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 Pfizer 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. Jun 2018 Astellas/Medivation Page 1 of 126 Enzalutamide (MDV3100) CONFIDENTIAL Cancer Investigator’s Brochure Edition 10 Table of Contents 1 SUMMARY·························································································10 2 INTRODUCTION·················································································19 2.1 Prostate Cancer ················································································19 2.2 Breast Cancer ··················································································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 In Vitro 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 Central Nervous System 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 Pharmacokinetics and Product Metabolism················································30 4.2.1 Absorption················································································30 4.2.2 Distribution···············································································30 4.2.3 Metabolism···············································································30 4.2.4 Excretion ·················································································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 Jun 2018 Astellas/Medivation Page 2 of 126 Enzalutamide (MDV3100) CONFIDENTIAL Cancer Investigator’s Brochure Edition 10 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 Hormone-naïve Prostate Cancer ···································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 Jun 2018 Astellas/Medivation Page 3 of 126 Enzalutamide (MDV3100) CONFIDENTIAL Cancer Investigator’s Brochure Edition 10 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 Pregnancy 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 ·························································