort: Cohort 1: patients who received no prior hormone treatment for advanced breast cancer and the subset that is also androgen receptor-positive (AR+) Cohort 2: patients who progressed following 1 hormone treatment for advanced breast cancer and the subset that is also AR+ Secondary objectives Clinical benefit rate (proportion of patients with a best response of CR, PR or stable disease lasting  24 weeks); best ORR; duration and time to response; pharmacokinetics of exemestane and enzalutamide; safety and tolerability Drug administration Enzalutamide or matching placebo; exemestane Dose Enzalutamide 160 mg once daily with or without food + exemestane 50 mg after food (hereafter referred to as enzalutamide) or placebo once daily with or without food + exemestane 25 mg after food (hereafter referred to as placebo) Enrolled/treated 247 enrolled (Cohort 1: 63 enzalutamide, 64 placebo; Cohort 2: 60 enzalutamide, 60 placebo)/245 treated (Cohort 1: 62 enzalutamide, 63 placebo; Cohort 2: 60 enzalutamide, 60 placebo); 33 patients (21 Cohort 1, 12 Cohort 2) who received double-blind placebo were enrolled into the open-label period and 32 of them (21 Cohort 1, 11 Cohort 2) received open-label enzalutamide. Demographics Cohort 1: In the ITT population, the age at baseline ranged from 34 to 89 years overall; median age at baseline was similar in the enzalutamide and placebo groups (59.0 and 63.5 years, respectively), with no apparent major differences in ethnicity and race. In the enzalutamide and placebo groups, ECOG performance status was 0 in 69.8% vs 57.8% of patients and was 1 in 28.6% vs 40.6% of patients. Cohort 2: In the ITT population, the age at baseline ranged from 34 to 89 years overall; median age at baseline was similar in the enzalutamide and placebo groups (58.0 and 60.5 years, respectively), with no apparent major differences in ethnicity, race or ECOG performance status. Efficacy For the Cohort 1 ITT population primary analysis, the incidence of PFS events was lower in the enzalutamide group than in the placebo group (66.7% and 75.0%, respectively). The difference between the treatment groups was not statistically significant (P = 0.3631, stratified log-rank test). Similar results were obtained for the Cohort 2 ITT population primary analysis: the incidence of PFS events was lower in the enzalutamide group than in the placebo group (73.3% and 83.3%, respectively). The difference between the treatment groups was not statistically significant (P = 0.9212, stratified log-rank test). No statistically significant differences between treatment groups were observed for the secondary efficacy endpoints in the Cohort 1 ITT population or the Cohort 2 ITT population. Table continued on next page

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MDV3100-12 (continued) Pharmacokinetics Mean plasma concentrations of exemestane 50 mg taken in combination with enzalutamide 160 mg were comparable to those for exemestane 25 mg alone. Exemestane exhibited very high interpatient variability of 100% to 254% and 83% to 133% for predose and postdose samples, respectively. Enzalutamide, M2 and exemestane plasma concentrations were similar across weeks 5, 9 and 17. Enzalutamide and M2 trough concentrations exhibited interpatient variability of 21% to 34% and 31% to 38%, respectively. Results for enzalutamide and M2 in this study are consistent with historical data when enzalutamide was dosed as a single agent (Study MDV3100-08); this suggested that exemestane did not have an impact on the pharmacokinetics of enzalutamide and the metabolite M2. Safety In the double-blind treatment period, at least 1 AE was reported for > 90% of patients in the safety population of each cohort (Cohort 1: 93.6%; Cohort 2: 92.5%). In the Cohort 1 safety population, most AEs occurred with a difference of ≥ 5% between treatment groups; only fatigue, diarrhea and dyspnea occurred with similar frequency in each treatment group. In the Cohort 2 safety population, fatigue, nausea, hot flush, arthralgia, anemia, vomiting, decreased appetite, alopecia, bone pain and dizziness occurred more frequently in the enzalutamide group (i.e., difference of ≥ 5% between treatment groups); back pain and diarrhea occurred more frequently in the placebo group. At least 1 grade 3 or higherAE was reported for 28% of patients in each cohort and the frequency of grade 3 or higher AEs was greater in the enzalutamide group in each cohort. In the Cohort 1 safety population, the most frequently reported grade ≥ 3 AE was hypertension, which was reported more frequently in the enzalutamide group compared to the placebo group. In the Cohort 2 safety population, the most frequently reported grade 3 or higher AE was anemia (5.0%); the patient incidence of this event was similar between treatment groups. Fifteen patients (10 in cohort 1, 5 in cohort 2) died as of the data cutoff date (23 Sep 2016). None of the deaths were considered related to study drug. In Cohort 1, 5 patients (including 1 patient who entered the open-label period) had fatal AEs, 4 of whom died within 30 days after the last dose of study drug. Five additional patient deaths were captured after safety follow-up was completed, 1 of which occurred within 30 days after stopping study drug. In Cohort 2, 2 patients had a fatal AE, both associated with disease progression; 1 patient died within 30 days after the last dose of study drug. Three additional patient deaths were captured after safety follow-up was completed, 1 of which occurred within 30 days of stopping study drug. A total of 21.6% of patients in Cohort 1 and 15.0% of patients in Cohort 2 reported other SAEs. Within each cohort, the frequency was similar between treatment groups. In Cohort 1, the most frequently reported SAEs were dyspnea, hypercalcemia, malignant pleural effusion and metastatic pain (2 [1.6%] patients each). Two (1.6%) patients reported 4 SAEs that were considered related to study drug (chills, disease progression, dizziness and pain in extremity). In Cohort 2, the most frequently reported SAE was hypercalcemia (3 [2.5%] patients). Two (1.7%) patients reported 2 SAEs that were considered related to study drug (hypercalcemia and hyponatremia). Most patients had no interruptions of study drug dose (Cohort 1: 81.9% enzalutamide/placebo, 83.5% exemestane; Cohort 2: 88.3% enzalutamide/placebo, 87.5% exemestane). The most common reason for dose modification (interruption or reduction) of study drug was AE. A total of 15.2% of patients in Cohort 1 and 13.3% of patients in Cohort 2 reported AEs that led to permanent discontinuation of study drug. In Cohort 1, the frequency was similar between treatment groups, but in Cohort 2, the frequency was greater in the enzalutamide group. A total of 3.2% of patients in Cohort 1 and 2.5% of patients in Cohort 2 had 1 or more AEs that led to dose reduction; and 20.8% of patients in Cohort 1 and 19.2% of patients in Cohort 2 had 1 or more AEs that led to interruption. Data cutoff date 23 Sep 2016 (CSR) 30 Aug 2017 (clinical status) AE: adverse event; AR+: androgen receptor positive; AST: aspartate aminotransferase; CR: complete response; CSR: clinical study report; ECOG: Eastern Cooperative Oncology Group; ER+: estrogen receptor positive; HER2: human epidermal growth factor 2; ITT: intent-to-treat; M2: MDPC0002 (N-desmethyl enzalutamide); ORR: objective response rate; PFS: progression free survival; PgR+: progesterone receptor positive; PR: partial response; SAE: serious adverse event

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7.8.3 9785-CL-1121 Study title A Phase 2, Multicenter, Open-label Study to Assess the Efficacy and Safety of Enzalutamide with Trastuzumab in Subjects with HER2+ AR+ Metastatic or Locally Advanced Breast Cancer Clinical status Ongoing (enrollment complete) Study design Phase 2, open-label, single-arm, Simon 2-stage Indication HER2+AR+ metastatic or locally advanced breast cancer Key eligibility criteria Females ≥ 18 years of age with histologically or cytologically proven adenocarcinoma of the breast that is HER2+ and AR+, whose disease is metastatic or locally advanced and not amenable to curative treatment. Measurable disease or nonmeasurable disease, evaluable per RECIST 1.1; received at least 1 line of therapy in the metastatic or locally advanced disease setting; ECOG ≤ 1 and life expectancy of ≥ 6 months. Patients with current or previously treated brain metastasis or active leptomeningeal disease or nonbreast cancer malignancy (with the exception of noninvasive carcinoma with successful curative treatment or disease free for at least 5 years), are excluded from this study. Enrollment (planned) 80 enrolled/66 evaluable patients Primary objective CBR defined as the proportion of evaluable subjects with best objective response of confirmed CR or PR per RECIST or prolonged stable disease at 24 weeks. Secondary objectives Best ORR, ORR at 24 weeks, PFS, TTP, DOR, TTR, safety and tolerability Drug administration Enzalutamide; trastuzumab Dose Enzalutamide 160 mg once daily plus trastuzumab given per local guidelines Enrolled/treated 103 enrolled/103 treated Demographics The FAS consisted of 96 (93.2%) patients who had a central assessment of AR+ expression ≥ 10%. The EES consisted of 89 (86.4%) patients from the FAS who had at least 1 postbaseline tumor assessment. Overall in the SAF (consisting of all treated patients), the median patient age was 60.0 years, the majority of the patients were white (90 [87.4%] patients) and 51 (49.5%) patients had an ECOG performance score of 1 at baseline. Efficacy The CBR for patients with confirmation was 23.6% (95% CI: 15.2%, 33.8%), with 4 (4.5%) patients achieving PR and 42 (47.2%) patients achieving stable disease. This rejected the null hypothesis (CBR ≤ 10%); therefore, the study met its primary endpoint. The best confirmed overall response rate was 4.5% (95% CI: 1.2%, 11.1%). CBR was similar across the majority of the subgroups including lines of prior therapy, ER/progesterone receptor status, AR% nuclear staining and patients with or without measurable disease. The median (95% CI) PFS was 105 (61, 116) days. Pharmacokinetics The mean (SD) enzalutamide plasma concentration at week 16 was 14.368 (3.846) µg/mL. The mean (SD) plasma concentration of N-desmethyl enzalutamide at week 16 was 14.077 (4.039) µg/mL. Results for enzalutamide and N-desmethyl enzalutamide in this study are in agreement with historical data when enzalutamide was dosed as a single agent; this suggested that trastuzumab did not have impact on the pharmacokinetics of enzalutamide and the metabolite M2. The mean (SD) serum trastuzumab concentration at week 16 was 20.055 (15.623) µg/mL. Trastuzumab trough concentrations had very high interpatient variability of 61.4% to 88.3% . Table continued on next page

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9785-CL-1121 (continued) Safety Most patients (97 [94.2%] patients) experienced at least 1 TEAE; overall 694 events were reported. Seventy-five (72.8%) patients experienced 283 enzalutamide-related TEAEs, 39 (37.9%) patients experienced 97 trastuzumab-related TEAEs and 78 (75.7%) patients experienced 299 enzalutamide- or trastuzumab-related TEAEs. Twenty-two (21.4%) patients experienced at least 1 serious TEAE with a total of 42 events reported. Three (2.9%) patients experienced 8 enzalutamide-related serious TEAEs. There were no trastuzumab-related serious TEAEs. Four (3.9%) patients experienced a TEAE that led to death. Twenty (19.4%) patients experienced a TEAE that led to permanent discontinuation of enzalutamide; 18 (17.5%) patients experienced a TEAE that led to permanent discontinuation of trastuzumab and 21 (20.4) patients experienced a TEAE that led to permanent discontinuation of enzalutamide or trastuzumab. Five (4.9%) patients experienced an enzalutamide-related TEAE that led to permanent discontinuation of study drug. Four (4.9%) patients experienced a trastuzumab-related TEAE that led to permanent discontinuation of study drug. Eight (7.8%) patients experienced an enzalutamide- or trastuzumab-related TEAE that led to permanent discontinuation of study drug. Seven (6.8%) patients experienced a TEAE that led to dose reduction and 23 (22.3%) patients experienced a TEAE that led to dose interruption. Data cutoff date 28 Feb 2017 (CSR) 30 Aug 2017 (clinical status) AR: androgen receptor; AR+: androgen receptor positive; CBR: clinical benefit rate; CI: confidence interval; CR: complete response; CSR: clinical study report; DOR: duration of response; ECOG: Eastern Cooperative Oncology Group; EES: efficacy evaluable set; ER: estrogen receptor; FAS: full analysis set; HER2+: human epidermal growth factor receptor 2 positive; M2: MDPC0002 (N-desmethyl enzalutamide); ORR: overall response rate; PFS: progression-free survival; PR: partial response; RECIST: Response Evaluation Criteria in Solid Tumors; SAF: safety analysis set; TEAE: treatment-emergent adverse event; TTP: time to progression; TTR: time to response

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7.9 Phase 2 Studies in Hepatocellular Carcinoma 7.9.1 9785-CL-3021 Study title A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study to Assess the Efficacy and Safety of Enzalutamide in Subjects with Advanced Hepatocellular Carcinoma Clinical status Ongoing (enrollment complete) Study design Phase 2, double-blind, placebo-controlled Indication Advanced hepatocellular carcinoma Key eligibility criteria Male or female patients ≥ 18 years of age with advanced HCC of any etiology, with BCLC stage B or C, whose lesions are not amenable to local therapies. Patients hepatic function status must be Child-Pugh Class A and must have received prior systemic treatment with anti-VEGF therapy and had confirmed disease progression or drug-related toxicity. In addition, the patient must have an ECOG status ≤ 1 and a life expectancy of ≥ 3 months. Patients with a fibrolamellar variant of HCC, a history of organ allograft including liver transplant, brain metastasis or active leptomeningeal disease or a history of non-HCC malignancy (with the exception of noninvasive carcinoma) are excluded from the study. Enrollment (planned) Approximately 144 Primary objective Efficacy as measured by overall survival Secondary objectives Safety, pharmacokinetics, PFS Drug administration Enzalutamide or placebo Dose 160 mg once daily Enrolled/treated 165 enrolled/162 treated (107 enzalutamide, 55 placebo) Demographics Of the 165 patients enrolled, 144 (87.3%) were male. The mean age was 63.3 years; most patients (55.2%) were ≤ 55 years of age. Most patients were either white (47.3%) or Asian (46.7%). The mean BMI was 24.3 kg/m2. The median duration from diagnosis of HCC to enrollment was 866.0 days or approximately 2.4 years (range: 74 to 4401 days). Most (65.2%) patients had undergone 1 line of prior systemic therapy; 78.2% of patients discontinued the last prior systemic therapy because of disease progression. Most (72.1%) patients had not undergone radiation therapy for treatment of HCC. Overall, the enzalutamide and placebo groups were similar with respect to demographic characteristics and disease history with the exception of abuse and cirrhosis. Twenty percent of patients in the enzalutamide group experienced alcohol abuse compared with 12.7% of patients in the placebo group. In the placebo group, 4 (7.3%) patients had nonalcoholic fatty liver disease cirrhosis and 1 (1.8%) patient had stage 4 primary biliary cirrhosis compared with 3 (2.7%) patients and 0 patients, respectively, in the enzalutamide group. Efficacy Overall, the efficacy results show that enzalutamide was not significantly different from placebo in the treatment of patients with HCC of any etiology who had progressed on or were intolerant to sorafenib or other anti-VEGF therapy in the advanced setting. There were no significant differences between the enzalutamide group and the placebo group for either the primary endpoint of OS (HR based on the stratified analysis: 1.146), the secondary endpoint of PFS (HR based on the stratified analysis: 1.039) or the exploratory endpoints of TTP, ORR or DCR. Likewise, none of the subgroup analyses of OS revealed any statistically significant differences between subgroups. Table continued on next page

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9785-CL-3021 (continued) Pharmacokinetics The mean (SD) enzalutamide plasma concentration at week 13 was 12.45 (5.44) µg/mL. The mean (SD) plasma concentration of N-desmethyl enzalutamide at week 13 was 12.21 (4.94) µg/mL. Results for enzalutamide and N-desmethyl enzalutamide in this study are in agreement with historical data when enzalutamide was dosed as a single agent. In general, trough concentrations for enzalutamide and N-desmethyl enzalutamide had interpatient variability between 29.0% to 43.7% and 30.7% to 40.4%, respectively. Safety The most frequently (> 20% of patients) reported TEAEs in the enzalutamide group were fatigue (37 [34.6%] patients), decreased appetite (34 [31.8%] patients) and nausea (28 [26.2%] patients); and in the placebo group were diarrhea (13 [23.6%] patients) and decreased appetite (12 [21.8%] patients). TEAEs that occurred more frequently (≥ 10%) with enzalutamide than with placebo were fatigue (34.6% vs 18.2%), decreased appetite (31.8% vs 21.8%), nausea (26.2% vs 10.9%), ascites (14.0% vs 3.6%) and gynecomastia (11.2% vs 0). Grade 3 TEAEs were reported in 42 (39.3%) patients in the enzalutamide group and 20 (36.4%) patients in the placebo group. The most frequently (≥ 5% of patients) reported grade 3 TEAEs in the enzalutamide group were AST increased (11.2%), fatigue (6.5%) and asthenia (5.6%) and in the placebo group were AST increased (7.3%), diarrhea (7.3%) and abdominal pain (5.5%). Grade 4 TEAEs were reported in 3 (2.8%) patients in the enzalutamide group, which included hyponatremia in 2 (1.9%) patients and blood bilirubin increased, hypophosphatemia, thrombocytopenia, hyperkalemia, metabolic acidosis, ECG QRS complex and pulmonary embolism in 1 (0.9%) patient each. Grade 4 TEAEs were reported in 3 (5.5%) patients in the placebo group, including ALT increased and AST increased in 2 (3.6%) patients each and anemia, hyperkalemia and renal failure acute in 1 (1.8%) patient each. SAEs that occurred in ≥ 2% of patients in either group included, in the enzalutamide group, malignant neoplasm progression (13.1%), abdominal pain (6.5%), ascites (4.7%), renal failure acute (3.7%), anemia (2.8%) and back pain (2.8%) and, in the placebo group, malignant neoplasm progression (10.9%), tumor hemorrhage (3.6%) and renal failure acute (3.6%). All other SAEs in either group occurred in 1 or 2 patients each. AEs with fatal outcome occurred in 14 (13.1%) and 6 (10.9%) patients in the enzalutamide and placebo groups, respectively. In the enzalutamide group, these were malignant neoplasm progression in 11 patients, sepsis in 2 patients and general physical health deterioration and renal failure acute in 1 patient each. In the placebo group, these were malignant neoplasm progression in 5 patients and septic shock in 1 patient. By the data cutoff date, 35 (32.7%) patients in the enzalutamide group and 14 (25.5%) patients in the placebo group discontinued treatment due to TEAEs. TEAEs leading to withdrawal of treatment and assessed as related to any of the study drugs included, in the enzalutamide group, fatigue in 3 (2.8%) patients, asthenia in 2 (1.9%) patients and abdominal discomfort, dyspepsia, nausea, hepatic failure, weight decreased, decreased appetite, lethargy and dyspnea in 1 (0.9%) patient each; and in the placebo group, ALT increased and AST increased in 2 (3.6%) patients each and rectal hemorrhage and asthenia in 1 (1.8%) patient each. Data cutoff date 02 Oct 2017 (CSR) AE: adverse event; ALT: alanine aminotransferase; AST: aspartate aminotransferase; BCLC: Barcelona-Clinic Liver Cancer; BMI: body mass index; CSR: clinical study report; DCR: disease control rate; ECG: electrocardiogram; ECOG: Eastern Cooperative Oncology Group; HCC: hepatocellular carcinoma; HR: hazard ratio; ORR: overall response rate; OS: overall survival; PFS: progression-free survival; SAE: serious adverse event; TEAE: treatment-emergent adverse event; TTP: time to progression; VEGF: vascular endothelial growth factor

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ATTACHMENT 1 REVIEW AND APPROVAL

Key Reviewers This Investigator’s Brochure was reviewed with respect to consistency, completeness and traceability of the scientific content, as well as for the accurate representation of the data/information and its interpretation in the document, as relevant to the indicated discipline. Astellas Pharma Global Development, Inc. Natalia Nikolayeva, MD, PhD, Associate Medical Director Medical Safety Seema Gorla, MD, Senior Medical Director Medical Safety Jason Studer, Associate Director Project & Product Management Karin Vlugt-Wensink, PhD, Associate CMC Director Project & Product Management Maggie Liosatos, MS, Associate Director Clinical Science Kelley Micklus, Associate Director Clinical Science Jeffrey Barrus, BSc, RAC, Senior Director Regulatory Affairs Maricel Rutter, PharmD, Associate Director Regulatory Affairs Mary Mantock, Senior Director Regulatory Affairs Masamichi Mori, MSc, Associate Director Drug Discovery Research Program Management Danny Burg, PhD, ERT, Associate Director Drug Discovery Science Chinatsu Sakata, Senior Manager Development Project Management-Japan Clinical Pharmacology and Exploratory Shiva Patil, Director Development Andrew Krivoshik, MD, PhD, Vice President Medical Oncology Joyce Steinberg, MD, Executive Medical Director Medical Oncology De Phung, BSc, Biostatistics Director Data Science Jennifer Sugg, MS, Biostatistics Director Data Science Irene Martinez-Regueira, Senior Director Development Project Leader, Oncology Steve van Os, MD, Senior Director Development Project Leader, Oncology Steven Benner, MD, Senior Vice President Development Oncology

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Approver (Scientific Content) I confirm that, to the best of my knowledge, this Investigator’s Brochure provides an accurate compilation of clinical and nonclinical data on the investigational product that are relevant to the study of the product in human subjects. This Investigator’s Brochure has been evaluated with respect to readability for investigators and Institutional Review Boards/Independent Ethics Committees and for completeness of safety information.

(e-signature attached at end of document)

Signature: Date:

Joyce Steinberg, MD Executive Medical Director Medical Oncology, Medical Science

Approver (Senior Management)

(e-signature attached at end of document)

Signature: Date:

Steven Benner, MD Senior Vice President, Therapeutic Area Head for Oncology, Development

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ELECTRONIC SIGNATURE PAGE Document Type : Investigator's Brochure Document Control Number : MGC1800229 Amendment Number : N/A International Study Number : N/A Departmental Study Number : N/A Actual Version Number : Edition 10 Document Version : 2.0 Nonclinical Initial SD Approved Date (UTC) : N/A

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Responsible Medical Officer 06/18/2018 14:19:24 Joyce Steinberg

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Authorized Document Officer Approval 06/18/2018 15:35:09 Steven Benner

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