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Janssen Research & Development*

Investigator's Brochure

JNJ-212082 ZYTIGA® (abiraterone )

August 2015

*Janssen Research & Development is a global organization that operates through different legal entities in various countries. Therefore, the legal entity acting as the sponsor for Janssen Research & Development studies may vary, such as, but not limited to , Inc.; Janssen Products, LP; Janssen Biologics, BV; Janssen- International NV; Janssen, Inc; Janssen Infectious Diseases BVBA; Janssen Sciences Ireland UC; or Janssen Research & Development, LLC.

Edition No: 12 Status: Approved Date: 26 August 2015 Replaces Previous Edition No.: 11 Date of Previous Edition: 22 September 2014 Prepared by: Janssen Research & Development, LLC EDMS No. & Version: EDMS-ERI-14497303:9.0

Confidentiality Statement The information in this document contains trade secrets and commercial information that are privileged or confidential and may not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to whom the information is disclosed must be informed that the information is privileged or confidential and may not be further disclosed by them. These restrictions on disclosure will apply equally to all future information supplied to you that is indicated as privileged or confidential.

1 Approved, Date: 26 August 2015 JNJ-212082 () Investigator's Brochure - Edition 12

INVESTIGATOR'S BROCHURE EDITION HISTORY Edition No. / Edition/Addendum Issue IB Data Cutoff Date(s) Addendum No. Date Edition 12 26 August 2015 27 April 2015 (Clinical and Safety Databases) Addendum 1 to 10 December 2014 01 October 2014 (Postmarketing CCO) Edition 11 Edition 11 22 September 2014 27 April 2014 (Safety Database) 11 August 2014 (Clinical Database) Addendum 1 to 10 January 2014 15 July 2013 (Study 212082PCR1011) Edition 10 Edition 10 26 August 2013 26 July 2013 (Clinical Efficacy and Safety), 01 June 2013 (Nonclinical), 27 April 2013 (Postmarking Safety), Postmarketing Cumulative Exposure (30 April 2013), Postmarketing adverse drug reaction search of Global Medical Safety Database for allergic alveolitis (01 July 2013) Edition 9 27 April 2012 20 December 2011 (Clinical), 22 March 2012 (Nonclinical) Edition 8 4 April 2011 22 January 2010 (Clinical Efficacy and Safety) 20 September 2010 (SAEs) Edition 7 17 September 2010 20 September 2009 (Safety) 30 November 2009 (SUSARs) 22 January 2010 (Efficacy and AEs of COU-AA-301) Addendum 1 to 31 March 2010 22 January 2010 (Efficacy and Safety) Edition 6 Edition 6 20 January 2010 20 September 2009 (Nonclinical, Clinical) 30 November, 2009 (SUSARs) Edition 5 20 January 2009 21 September 2008 (Clinical Efficacy and Safety) 31 December 2008 (SUSARs) Edition 4 30 June 2008 20 October 2007 (Clinical) 30 May 2008 (SUSARs) Edition 3 4 March 2008 20 October 2007 (Clinical Efficacy and Safety, and SUSARs) Edition 2 7 May 2007 1 April 2007 (Clinical Efficacy and Safety) Edition 1 22 December 2005 Original Investigator’s Brochure CCO=clinical cutoff; SAE=serious adverse event; SUSAR=suspected unexpected serious adverse reaction

2 Approved, Date: 26 August 2015 JNJ-212082 (abiraterone acetate) Investigator's Brochure - Edition 12

SUMMARY OF CHANGES FROM PREVIOUS VERSION The following summarizes only the major changes to the previous edition (No. 11; 22 September 2014) of this Investigator’s Brochure (IB).

Section Summary of Change General All changes made to other sections have been incorporated into the Summary Section as appropriate.

Section 1, Introduction Updated information on the overall rationale for studies in cancer.

Section 2, Physical, Chemical, and Pharmaceutical Updated the information on the clinical Properties, and Formulation formulations. Section 3, Nonclinical Studies No changes

Section 4, Effect in Humans Updated information as relevant for studies included in the previous version and added information on new studies that were not included in the previous version.

Updated Section 4.5 with postmarketing exposure, ADR of /myopathy, and reports of hepatotoxicity in Japan.

Section 5, Summary of Data and Guidance for the Updated information to align with new information in Investigator other sections.

Reference Safety Information Added new ADR of rhabdomyolysis/myopathy identified since the previous version.

Appendices Updated tables of clinical studies as appropriate.

References Updated reference list consistent with changes made to other sections.

3 Approved, Date: 26 August 2015 JNJ-212082 (abiraterone acetate) Investigator's Brochure - Edition 12

TABLE OF CONTENTS

INVESTIGATOR'S BROCHURE EDITION HISTORY ...... 2

SUMMARY OF CHANGES FROM PREVIOUS VERSION...... 3

TABLE OF CONTENTS ...... 4

LIST OF IN-TEXT TABLES AND FIGURES ...... 7

LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS...... 8

SUMMARY...... 10

1. INTRODUCTION...... 16 1.1. The Rationale for Abiraterone Acetate in the Management of -Resistant (CRPC)...... 18 1.2. The Rationale for Abiraterone Acetate in -naïve Metastatic Prostate Cancer and as Neoadjuvant Therapy in High-risk Localized Prostate Cancer ...... 18 1.3. The Rationale for Abiraterone Acetate in the Management of ...... 19 1.4. The Rationale for the Study of Abiraterone Acetate in Combination with ...... 19 1.5. Rationale for the Study of Abiraterone Acetate in Combination with JNJ-56021927 (also known as ARN-509) ...... 19

2. PHYSICAL, CHEMICAL, AND PHARMACEUTICAL PROPERTIES AND FORMULATIONS ...... 21 2.1. Product Identification...... 21 2.2. Physical and Chemical Characteristics...... 21 2.3. Formulation Information ...... 21 2.4. Packaging, Storage, and Handling ...... 21

3. NONCLINICAL STUDIES...... 22 3.1. Nonclinical Pharmacology...... 22 3.1.1. Primary and Secondary Pharmacologic Effects ...... 22 3.1.2. Safety Pharmacology...... 22 3.2. and Metabolism in Animals ...... 22 3.3. Toxicology ...... 23 3.4. Conclusions for Nonclinical Studies...... 24

4. EFFECTS IN HUMANS ...... 24 4.1. Overview ...... 24 4.1.1. Phase 1 and Phase 1/2 Studies ...... 25 4.1.2. Phase 2 Studies...... 25 4.1.3. Phase 3 Studies...... 25 4.1.4. Phase 4 Study ...... 25 4.2. Pharmacokinetics and Product Metabolism...... 25 4.2.1. Pharmacokinetics ...... 25 4.2.2. Effect of Food on the Pharmacokinetics of Abiraterone ...... 27 4.2.3. Drug-drug Interactions Studies...... 28 4.2.4. Special Populations ...... 28 4.2.5. Pharmacodynamics ...... 29 4.2.5.1. Cardiac Safety Study...... 29 4.2.5.2. Pharmacodynamic Effect of ...... 29 4.2.6. Effects of Age ...... 30 4.2.7. Effects of Race and Ethnicity...... 30 4.3. Efficacy Results...... 31 4.3.1. Other Efficacy Results in Phase 1/2 and Phase 2 Studies...... 34 4.3.1.1. Bone Scan Flare and Discordance with PSA and Clinical Response...... 34 4 Approved, Date: 26 August 2015 JNJ-212082 (abiraterone acetate) Investigator's Brochure - Edition 12

4.3.1.2. Neoadjuvant Studies of Abiraterone Acetate in Prostate Cancer ...... 34 4.3.1.3. Non-metastatic Prostate Cancer ...... 35 4.3.1.4. Combination of Abiraterone Acetate with Docetaxel in Prostate Cancer...... 36 4.3.1.5. Breast Cancer...... 36 4.3.2. Efficacy Results in Phase 3 Studies ...... 36 4.3.2.1. COU-AA-301 (Appendix B.6)...... 36 4.3.2.2. COU-AA-302 (Appendix B.6)...... 38 4.3.2.3. Bridging Studies: ABI-PRO-3001 and ABI-PRO-3002 ...... 41 4.4. Summary of Safety in Studies with Abiraterone Acetate ...... 41 4.4.1. Summary of Adverse Events in Studies COU-AA-301 and COU-AA-302 ...... 41 4.4.1.1. Adverse Events of Special Interest ...... 42 4.4.1.2. Deaths, Serious Adverse Events and Other Significant Adverse Events ...... 44 4.4.1.2.1. Serious Adverse Events...... 44 4.4.1.2.2. Deaths ...... 45 4.4.1.2.3. Adverse Events Leading to Discontinuation of Treatment...... 45 4.4.2. Bridging Studies...... 46 4.4.3. Food Safety Study ...... 46 4.4.4. Expanded Access Study...... 47 4.4.5. Safety in Subjects with Non-metastatic Prostate Cancer ...... 47 4.4.6. Combination of Abiraterone Acetate With Other Drugs in Men With Prostate Cancer ...... 48 4.4.6.1. Abiraterone Acetate and With Docetaxel ...... 48 4.4.7. Study COU-AA-BMA...... 48 4.4.8. Japanese Phase 2 Studies...... 49 4.4.9. Breast Cancer...... 49 4.5. Marketing Experience ...... 49

5. SUMMARY OF DATA AND GUIDANCE FOR INVESTIGATORS ...... 50

6. REFERENCE SAFETY INFORMATION ...... 60

REFERENCES...... 62

APPENDIX A ...... 65 Appendix A.1: Single and Repeated Oral Dose GLP Toxicity Studies ...... 66 Appendix A.2: Reproductive and Developmental GLP Toxicity Studies...... 73

APPENDIX B ...... 75 Appendix B.1: Completed Phase 1 and Phase 1/2 Clinical Studies (as of 27 April 2015)a ...... 76 Appendix B.2: Ongoing Phase 1 and Phase 1/2 Clinical Studies (as of 27 April 2015) ...... 91 Appendix B.3: Completed Phase 2 Clinical Studies (as of 27 April 2015)...... 93 Appendix B.4: Ongoing Phase 2 Clinical Studies (as of 27 April 2015) ...... 97 Appendix B.5: Completed Phase 3 Clinical Studies (as of 27 April 2015)...... 98 Appendix B.6: Ongoing Phase 3 Clinical Studies (as of 27 April 2015) ...... 99 Appendix B.7: Ongoing Phase 4 Clinical Studies (as of 27 April 2015) ...... 102

APPENDIX C ...... 103 Appendix C.1: Pharmacokinetic Parameters for Abiraterone after a 1,000 mg Single or Daily Administration of Abiraterone Acetate under Fasting or Modified Fasting Conditions...... 104

APPENDIX D ...... 105 Appendix D.1: Treatment-Emergent Adverse Events by Toxicity Grade where Combined AA is at least 1% Greater Than Combined Placebo Integrated Safety Population Receiving 1,000mg/day AA in All Clinical Trials...... 106 Appendix D.2: Treatment-Emergent Adverse Events Reported in at Least 10% of Subjects in Any Group; Integrated Safety Population...... 118 Appendix D.3: Treatment-Emergent Adverse Events of Special Interest; Integrated Safety Population ...... 120

5 Approved, Date: 26 August 2015 JNJ-212082 (abiraterone acetate) Investigator's Brochure - Edition 12

Appendix D.4: Treatment-Emergent Serious Adverse Events Reported in at Least 1% of Subjects in Any Group; Integrated Safety Population ...... 124

LAST PAGE...... 125

6 Approved, Date: 26 August 2015 JNJ-212082 (abiraterone acetate) Investigator's Brochure - Edition 12

LIST OF IN-TEXT TABLES AND FIGURES TABLES Table 1: Summary of Key Pharmacokinetic and Biopharmaceutic Studies ...... 26 Table 2: Summary of Studies on Effect of Food and Food Timing on the Pharmacokinetics of Abiraterone ...... 27 Table 3: Summary of Drug-drug Interaction Studies with Abiraterone Acetate...... 28 Table 4: Summary of Pharmacokinetic Studies of Abiraterone in Special Populations ...... 29 Table 5: Summary of the Pharmacokinetics of Abiraterone in Asian Subjects ...... 31 Table 6: Key Efficacy Results for Studies of Abiraterone Acetate in Subjects with mCRPC ...... 32 Table 7: Summary of Other Efficacy Endpoints (Study COU-AA-301)...... 38 Table 8: Summary of Efficacy Data for the Secondary Endpoints (Study COU-AA-302) ...... 40 Table 9: Summary of FACT-P Subscale Results (Study COU-AA-302: ITT Population)...... 40 Table 10: Overall Safety Profile (Integrated Safety Population) ...... 42 Table 11: Adverse Drug Reactions Associated with Abiraterone Acetate (ZYTIGA®) ...... 61

FIGURES Figure A: Conversion of Abiraterone Acetate to Abiraterone ...... 16 Figure B: Inhibition of the 17α hydroxylase/C17,20-lyase Pathways by Abiraterone Acetate and Abiraterone ...... 17

7 Approved, Date: 26 August 2015 JNJ-212082 (abiraterone acetate) Investigator's Brochure - Edition 12

LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS Abbreviations ADR adverse drug reaction ADT deprivation therapy AE adverse event ALP alkaline phosphatase ALT alanine aminotransferase AR AST aspartate aminotransferase BPI-SF Brief Pain Inventory-Short Form CCDS Company Core Data Sheet CCO clinical cutoff CI confidence interval CRPC castration-resistant prostate cancer CYP cytochrome DHEA DHEA-S dehydroepiandrosterone-sulfate DHT ECG electrocardiograms ECOG Eastern Cooperative Oncology Group eDISH electronic tool for drug-induced serious hepatotoxicity ER (+) receptor (positive) ESRD end-stage renal disease EU European Union FACT-P Functional Assessment of Cancer Therapy-Prostate GI gastrointestinal GLP Good Laboratory Practice GnRH -releasing hormone HDPE high-density polyethylene hERG human ether-á-go-go-related gene HR hazard ratio IB Investigator’s Brochure ICH International Conference on Harmonisation IV intravenous(ly) LFT Liver Function Test LHRHa luteinizing hormone-releasing hormone analog L-E Long-Evans mCRPC metastatic castration-resistant prostate cancer MedDRA Medical Dictionary for Regulatory Activities NYHA New York Heart Association OATP organic anion-transporting polypeptide OS overall survival PK pharmacokinetics PSA prostate-specific antigen rPFS radiographic progression-free survival RECIST Response Evaluation in Solid Tumors SAE serious adverse event S-D Sprague-Dawley ULN upper limit of normal US United States

8 Approved, Date: 26 August 2015 JNJ-212082 (abiraterone acetate) Investigator's Brochure - Edition 12

Definitions of Terms AA+LHRHa abiraterone acetate plus prednisone in combination with LHRHa AAP abiraterone acetate plus prednisone AAPE abiraterone acetate plus prednisone plus AUC area under the plasma concentration-time curve, calculated by linear trapezoidal summation

AUC area under the plasma concentration-time curve from time zero to infinite time AUC24 area under the plasma concentration-time curve from time 0 to 24 hours AUClast area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration Cmax maximum plasma concentration Qtc QT interval corrected for heart rate QTcF QTc using Fridericia method tmax time to the maximum observed plasma concentration t1/2 apparent elimination half-life

9 Approved, Date: 26 August 2015 JNJ-212082 (abiraterone acetate) Investigator's Brochure - Edition 12

SUMMARY INTRODUCTION: Abiraterone acetate (3β)-17-(3-pyridinyl) androsta-5, 16-dien-3-yl acetate, formerly code named CB7630; JNJ-212082) is rapidly converted in vivo to abiraterone (JNJ-589485; formerly code named CB7598). Abiraterone is a selective irreversible inhibitor of 17α hydroxylase/C17, 20-lyase (cytochrome P450c17 [CYP17]), an enzyme that is critical in the production of in the testes, adrenal glands and prostate tumor tissue. Inhibition of CYP17 inhibits the conversion of pregnenolone or progesterone into dehydroepiandrosterone (DHEA) or , respectively, each of which is a precursor of . The pharmacodynamic effect in androgen depletion is greater than can be induced by surgical castration, or medically by gonadotropin releasing hormone (GnRH) analogs (referred to in this document as luteinizing hormone releasing hormone analogs [LHRHa]) used as first line in prostate cancer. The first marketing authorization was granted in the United States (US) on 28 April 2011, where currently abiraterone acetate combined with prednisone is indicated for the treatment of metastatic castration-resistant prostate cancer (mCRPC). In addition to its approved use in patients with mCRPC, abiraterone acetate is being or was studied in combination with docetaxel, JNJ-56021927 (ARN509), and Xofigo (223Ra) in mCRPC; in postmenopausal women with positive (ER+) metastatic breast cancer progressing after letrozole or anastrozole therapy; in men who are newly diagnosed with metastatic prostate cancer and who have not received hormonal therapy; as neoadjuvant hormonal therapy in men with advanced prostate cancer without radiographic evidence of metastatic disease; in men with advanced, non- metastatic CRPC; and in patients with congenital adrenal hyperplasia. Further development for breast cancer and congenital adrenal hyperplasia has been discontinued. PHYSICAL, CHEMICAL, AND PHARMACEUTICAL PROPERTIES: The drug substance abiraterone acetate, referred to as JNJ-212082, has a molecular weight of 391.55, a molecular formula of C26H33NO2, and its chemical name is (3β)-17-(3-pyridinyl)androsta-5,16-dien-3-yl acetate. The investigational drug product can be supplied as oral immediate release tablets of 250-mg strength (film coated or uncoated) or 500-mg strength (film coated). The formulations should be stored as stated on the label. NONCLINICAL STUDIES: Nonclinical Pharmacology Abiraterone has nanomolar potency in several in vitro CYP17α hydroxylase/C17,20-lyase test systems including rat and human microsomes. When tested for binding to human nuclear receptors at a concentration of 1 µM, abiraterone did not inhibit ligand binding to the receptor, the estrogen receptors or androgen receptor. Some weak binding activity was observed for the nuclear progesterone receptor at concentrations above 100 nM. However, neither progesterone nor antagonist activity was observed in an intact cell assay. Abiraterone was also inactive as agonist for the rat or mouse glucocorticoid receptor at concentrations ranging from 0.05 to 10 µM. The in vivo effects of abiraterone acetate administered orally either as a single dose or in daily repeated doses on the circulating hormone levels and androgen target organ weights were characterized in mice, rats, and monkeys. The effects were consistent with a selective inhibition of androgen . Antitumor activity was demonstrated in a human castration-resistant prostate tumor xenograft, wherein inhibition of intratumoral androgen biosynthesis was demonstrated.

10 Approved, Date: 26 August 2015 JNJ-212082 (abiraterone acetate) Investigator's Brochure - Edition 12

In in vitro (human ether-á-go-go-related gene [hERG]) and in vivo safety pharmacology studies, the latter after oral administration in rodents and telemetered monkeys, abiraterone acetate and abiraterone had no relevant effects on the central nervous system, cardiovascular and respiratory systems, and gastric irritation. Toxicology Good Laboratory Practice (GLP) toxicology studies in the mouse, rat, and monkey, do not indicate any significant abiraterone acetate treatment-related effects on the central nervous, respiratory, cardiovascular, or renal systems. After 13 weeks or longer of abiraterone acetate treatment in rat and monkey studies, GI effects were limited to a minimal to slight increase in bile duct hyperplasia. In animal toxicity studies, main toxic effects in mice, rat and monkey were related to the pharmacologic activity of abiraterone acetate affecting the animal’s steroidogenesis, reproductive organs as well as the adrenal, pituitary, and (male) mammary glands. Additionally, partially reversible bile duct changes were seen in the rat and monkey and hepatocellular hypertrophy in the rat (reversible) and mouse only. In comparison with 13 weeks of dosing, these findings did not become worse during long term treatment (up to 26 and 39 weeks in rat and monkey, respectively). In the mouse, periportal inflammation and necrosis of hepatocytes were also observed in the liver (28 days of dosing). Cataracts (irreversible) were observed in the rat (after 26 weeks of dosing only) but not in the monkey (39 weeks of dosing). In vitro and in vivo genotoxicity studies conducted with abiraterone acetate or abiraterone did not show any mutagenic or clastogenic activity. No increase in tumors was observed in a 6-month transgenic mouse GLP carcinogenicity study at doses up to 750 mg/kg/day. In a 2-year rat GLP carcinogenicity study, there was an increased incidence of testicular interstitial (Leydig) cell adenomas and carcinomas; however, this finding was considered rat- specific and related to the pharmacological activity of abiraterone acetate. As a result of the pharmacologic activity of abiraterone, dosing of abiraterone acetate resulted in complete loss of fertility in male rats; the effect was completely reversible 8 to 16 weeks after cessation of dosing. Pregnant rats showed difficulties in the maintenance of due to the perturbation of the hormonal landscape but fertility per se was unaffected and abiraterone acetate had no teratogenic potential. Administration of abiraterone acetate to juvenile rats during the pre-pubertal period did not affect reproductive performance and fertility. EFFECTS IN HUMANS: Overview Overall, as of 27 April 2015, over 900 subjects have been exposed to abiraterone acetate in Phase 2 studies and over 3,000 subjects in Phase 3 studies. Additionally, more than 7,500 subjects under the Named Patient Program and over 2,000 subjects under the Early Access Program received abiraterone acetate. Results from Study COU-AA-301 were the basis for the marketing authorization of abiraterone acetate plus prednisone or (hereafter referred to as prednisone) for mCRPC in subjects who had disease progression on or after docetaxel-based . The last patient last visit occurred on 1 October 2012, and ongoing subjects were rolled into the long-term safety Study 212082PCR3010. Results from Study COU-AA-302 were the basis of marketing authorization of abiraterone acetate plus prednisone for mCRPC in subjects who were asymptomatic or mildly symptomatic after failure of androgen deprivation therapy (ADT). The final analysis of efficacy and safety was performed with a clinical cutoff date of 31 March 2014.

11 Approved, Date: 26 August 2015 JNJ-212082 (abiraterone acetate) Investigator's Brochure - Edition 12

Pharmacokinetics and Product Metabolism The pharmacokinetics (PK) of abiraterone acetate was evaluated in healthy men and in men with prostate cancer. After a single dose of abiraterone acetate (1,000 mg) under fasting conditions in healthy male subjects the mean Cmax, AUC∞, and t1/2 were approximately 100 ng/mL, 500 ng*h/mL, and 15.0 hours, respectively. The peak concentration of abiraterone was generally reached at 2 hours after dosing. Systemic exposure to abiraterone increased linearly with dose following single-dose administration of abiraterone acetate tablets at 250 mg, 500 mg, 750 mg, and 1,000 mg doses under fasting conditions in healthy male subjects. Following multiple dosing in subjects with mCRPC, abiraterone appeared to reach a steady-state condition after 7 days. Mean systemic exposure of abiraterone at steady-state following 1,000 mg once daily as assessed by Cmax and AUC24h was 232 ng/mL and 1,060 ng*h/mL, respectively. The mean accumulation ratio of abiraterone at steady-state after once daily dosing was approximately 2-fold for both Cmax and AUC24h. Overall, the exposure to abiraterone in subjects with mCRPC was higher than in healthy male subjects. The inter-subject variability in disposition of abiraterone was high. In healthy subjects, between-subject variability ranged from 32.7% to 119.8% for Cmax and from 40.5% to 140.6% for AUC∞. The estimated between-subject variability in subjects with mCRPC, based on simulated data, was 91% for Cmax at steady state and 83% for AUC at steady state. The of 14C-abiraterone in human plasma was 99.8%. The apparent central volume of distribution was approximately 5,630 L, suggesting that abiraterone extensively distributes to peripheral tissues. The binding of the two major human metabolites of abiraterone acetate, abiraterone sulphate and N-oxide abiraterone sulphate to human plasma proteins was also high. Renal elimination was not a primary elimination pathway since less than 5% of the dose was recovered in the after administration of 1,000 mg radiolabeled abiraterone acetate. Abiraterone acetate, abiraterone and the downstream inactive metabolites were recovered in the (approximately 80%). Renal Impairment The PK of abiraterone was compared in subjects with end-stage renal disease (ESRD) on a stable hemodialysis schedule versus matched control subjects with normal renal function. Systemic exposure to abiraterone after a single oral 1,000 mg dose did not increase in subjects with ESRD on dialysis. Hepatic Impairment The PK of abiraterone was examined in subjects with pre-existing mild or moderate hepatic impairment (Child-Pugh class A and B, respectively) and in healthy control subjects. Systemic exposure to abiraterone acetate after a single oral 1,000 mg dose increased by approximately 11% and by 260% in subjects with mild and moderate pre-existing hepatic impairment, respectively. No dosage adjustment was necessary for patients with pre-existing mild hepatic impairment. Systemic exposure to abiraterone after administration of 125 mg abiraterone acetate suspension (62.5 mg tablet equivalent) in subjects with severe hepatic impairment was 22.4% for Cmax, 47.3% for AUClast, and 43.6% for AUC of that found in subjects with normal hepatic function after administration of 2,000 mg abiraterone acetate suspension (1,000 mg tablet equivalent). Abiraterone acetate should be used with caution in patients with moderate hepatic impairment only if the benefit clearly outweighs the possible risk and should not be used in patients with pre-existing severe hepatic impairment.

12 Approved, Date: 26 August 2015 JNJ-212082 (abiraterone acetate) Investigator's Brochure - Edition 12

Potential for Food or Drug Interactions with Abiraterone Acetate Food Effects Administration of abiraterone acetate with food significantly increased the absorption of abiraterone acetate in healthy subjects. Administration of a single 1,000 mg dose of abiraterone acetate tablets increased abiraterone mean Cmax and AUC values by approximately 7- and 5-fold, respectively, when administered immediately after a low-fat meal compared to the fasted state. Abiraterone mean Cmax and AUC values increased approximately 17- and 10-fold, respectively, when administered immediately after a high-fat meal compared to the fasted state. Drug-drug Interactions with Abiraterone Acetate After administration of 1,000 mg dose of abiraterone acetate tablets, mean systemic exposure of dextromethorphan, a CYP2D6 probe substrate, was approximately 200% higher when dextromethorphan was co-administered with abiraterone acetate compared to when dextromethorphan was administered alone. No effect was observed with theophylline, a CYP1A2 probe substrate. Caution is advised when co-administering abiraterone acetate with drugs activated by or metabolized by CYP2D6, particularly those with a narrow therapeutic index. Abiraterone is a strong inhibitor in vitro of CYP2C8, which indicates a potential for drug-drug interaction between abiraterone acetate and medications metabolized by CYP2C8. When healthy subjects in a drug- drug interaction study were administered a 1,000-mg dose of abiraterone acetate tablets with a 15-mg dose of the CYP2C8 probe substrate pioglitazone (pioglitazone given 1 hour following abiraterone acetate), the mean exposure of pioglitazone increased by 46% while the mean exposure of its active metabolites, M-III and M-IV, each decreased by 10%. Although these results indicate that no clinically meaningful increases in exposure are expected when abiraterone acetate is combined with drugs that are predominantly eliminated by CYP2C8, patients should be monitored for signs of toxicity related to a CYP2C8 substrate with a narrow therapeutic index if used concomitantly with abiraterone acetate. In a clinical PK interaction study of healthy subjects pretreated with a strong CYP3A4 inducer (rifampicin, 600 mg daily for 6 days) followed by a single dose of abiraterone acetate 1,000 mg, the mean plasma AUC∞ of abiraterone was decreased by 55%. Strong inducers of CYP3A4 (eg, , carbamazepine, rifampicin, rifabutin, rifapentine, phenobarbital) during treatment with abiraterone acetate are to be avoided. In a clinical PK interaction study of healthy subjects with a strong CYP3A4 inhibitor (, 400 mg daily for 3 days followed by co-administration with abiraterone acetate on Day 4), the mean systemic exposure to abiraterone was increased by 9% for Cmax and 15% for AUC∞ compared with abiraterone acetate alone. The results from this study show that there is no clinically meaningful effect of ketoconazole, a strong inhibitor of CYP3A4 on the PK of abiraterone. In vitro, N-oxide abiraterone sulfate, but not abiraterone or abiraterone sulfate, is a substrate of breast cancer resistance protein. Abiraterone and its 2 major metabolites, abiraterone sulfate and the N-oxide abiraterone sulfate, are inhibitors of organic anion transporting polypeptide (OATP)-mediated substrate uptake in hepatocytes. Pharmacodynamics The potential cardiotoxic effects of abiraterone acetate (1,000 mg daily dose), and specifically the QT/QTc interval duration, were assessed in subjects with mCRPC using time-matched electrocardiograms (ECGs) and PK analyses. Treatment with abiraterone acetate and prednisone at therapeutic doses in Study COU-AA-006 had no significant effect on the QT/QTc interval, and did not affect the ventricular repolarization to an extent that would require substantial risk considerations in subjects with mCRPC. In addition, no relationship between abiraterone plasma concentration and change in QTcF was observed.

13 Approved, Date: 26 August 2015 JNJ-212082 (abiraterone acetate) Investigator's Brochure - Edition 12

Published preclinical data indicate that spironolactone can activate both wild-type and mutant androgen receptors (ARs). This activation is independent of abiraterone acetate. In patients with castration-resistant prostate cancer, such activation could result in increases in PSA. Because of the potential for AR activation by spironolactone, subjects in pivotal clinical studies with abiraterone acetate were not allowed to use spironolactone. Efficacy At the time of the final analysis (775 death events) for the pivotal Phase 3 study, COU-AA-301, with a median follow up of 20.2 months, treatment with abiraterone acetate plus prednisone prolonged overall survival (OS) in this patient population and reduced the risk of death by 26% compared with placebo plus prednisone (hazard ratio [HR]=0.740; 95% confidence interval [CI]: 0.638, 0.859; p<0.0001). The median survival was 15.8 months in the abiraterone acetate group and 11.2 months in the placebo group. In addition to the observed improvement in OS, all secondary study endpoints favored abiraterone acetate plus prednisone. Abiraterone acetate plus prednisone demonstrated an improvement compared with placebo plus prednisone in patient-reported pain outcomes and time to first skeletal-reported event. For the pivotal Phase 3 study, COU-AA-302, treatment with abiraterone acetate plus prednisone reduced the risk of radiographic progression (rPFS) or death by 58% compared with placebo plus prednisone (HR=0.425; 95% CI: 0.347, 0.522; p<0.0001). At the time of the final analysis after 96% of death events had occurred, the median OS in the abiraterone acetate and placebo groups was 34.7 months and 30.3 months, respectively (HR=0.806; 95% CI=0.697, 0.931, p=0.0033). In addition to the significant improvement in radiographic progression-free survival (rPFS) and OS, all secondary endpoints favored the abiraterone acetate plus prednisone group. Abiraterone acetate plus prednisone also demonstrated improvements in patient-reported pain and outcome measures compared with placebo plus prednisone. Two Phase 2 studies evaluated the effect of adding abiraterone acetate plus prednisone to ADT with LHRHa in subjects with high risk localized prostate cancer before prostatectomy. Study COU-AA-201 demonstrated that abiraterone acetate plus prednisone treatment in combination with LHRHa lowered serum and prostate tumor androgens below levels observed with LHRHa alone and demonstrated a higher prostate specific antigen (PSA) response rate (PSA ≤0.2 ng/mL) at Week 12 (p<0.0001). Study COU-AA-203 tested a 12 week abiraterone acetate plus prednisone and LHRHa regimen. For Study COU-AA-203 the primary endpoint (proportion of subjects pathologic ≤pT2) was not significantly different with the addition of abiraterone acetate to LHRHa. However, the PSA response rate (PSA ≤0.2 ng/mL) in the abiraterone acetate plus LHRHa group was significantly higher compared with LHRHa alone (p<0.0001). In Study 212082PCR2005 in men with non-metastatic prostate cancer, 87% of evaluable subjects achieved a ≥50% reduction in PSA (p<0.0001) during the Core Treatment Phase (Cycles 1 to 6). The median time to PSA progression was 28.7 months. The efficacy results from the Phase 2 Study 212082BCA2001 in women with metastatic breast cancer did not show a significant benefit of adding abiraterone acetate to exemestane with respect to the primary efficacy endpoint, PFS. Further development for this indication has been discontinued. Safety and Tolerability For the integrated data from the Phase 3 studies (COU-AA-301 and COU-AA-302), the most frequently reported adverse events (AEs) (20% of subjects in either combined treatment group) were , back pain, arthralgia, constipation, bone pain, peripheral , hot flush, and , AEs that are consistent with mCRPC disease. Adverse events of special interest associated with abiraterone acetate treatment and reported at a higher incidence in the abiraterone acetate plus prednisone group compared with the placebo plus prednisone group were fluid retention/edema (mainly peripheral edema), , , cardiac disorders, and hepatotoxicity (liver function test abnormalities). Adverse events of special interest

14 Approved, Date: 26 August 2015 JNJ-212082 (abiraterone acetate) Investigator's Brochure - Edition 12 were generally managed medically or with dose modifications or interruptions. Discontinuation of treatment due to AEs was similar for the 2 treatment groups. Safety data from bridging study evaluations in Asian subjects with mCRPC and in subjects with localized prostate cancer were consistent with the Phase 3 studies. Data from a study evaluating the combination of abiraterone acetate plus docetaxel in subjects with mCRPC demonstrated that both agents could be safely co-administered at the currently approved doses (abiraterone acetate 1,000 mg/day and docetaxel 75 mg/m2 every 3 weeks). Marketing Experience As of 27 April 2015, abiraterone acetate, in combination with prednisone/prednisolone is authorized in 100 countries worldwide (including the European Union [EU] and US) for the treatment of men with mCRPC (indications vary). Based on the 43,431,956 grams distributed worldwide, the estimated postmarketing exposure for abiraterone acetate from launch to 30 April 2015 is 118,992 person-years (6,204,565 person-weeks). The uncommon adverse drug reaction (ADR) rhabdomyolysis/myopathy was identified during postmarketing experience and has been added to the reference safety information. In Japanese postmarketing experience, cases of severe hepatotoxicity were identified.

15 Approved, Date: 26 August 2015 JNJ-212082 (abiraterone acetate) Investigator's Brochure - Edition 12

1. INTRODUCTION Abiraterone acetate is a prodrug of abiraterone (Figure A). Abiraterone is a selective irreversible inhibitor of 17α hydroxylase/C17,20-lyase (cytochrome P450c17 [CYP17]).34 This enzyme is found in the testes, adrenals, and in prostate tumors.5,43,44,45 Inhibition of CYP17 inhibits the conversion of pregnenolone or progesterone into dehydroepiandrosterone (DHEA) or androstenedione, respectively.

Figure A: Conversion of Abiraterone Acetate to Abiraterone

Abiraterone acetate Abiraterone

N N

AcO HO JNJ 212082 JNJ 589485

Figure B summarizes the mechanism by which abiraterone acetate causes reductions in testosterone concentrations by specifically inhibiting 17α hydroxylase/C17,20-lyase.

16 Approved, Date: 26 August 2015 JNJ-212082 (abiraterone acetate) Investigator's Brochure - Edition 12

Figure B: Inhibition of the 17α hydroxylase/C17,20-lyase Pathways by Abiraterone Acetate and Abiraterone

Abiraterone acetate is indicated in combination with prednisone for the treatment of patients with metastatic castration resistant prostate cancer (mCRPC).

In addition, abiraterone acetate is being or was studied for the following:

 in men with newly diagnosed hormone-naïve metastatic prostate cancer  as neoadjuvant hormonal therapy in men with advanced prostate cancer without radiographic evidence of metastatic disease  in postmenopausal women with estrogen receptor positive (ER+) metastatic breast cancer progressing after letrozole or anastrozole therapy. The Phase 2 study did not meet its primary endpoint; further development has been discontinued in this indication.  in patients with congenital adrenal hyperplasia. Further development in this area has been discontinued.  as combination therapy with docetaxel, JNJ-56021927 (ARN509), or Xofigo (223Ra) in men with mCRPC  in men with non-metastatic prostate cancer

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1.1. The Rationale for Abiraterone Acetate in the Management of Castration-Resistant Prostate Cancer (CRPC) Testosterone production is a key element in the control of prostate cancer growth,6,53 and inhibitors of the key enzyme in androgen synthesis, 17α hydroxylase/C17,20-lyase, such as abiraterone acetate and abiraterone, block testosterone production both in the testis and adrenal gland, as well as the autocrine synthesis in prostate tumors.4,12,38,42,55,58

Furthermore, the androgen receptor (AR) becomes amplified in prostate tumor cells, and the amplified AR is activated by extremely low androgen concentrations.10 The sensitivity of the AR is also increased by the overexpression of 2 nuclear coactivators, which enhances activation of the AR at lower testosterone concentrations.22,23 Together, the increased sensitivity of AR with persistent androgens after castration results in tumor progression in many men with CRPC.

Therefore, even though the progression of prostate cancer may be slowed in the absence of testicular androgens, the tumor remains responsive to stimulation from extragonadal (ie, adrenal or autocrine androgens). Because of this responsiveness, abiraterone acetate treatment was hypothesized to be effective after medical or surgical castration by leading to subcastrate levels of androgen.

The clinically meaningful improvements demonstrated in the 2 randomized, placebo-controlled, double-blind Phase 3 studies (COU-AA-301 and COU-AA-302; see Section 4.3.2) confirmed the hypothesis that more complete suppression of androgen production from extragonadal sources is an effective treatment for mCRPC, given either before or after docetaxel. These studies also served as the pivotal studies for the marketing authorization of abiraterone acetate in combination with prednisone or prednisolone in men with mCRPC and disease progression on ADT and who had or had not received docetaxel-based chemotherapy.

1.2. The Rationale for Abiraterone Acetate in Hormone-naïve Metastatic Prostate Cancer and as Neoadjuvant Therapy in High-risk Localized Prostate Cancer Patients with metastatic prostate cancer at the time of initial diagnosis (~30% in Europe, >50% in Asia, and 4% in the USA) typically progress to mCRPC with a poor prognosis.7,18,29,33,35 The Southwest Oncology Group (SWOG S8894) reported that 77% of men newly diagnosed with metastatic prostate cancer lived less than 5 years and only approximately 7% of men treated with hormonal therapy were alive at or after 10 years. 56 Several prognostic factors influence survival in M1 disease. Median OS has been reported to range from 13 months up to 75 months depending on the presence of high-risk prognostic features such as high PSA concentration at diagnosis, high Gleason score, increased volume of metastatic disease, presence of bony symptoms,41 or presence of visceral .20

The rationale for using abiraterone acetate in patients with metastatic hormone-naïve prostate cancer and high-risk prognostic factors is based on the positive results of Study COU-AA-301 and COU-AA-302, and the unmet medical need for alternative treatment options for these patients. Additionally, 2 studies (COU-AA-201 and COU-AA-203, see Section 4.3.1) using

18 Approved, Date: 26 August 2015 JNJ-212082 (abiraterone acetate) Investigator's Brochure - Edition 12 abiraterone acetate plus low dose prednisone (5 mg orally once daily) in addition to ADT in the neoadjuvant setting demonstrated higher rates of PSA response (≤0.2 ng/mL) and higher rates of complete pathologic response or near-complete pathologic response in patients undergoing prostatectomy for high risk localized prostate cancer, suggesting a potential therapeutic role for inhibiting extragonadal androgen synthesis prior to the emergence of castration resistance.

1.3. The Rationale for Abiraterone Acetate in the Management of Breast Cancer Several lines of evidence supported the investigation of abiraterone acetate for treatment of women with ER+ breast cancer, including in vitro data indicating DHEA and DHEA-S stimulate proliferation of breast cancer cell lines in a low-estrogen environment.17,37,40 Abiraterone acetate is the first compound specifically designed to inhibit CYP17 with resultant inhibition of biosynthesis. Hypothetically, depletion of androgens and by abiraterone acetate may inhibit tumor growth by disruption of ER-dependent growth signaling.

Patients with disease still driven by ER or AR signaling may not yet require systemic chemotherapy. Because CYP17 is upstream from aromatase in the steroid synthesis pathway, theoretically, abiraterone acetate more completely inhibits sex steroid synthesis, while other available endocrine therapies may not. Based on this rationale, a randomized Phase 2 study was conducted. The study did not meet its primary endpoint. The results are discussed in Section 4.3.1.5.

1.4. The Rationale for the Study of Abiraterone Acetate in Combination with Docetaxel Docetaxel was the first agent with demonstrated survival benefit in mCRPC. The approved dosing regimens for prostate cancer range from 60 to 75 mg/m2 administered intravenously (IV) over 1 hour every 3 weeks.57 As both compounds have proven positive effects in patients with mCRPC and have different mechanisms of action, combination therapy could lead to a synergistic effect.

To understand the safety of combining abiraterone acetate with docetaxel, a Phase 1b study was conducted in men with mCRPC. The results showed that both compounds can be combined at their full prescribed doses (see Section 4.3.1.4).

1.5. Rationale for the Study of Abiraterone Acetate in Combination with JNJ-56021927 (also known as ARN-509) Additional clinical benefit beyond suppression of testosterone production might be obtained by the use of second-generation anti-androgens in patients with mCRPC. This is supported by molecular profiling studies of CRPC, which commonly show increased AR gene expression.10 The increased AR levels are sufficient to confer resistance to anti-androgen therapy in mouse models, shorten tumor latency and confer agonist properties to first generation AR antagonists, such as or .8 Collectively, these findings implicate increased AR levels as one mechanism of drug resistance.

19 Approved, Date: 26 August 2015 JNJ-212082 (abiraterone acetate) Investigator's Brochure - Edition 12

JNJ-56021927 (also referred to as ARN-509) is such an orally available, small molecule, non-steroidal potent and selective antagonist of the AR. It is currently being developed for the treatment of CRPC. JNJ-56021927 has been developed to overcome the potential therapeutic deficiencies of first generation anti-androgens. JNJ-56021927 acts by inhibiting the action of androgen, nuclear translocation of the AR and DNA binding to androgen response elements and exhibits no significant agonist activity in AR overexpressing prostate cancer cells.11

Abiraterone acetate and JNJ-56021927 are both directed at the androgen axis with very distinct mechanisms to inhibit AR activation. Moreover, they do not appear to have overlapping clinical toxicity in patients.

There is early evidence that the combination of both drugs could theoretically delay the emergence of clinical resistance to either drug. Despite the survival benefit associated with abiraterone acetate treatment of mCRPC, both primary and secondary resistance to abiraterone acetate has been observed. In xenograft models of CRPC, treatment with abiraterone acetate inhibits tumor growth, production of serum PSA, and intratumoral androgens, thereby indicating that the anti-tumor activity of abiraterone acetate is primarily through effects on tissue androgens. Accompanying the marked suppression of tumor androgen levels are increased expression of the AR, ligand-independent AR splice variants, and induction of steroidogenic genes including CYP17A1.15 The increased expression of several of these genes showed strong correlation with dihydrotestosterone (DHT) levels in recurrent tumors. These data suggest that resistance can potentially be targeted by using combinations with potent AR antagonists such as JNJ 56021927.

The availability of 2 highly active agents from different classes with complementary mechanisms raises the important scientific and clinical question of whether the benefit of the combination is superior to that of individual agents and can overcome mechanisms of resistance developed to either drug alone. Three separate studies conducted at a single institution with abiraterone acetate, , and the combination of abiraterone acetate and enzalutamide showed improved PSA response with AR combination therapy compared with either agent alone.16

The following 3 studies are currently ongoing to assess the combination of abiraterone acetate and JNJ56021927 in men with mCRPC:

 Protocol ARN-509-004 (Appendix B.2), a Phase Ib study to assess the safety, pharmacokinetics, and preliminary anti-tumor activity of ascending doses of JNJ-56021927 and abiraterone acetate plus prednisone  Protocol 56021927PCR1010 (Appendix B.2), a Phase Ib study to assess the pharmacokinetics of abiraterone acetate and its metabolites when dosed alone or in combination with JNJ-56021927  Protocol 56021927PCR3001 (Appendix B.6), a Phase 3 study to assess the efficacy and safety of JNJ-56021927 in combination with abiraterone acetate plus prednisone compared with abiraterone acetate plus prednisone Further information is provided in the JNJ-56021927 (ARN-509) IB.

20 Approved, Date: 26 August 2015 JNJ-212082 (abiraterone acetate) Investigator's Brochure - Edition 12

2. PHYSICAL, CHEMICAL, AND PHARMACEUTICAL PROPERTIES AND FORMULATIONS

2.1. Product Identification Generic name: abiraterone acetate

Chemical name: (3β)-17-(3-pyridinyl)androsta-5,16-dien-3-yl acetate.

Company Compound Number: JNJ-212082

2.2. Physical and Chemical Characteristics Abiraterone acetate, the active ingredient, is the acetyl ester of abiraterone.

The molecular formula of abiraterone acetate is C26H33NO2. The chemical structure is presented in Figure A.1 of Appendix A. It has a molecular weight of 391.55. Abiraterone acetate is a white to off-white powder. Abiraterone acetate is practically insoluble in water and in the pH range of 2 to 13. It is very slightly soluble at a pH of 1.

2.3. Formulation Information Uncoated tablets containing 250 mg of abiraterone acetate are composed of the active ingredient (abiraterone acetate) and nonactive ingredients (colloidal silicon dioxide, croscarmellose sodium, lactose monohydrate, stearate, microcrystalline cellulose, povidone, and sodium lauryl sulfate).

The 250-mg uncoated tablet and its matching placebo tablet, a 250-mg film-coated tablet, and a 500-mg film-coated tablet are the formulations used in recent and ongoing clinical studies. Tablets are oval in shape. The uncoated tablets are white to off-white, and the film-coated tablets are either beige (250 mg) or purple (500 mg) in color. Excipients for these film-coated formulations include lactose monohydrate, croscarmellose sodium, sodium lauryl sulfate, magnesium stearate, colloidal silicon dioxide. Additionally, the 250-mg film-coated tablet formulation contains the excipients microcrystalline cellulose and povidone while the 500-mg film-coated tablet formulation contains silicified microcrystalline cellulose and hypromellose 2910 15 mPa.s. The 250-mg tablets are coated with Opadry® II85F170011 Beige, which contains polyvinyl alcohol, titanium dioxide, macrogol/PEG, talc, iron oxide red, and iron oxide yellow. The 500-mg tablets are coated with Opadry® II85F90093 Purple, which contains polyvinyl alcohol, titanium dioxide, macrogol/PEG, talc, iron oxide red, and iron oxide black.

All tablets are intended for oral administration. Refer to the clinical protocol for the formulation(s) used in a particular study.

2.4. Packaging, Storage, and Handling The container/closure system for tablets consists of a high-density polyethylene (HDPE) bottle with a child-resistant polypropylene cap. Bottles of abiraterone acetate tablets should be stored at room temperature in the original container closure system with cap tightly sealed.

21 Approved, Date: 26 August 2015 JNJ-212082 (abiraterone acetate) Investigator's Brochure - Edition 12

Based on its mechanism of action, abiraterone acetate may harm a developing fetus; therefore, women who are pregnant or women who may be pregnant should not handle uncoated abiraterone acetate tablets without protection, eg, gloves.

3. NONCLINICAL STUDIES Nonclinical pharmacology, pharmacokinetic/toxicokinetic, absorption, metabolism, and toxicology information on either abiraterone or abiraterone acetate are derived from both proprietary studies and the literature.5,14,25,26,32,34,44

3.1. Nonclinical Pharmacology

3.1.1. Primary and Secondary Pharmacologic Effects Abiraterone has nanomolar potency in several in vitro CYP17α hydroxylase/C17,20-lyase test systems including rat and human microsomes. When tested for binding to human steroid nuclear receptors at a concentration of 1 µM, abiraterone did not inhibit ligand binding to the glucocorticoid receptor, the estrogen receptors, or AR. Some weak binding activity was observed for the nuclear progesterone receptor at concentrations above 100 nM. However, neither progesterone agonist nor antagonist activity was observed in an intact cell assay. Abiraterone was also inactive as agonist for the rat or mouse glucocorticoid receptor at concentrations ranging from 0.05 to 10 µM. The in vivo effects of abiraterone acetate administered orally either as a single dose or in daily repeated doses on the circulating hormone levels and androgen target organ weights were characterized in mice, rats, and monkeys. The effects were consistent with a selective inhibition of androgen biosynthesis. Antitumor activity was demonstrated in a human castration-resistant prostate tumor xenograft, wherein inhibition of intratumoral androgen biosynthesis was demonstrated.

Due to the specificity and mechanism of action of abiraterone acetate in inhibiting CYP17, no off-target effects were observed in non-clinical studies. All of the effects observed for abiraterone acetate appear to be related to androgen deprivation. These effects are well characterized by extensive literature on androgen physiology in nonclinical studies.

3.1.2. Safety Pharmacology Potential effects of abiraterone acetate on the body systems were investigated as an integral part of the GLP toxicology program. In the in vitro hERG and in vivo safety pharmacology studies, the latter after oral administration in rodents and telemetered monkeys, abiraterone acetate and abiraterone had no relevant effects on the central nervous system, cardiovascular and respiratory systems, and gastric irritation.

3.2. Pharmacokinetics and Metabolism in Animals Please refer to Section 4.2 for information on pharmacokinetics and product metabolism in humans.

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3.3. Toxicology Appendix A.1 provides a tabular summary of GLP single- and repeated-dose toxicology studies that are completed with abiraterone acetate. Appendix A.2 provides a tabular summary of GLP developmental toxicity studies that are completed with abiraterone acetate.

Single and repeated orally dosed studies with dosing up to 26 and 39 weeks were carried out in rats and monkeys. The carcinogenic potential of abiraterone acetate was studied in the transgenic (TG.rasH2) mouse (6 months) and in the S-D rat (24 months). The effect of abiraterone acetate on fertility and embryofetal development was studied in the rat. A toxicity study in juvenile rats also was performed. Most studies included recovery periods following abiraterone acetate dosing to determine the reversibility potential of treatment-induced toxicity. The mutagenic potential of abiraterone acetate, abiraterone, and synthesis impurities and degradation products were also characterized. Pivotal toxicity studies adhered to internationally accepted GLP standards (OECD Principles of GLP).

In GLP animal toxicity studies, main toxic effects in mice, rat, and monkey were related to the pharmacologic activity of abiraterone acetate affecting the animal’s steroidogenesis, reproductive organs as well as the adrenal, pituitary, and (male) mammary glands. Additionally, partially reversible bile duct changes were seen in the rat and monkey and hepatocellular hypertrophy in the rat (reversible) and mouse only. In comparison with 13 weeks of dosing, these findings did not become worse during long-term treatment (up to 26 and 39 weeks in rat and monkey, respectively). In the mouse, periportal inflammation and necrosis of hepatocytes were also observed in the liver (28 days of dosing). Cataracts (irreversible) were observed in the rat (after 26 weeks of dosing only), but not in the monkey (39 weeks of dosing) or transgenic (Tg.rasH2) mouse (6 months of dosing). Therefore the ocular findings in the rat were considered to be a species-specific .

In the animal toxicity studies there was no indication of any significant abiraterone acetate treatment-related effects on the central nervous, respiratory, cardiovascular, or renal systems

Abiraterone acetate and abiraterone were devoid of genotoxic potential in the standard panel of genotoxicity tests, including an in vitro bacterial reverse mutation assay (the Ames test), an in vitro mammalian chromosome aberration test (using human lymphocytes), and an in vivo rat micronucleus assay.

No increase in tumors was observed in a 6-month transgenic mouse GLP carcinogenicity study at doses up to 750 mg/kg/day. In a 2-year rat GLP carcinogenicity study, there was an increased incidence of testicular interstitial (Leydig) cell adenomas and carcinomas; however, this finding was considered rat-specific and related to the pharmacological activity of abiraterone acetate.

As a result of the pharmacologic activity of abiraterone, dosing of abiraterone acetate resulted in complete loss of fertility in male rats; the effect was completely reversible 8 to 16 weeks after cessation of dosing. Pregnant rats showed difficulties in the maintenance of pregnancy due to the perturbation of the hormonal landscape but fertility per se was unaffected and abiraterone acetate had no teratogenic potential. 23 Approved, Date: 26 August 2015 JNJ-212082 (abiraterone acetate) Investigator's Brochure - Edition 12

Administration of abiraterone acetate to juvenile rats during the pre-pubertal period did not affect reproductive performance and fertility.

Synthesis impurities and degradation products were toxicology qualified.

3.4. Conclusions for Nonclinical Studies  In in vitro and in vivo safety pharmacology studies, abiraterone acetate and abiraterone had no relevant effects on the central nervous system, cardiovascular and respiratory systems, and gastric irritation.  Neither abiraterone acetate nor abiraterone is a substrate for P-glycoprotein.  Main toxic effects in mouse, rat and monkey were related to the pharmacological activity of abiraterone acetate affecting the animal’s steroidogenesis, reproductive organs as well as the adrenal, pituitary, and (male) mammary glands. Additionally, partially reversible bile duct changes were seen in the rat and monkey, and hepatocellular hypertrophy in rat (reversible) and mouse. In the mouse, hepatic periportal inflammation and necrosis were also observed. Irreversible cataract was observed in the rat, but not in the mouse or monkey.  Abiraterone acetate and abiraterone were non-mutagenic in both in vitro and in vivo test systems.  No increase in tumors was observed in a 6-month transgenic mouse GLP carcinogenicity study at doses up to 750 mg/kg/day. In a 2-year rat GLP carcinogenicity study, there was an increased incidence of testicular interstitial (Leydig) cell adenomas and carcinomas; however, this finding was considered rat-specific and related to the pharmacological activity of abiraterone acetate.  As a result of the pharmacologic activity of abiraterone, dosing abiraterone acetate resulted in complete loss of fertility in male rats; the effect was completely reversible 8 to 16 weeks after cessation of dosing. Pregnant rats showed difficulties in the maintenance of pregnancy due to the perturbation of the hormonal landscape but fertility per se was unaffected and abiraterone acetate had no teratogenic potential.  Administration of abiraterone acetate to juvenile rats during the pre-pubertal period did not affect the reproductive performance and fertility.

4. EFFECTS IN HUMANS

4.1. Overview Overall, as of 27 April 2015, over 900 subjects have been exposed to abiraterone acetate in Phase 2 studies and over 3,000 subjects in Phase 3 studies. Additionally, more than 7,500 subjects under the Named Patient Program and over 2,000 subjects under the Early Access Program received abiraterone acetate. Estimated exposure with postmarketing experience is discussed in Section 4.5.

Key efficacy and safety information for abiraterone acetate are summarized in this IB and include data available from clinical studies and from the safety database as of 27 April 2015.

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4.1.1. Phase 1 and Phase 1/2 Studies A summary of all completed Phase 1 and Phase 1/2 studies is provided in Appendix B.1, and a summary of all ongoing Phase 1 or Phase 1/2 studies is provided in Appendix B.2. Efficacy results from key studies are summarized in Section 4.2 (Phase 1) and Section 4.3.1 (Phase 1/2). Safety results are summarized in Section 4.4.

4.1.2. Phase 2 Studies A summary of completed Phase 2 studies is provided in Appendix B.3, and a summary of the ongoing Phase 2 studies is provided in Appendix B.4. Efficacy and safety results from key studies are summarized in Section 4.3.1 and Section 4.4, respectively.

4.1.3. Phase 3 Studies A summary of completed Phase 3 studies is provided in Appendix B.5, and a summary of ongoing Phase 3 studies is provided in Appendix B.6.

Studies COU-AA-301 and COU-AA-302 were the pivotal studies for the marketing authorizations of abiraterone acetate in combination with prednisone for the treatment of mCRPC. Since the last update, Study COU-AA-301 was completed. The final safety and efficacy analysis for Study COU-AA-302 was completed; the study is ongoing for subjects continuing to receive abiraterone acetate. Efficacy and safety information for these studies is summarized in Sections 4.3.2 and 4.4.1, respectively.

Studies ABI-PRO-3001 and ABI-PRO-3002 were the bridging studies (in subjects from China) of abiraterone acetate plus prednisone in mCRPC. Efficacy and safety information for these studies is summarized in Sections 4.3.2.3 and 4.4.2, respectively.

4.1.4. Phase 4 Study There is 1 Phase 4 study ongoing in Japan (Appendix B.7).

4.2. Pharmacokinetics and Product Metabolism A summary of the PK parameters of abiraterone after a 1,000 mg single or daily administration of abiraterone acetate under fasting or modified fasting conditions is provided in Appendix C.1.

4.2.1. Pharmacokinetics After a single 1,000-mg dose of abiraterone acetate tablets under fasting conditions, peak concentrations of abiraterone were observed at a median tmax of 2 hours post-dose across all studies in healthy subjects (Appendix C.1). Half-life was estimated to be approximately 15.0 hours. Exposure after a 1,000-mg dose was comparable across studies with an overall mean

Cmax of approximately 100 ng/mL and AUC of approximately 500 ng*h/mL.

Mean systemic exposure of abiraterone after multiple dosing of 1,000 mg per day in patients with mCRPC under modified fasting conditions (abiraterone acetate administered at least 2 hours after eating and no food was to be eaten for at least 1 hour after taking abiraterone acetate) as

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assessed by Cmax and AUC24h was 232 ng/mL and 1,060 ng*h/mL, respectively (Appendix C.1). A steady-state condition appeared to be reached after 7 days of dosing. The mean accumulation ratio of abiraterone at steady-state with once daily dose administration was approximately 2-fold for both Cmax and AUC24h.

Systemic exposure of abiraterone increased with increasing doses of abiraterone acetate. Systemic exposure of abiraterone was dose proportional between 1,000 and 750 mg. Systemic exposure of abiraterone after 250 and 500 mg was slightly greater than dose proportional compared with reference dose of 1,000 mg (Study COU-AA-016).

The plasma protein binding of 14C-abiraterone in human plasma is 99.8%. The apparent volume of distribution is approximately 5,630 L, suggesting that abiraterone extensively distributes to peripheral tissues.

A summary of PK results from key pharmacokinetic and biopharmaceutic studies are provided in Table 1. Additional PK study results in Asian subjects are summarized in Table 5.

Table 1: Summary of Key Pharmacokinetic and Biopharmaceutic Studies Study Number Number of Subjects Study Descriptiona Summary of Results Study Population COU-AA-016 Single-dose, four-way Systemic exposure of abiraterone increased with increasing doses of N=32 crossover study to evaluate abiraterone acetate. Systemic exposure of abiraterone was dose proportional Healthy men the effect of dose on the PK between 1,000 and 750 mg. Systemic exposure of abiraterone after 250 and of abiraterone 500 mg was slightly greater than dose proportional compared with reference dose of 1,000 mg COU-AA-005 Relative bioavailablity Abiraterone acetate tablets manufactured using the Patheon Commercial N=120 study of abiraterone acetate process and abiraterone acetate tablets manufactured using the Pii Clinical Healthy men tablets manufactured by Trial process were bioequivalent. 2 different manufacturing processes

212082PCR1010 Relative Systemic exposure to abiraterone, as assessed by the GMR of Cmax, AUClast, N=30 (completed study of 4 different coated and AUC for each of the 4 coated formulations, was comparable to that of study); abiraterone acetate tablet the uncoated commercial tablets (Treatment B [4x250 mg, new N=32 (safety) formulations compared composition]: 99.07 to 101.23%, Treatment C [2x500 mg, new Healthy men with commercial uncoated composition]: 101.94 to 103.67%, Treatment D [4x250 mg, commercial tablets composition]: 94.52 to 96.09%, Treatment E [2x500 mg, commercial composition]: 90.66 to 91.68% of uncoated exposure). 212082PCR1007 Bioequivalence study of 2 The 2 new film-coated tablet formulations (250-mg & 500-mg strengths) and N=102 Healthy men different film-coated the commercial uncoated tablets were bioequivalent. (N=100 completed abiraterone acetate tablet study) formulations compared with commercial uncoated tablets

AUClast=AUC from time 0 to time of the last observed quantifiable concentration; AUC∞=AUC from time 0 to infinite time; Cmax=maximum observed plasma concentration; GMR= geometric mean ratio ; PK=pharmacokinetic(s) a Cross-reference: Appendix B.1 and Appendix C.1

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4.2.2. Effect of Food on the Pharmacokinetics of Abiraterone A summary of the studies in healthy subjects and subjects with mCRPC examining the effect of food on abiraterone PK is provided in Table 2. Study 212082PCR2008 was a food safety study that included PK evaluations. The safety aspects of this study are discussed in Section 4.4.3.

Table 2: Summary of Studies on Effect of Food and Food Timing on the Pharmacokinetics of Abiraterone Study Number Number of Subjects Study Descriptiona Summary of Results Study Population COU-AA-009 Comparison of fed and fasted states Administration of a 1,000 mg (4 x 250 mg tablets) single oral dose N=36 on the PK of abiraterone of abiraterone acetate in fed conditions increased exposure to Healthy men abiraterone compared with the fasted state. Abiraterone mean Cmax and AUC∞ values increased by approximately 7-and 5-fold, respectively, when administered immediately after a low-fat meal (geometric mean treatment ratios 7.3 and 4.6). Abiraterone mean Cmax and AUC∞ values increased by approximately 17- and 10 fold, respectively, when administered immediately after a high-fat meal (geometric mean treatment ratios 16.8 and 9.7). 212082PCR1005 Four-way crossover study to assess Following an overnight fast, a meal given 1 hour after Healthy Japanese the effect of the timinig of food administration of abiraterone acetate resulted in a modest increase and Caucasian men intake on the PK of abiraterone (approximately 57%) in abiraterone exposure (ie, AUC∞) as N=51 compared to when a meal was given 4 hours after administration of abiraterone acetate.

When a meal was given 2 hours before and either 2 or 4 hours after abiraterone acetate dosing, abiraterone exposure increased by approximately 7.0- to 7.5-fold as compared to when abiraterone acetate was administered following an overnight fast and followed by a meal 4 hours postdose.

When a meal was given 2 hours before and either 2 or 4 hours after abiraterone acetate dosing, abiraterone exposure increased by approximately 4.4- to 4.8-fold as compared to when abiraterone acetate was administered following an overnight fast and followed by a meal 1 hours postdose.

There is no clinically meaningful difference in the PK of abiraterone between Caucasian and Japanese across all treatment groups. 212082PCR2008 Short-term safety study of abiraterone Repeated dosing of abiraterone acetate plus prednisone with Men with mCRPC acetate and prednisone administered high-fat meals resulted in an approximately 2 fold increase in N=25 (24 subjects after meals of various fat contents to geometric mean exposure (based on AUC) to abiraterone compared were included in the subjects with mCRPC.b with the modified fasting state. There appeared to be a negligible evaluable Pharmacokinetics of abiraterone change in abiraterone exposure after repeated dosing with low-fat population) when abiraterone acetate was meals. administered continuously to subjects with mCRPC under fed and modified fasted conditions (no food for 2 hours before and 1 hour after the dose) also was evaluated.

AUC∞=AUC from time 0 to infinite time; Cmax=maximum observed plasma concentration; mCRPC=metastatic castration- resistant prostate cancer; PK=pharmacokinetic(s) a Cross-reference:Appendix B.1, Appendix B.3, and Appendix C.1. b Cross-reference: Section 4.4.3.

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4.2.3. Drug-drug Interactions Studies In vitro, abiraterone is a strong inhibitor of CYP2D6, CYP2C8 and CYP1A2; however, clinically abiraterone is a moderate inhibitor of CYP2D6, a mild inhibitor of CYP2C8 and had no clinically meaningful effect on CYP1A2.

A summary of the drug-drug interaction studies with abiraterone acetate is provided in Table 3.

Table 3: Summary of Drug-drug Interaction Studies with Abiraterone Acetate Study Number Number of Subjects Study Descriptiona Summary of Results Study Population COU-AA-015 Drug-drug interaction study to Mean systemic exposure to dextromethorphan (CYP2D6 probe N=34 evaluate the effect of substrate) and its metabolite, dextrorphan, were approximately 200% Men with mCRPC abiraterone acetate plus and approximately 33% higher, respectively, when dextromethorphan prednisone on the PK of probe was co administered with abiraterone acetate and prednisone compared substrates dextromethorphan with dextromethorphan administered alone. Mean systemic exposure to (CYP2D6) and theophylline theophylline (CYP1A2 probe substrate) was similar when theophylline (CYP1A2) was co-administered with abiraterone acetate and prednsione or when administered alone. These effects on the exposure of the probe substrates indicate that administration of abiraterone acetate plus prednisone led to inhibition of CYP2D6, but not CYP1A2.

212082PCR1002 Two-period sequential design Mean systemic exposure to abiraterone increased by 9% for Cmax and N=20 drug-drug interaction study to 15% for AUC∞ when abiraterone acetate was coadministered with Healthy men evaluate the effect of ketoconazole compared with when abiraterone acetate was administered ketoconazole on the PK of alone. The results from this study show that there is no clinically abiraterone meaningful effect of ketoconazole, a strong inhibitor of CYP3A4, on the PK of abiraterone. 212082PCR1003 Two-period sequential design The geometric mean systemic exposure to abiraterone decreased by N=19 drug-drug interaction study to 55% for Cmax, 58% for AUClast, and 55% for AUC∞ when abiraterone Healthy men evaluate the effect of rifampicin acetate was administered in subjects pre-treated with rifampicin, an on the PK of abiraterone inducer of CYP3A4,compared with abiraterone acetate administered alone.

212082PCR1011 Single-center, open-label, 2- Mean systemic exposure to pioglitazone increased by 25% for Cmax and N=16 period, sequential-design, DDI 46% for AUC when pioglitazone was coadministered with abiraterone Healthy men study of abiraterone acetate and acetate. The AUC for M-III and M-IV, the active metabolites of pioglitazone to evaluate the pioglitazone, each decreased by 10%. effects of abiraterone on the PK of pioglitazone

AUC=area under the plasma concentration-time curve; AUClast=AUC from time 0 to time of the last observed quantifiable concentration; AUC∞=AUC from time 0 to infinite time; Cmax=maximum observed plasma concentration; CYP=; DDI=drug-drug interaction; mCRPC=metastatic castration-resistant prostate cancer; PK=pharmacokinetic(s) a Cross-reference: Appendix B.1 and Appendix C.1.

4.2.4. Special Populations A summary of the PK results in special populations is provided in Table 4.

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Table 4: Summary of Pharmacokinetic Studies of Abiraterone in Special Populations Study Number Number of Subjects StudyDescriptiona Summary of Results Study Population COU-AA-012 Phase 1 single dose study to Systemic exposure to abiraterone was not increased in subjects with N=16 evaluate the PK of abiraterone ESRD compared with matched control subjects with normal renal Subjects with ESRD in subjects with ESRD. function. and subjects with normal renal function COU-AA-011 Phase 1 single dose study to Systemic exposure (AUC) to abiraterone after a single oral 1,000 mg N=24 evaluate the PK of abiraterone dose increased by approximately 11% and 260% in subjects with mild Subjects mild or in subjects with mild or and moderate pre-existing hepatic impairment, respectively, compared moderate pre-existing moderate hepatic impairment with subjects with normal hepatic function. hepatic impairment and subjects with normal hepatic function. 212082PCR1004 Phase 1 single dose study to Systemic exposure to abiraterone after administration of 125 mg N=16 evaluate the PK of abiraterone abiraterone acetate suspension (62.5 mg tablet equivalent) in subjects Subjects with severe in subjects with severe hepatic with severe hepatic impairment was 22.4% for Cmax, 47.3% for AUClast, hepatic impairment impairment and 43.6% for AUC, of that found in subjects with normal hepatic (Child Pugh function after administration of 2,000 mg abiraterone acetate suspension Classification C) and (1,000 mg tablet equivalent). subjects with normal hepatic function.

AUClast=AUC from time 0 to time of the last observed quantifiable concentration; AUC∞=AUC from time 0 to infinite time; Cmax=maximum observed plasma concentration; ESRD=end-stage renal disease; PK=pharmacokinetic(s) a Cross-reference: Appendix B.1 and Appendix C.1.

4.2.5. Pharmacodynamics

4.2.5.1. Cardiac Safety Study

COU-AA-006 (Appendix B.2)

Median tmax was identical (2 hours) after administration of single and multiple doses of 1,000 mg abiraterone acetate tablets. Systemic exposure to abiraterone generally increased upon multiple dosing compared with single-dose administration. Systemic exposure values were comparable after multiple dosing on Cycle 1 Day 8 and Cycle 2 Day 1. Mean accumulation ratios for the exposure parameters on Cycle 1 Day 8 (1.8 for Cmax and 2.0 for AUC24h) and Cycle 2 Day 1 (2.0 for Cmax and 2.2 for AUC24h) were similar.

The individual abiraterone plasma concentrations and corresponding changes from baseline in QTcF interval exhibited no apparent relationship. The results from both categorical analysis and central tendency analysis showed that there is no significant effect of abiraterone acetate plus prednisone on the cardiac QT/QTc interval using time-matched ECGs and PK in subjects with mCRPC.

4.2.5.2. Pharmacodynamic Effect of Spironolactone Review of preclinical data from published literature sources indicates that spironolactone can activate both wild-type and mutant ARs.48 This activation is independent of abiraterone acetate. In patients with castration-resistant prostate cancer, such activation could result in increases in

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PSA.21 Because of the potential for AR activation by spironolactone, subjects in pivotal clinical studies with abiraterone acetate were not allowed to use spironolactone.

4.2.6. Effects of Age No clinical studies evaluated effect of age on the PK of abiraterone. Abiraterone acetate has not been investigated in pediatric subjects.

4.2.7. Effects of Race and Ethnicity Studies examining the PK of abiraterone in Asian populations are summarized in Table 5. For study 212082PCR2007, a population PK analysis of PK results from study this were compared with PK results from the COU-AA-301 study (same patient population).

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Table 5: Summary of the Pharmacokinetics of Abiraterone in Asian Subjects Study Number Number of Subjects Study Descriptiona Summary of Results Study Population ABI-PRO-1016 Phase 1 single dose open-label The median time to reach peak plasma concentration of abiraterone N=15 randomized, 3-period crossover (tmax) was 1.5 hours with a range from 1.0 to 6.0 hours. Systemic Healthy Chinese men study exposures to abiraterone, as measured by Cmax, AUClast, and AUC∞ in plasma, increased with increasing dose in a less than proportional fashion. The mean terminal half-life (t1/2,λ) ranged from 11.0 to 13.3 hours across the dose range from 250 mg to 1,000 mg. In general, intersubject variability was high, with CVs% ranging from 46.2% to 55.3% for Cmax and from 42.7% to 45.6% for the AUClast and AUC∞.

JNJ-212082-JPN-101 Phase 1, single-dose, single Systemic exposure of abiraterone as assessed by mean Cmax, AUClast, N=30 center, open-label, randomized, and AUCinf increased with increasing dose but was less than dose Healthy Japanese men 3-period crossover study proportional between 250 and 1,000 mg. 212082PCR1005 See Table 2. See Appendix C.1. There was no clinically meaningful difference in Healthy Japanese and abiraterone PK between Caucasian and Japanese subjects. Caucasian men N=51 JNJ-212082-JPN-102 Phase 1 multicenter, open-label, When abiraterone acetate was repeatedly administrated once daily, the N=27 nonrandomized, dose-escalation mean plasma abiraterone concentrations reached a steady state by Japanese men with study 7days, regardless of the dose, and accumulation indexes are 1.31 to 1.74 CRPC who have for Cmax, and 1.40 to 1.69 for AUC24 values. progressed on ADT The Cmax and AUC24 values of abiraterone are affected by the timing but have not received between dosing and food. The mean Cmax and AUC24 values in the chemotherapy 1,000 mg (dosing at least 2 hr after a meal [+2hr]) cohort are 3.1 to 6.0 times higher, respectively than those in the 1,000 mg (dosing at least 1 hr before a meal [−1 hr]) cohort. From the plots on Cmax and AUC24 of plasma abiraterone versus dose (dose-normalized to 1,000 mg) by visit, Cmax and AUC24 values increased with increasing doses of 250 mg, 500 mg, and 1,000 mg (+2 hr). Because this study was not designed to evaluate the definitive dose proportionality, dose-proportionality of plasma abiraterone was not concluded from this study. 212082PCR2007 Population PK analysis of The concentration-time profile of abiraterone in the Korean and N=28 results from Studies Taiwanese subjects with mCRPC was similar to the Western population 212082PCR2007 and with mCRPC. No statistically significant difference in the primary PK Korean and COU-AA-301 parameters (ie, apparent clearance, apparent central volume of Taiwanese men with distribution, and absorption-related parameters) between the Korean and mCRPC and disease Taiwanese subjects and reference Western population. progression after chemotherapy

ADT=androgen deprivation therapy; AUC=area under the plasma concentration-time curve from time zero to infinite time; AUC24= area under the plasma concentration-time curve from time 0 to 24 hours; AUClast = area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration; Cmax= maximum plasma concentration; CV=coefficient of variation; mCRPC=metastatic castration-resistant prostate cancer; PK=pharmacokinetics; t1/2,λ=terminal half-life a Cross-references: Appendix B.2, Appendix B.4, and Appendix C.1.

4.3. Efficacy Results A summary of the key efficacy results from Phase 1, Phase 1/2, and Phase 3 studies in subjects with mCRPC is provided in Table 6. For all studies in subjects with mCRPC, the treatment regimen was abiraterone acetate (1,000 mg orally daily) and 5 mg prednisone (or prednisolone) twice daily. All subjects were medically (LHRHa) or surgically castrated. For the neoadjuvant studies in subjects with localized prostate cancer and study in subjects with non-metastatic prostate cancer, the prednisone dose was reduced to 5 mg orally once daily.

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Table 6: Key Efficacy Results for Studies of Abiraterone Acetate in Subjects with mCRPC Study Number Treatment Median Overall Median Time to Median Number of Subjects (Analysis Survival PSA Progression Radiographic PFS % of Subjects with Population) (Months) (Months) (Months) PSA Responsea Studies in Subjects With Previous Docetaxel-Based Chemotherapy for mCRPC COU-AA-003 (Phase 2) Abiraterone acetate 12.5 5.6 15.0 Week 12:36 N=47 (ITT)

COU-AA-004 (Phase 2) Abiraterone acetate 16.2 5.6 4.1 38 N=58 (ITT)

JNJ-212082-JPN-202 (Phase 2) Abiraterone acetate 18.1 Not assessed 3.5 Week 12: 28 N=46 (Full Analysis Set)

212082PCR2007 (Phase 2) bridging study in Korea and Taiwan) 17.7 4.6 Not assessed 43 Abiraterone acetate N=82 (All treated)

COU-AA-301 (Phase 3) Abiraterone acetate 15.8 8.5 5.6 30 N=797 (ITT) Placebo 11.2 6.6 3.6 6 N=398 (ITT) ABI-PRO-3001 (Phase 3 Bridging Study in China) Abiraterone acetate Not reached 5.6 Not assessed 50 N=143 (ITT) Placebo (ITT) Not reached 2.8 Not assessed 14 N=71 Studies in Subjects Without Previous Chemotherapy for mCRPC COU-AA-001/EXT (Phase 1/2) Abiraterone acetate Not assessed 10.8 Not assessed Week 12: 60 N=42 (1,000 mg AA group)b

COU-AA-002 (Phase 2) Abiraterone acetate Not reached 16.3 Not reached Week 12: 67 N=33 (ITT)

COU-AA-302 (Phase 3) Abiraterone acetate 34.7 11.1 Not reached 62 N=546 (ITT) Placebo 30.3 5.6 8.3 24 N=542 (ITT)

ABI-PRO-3002 (Phase 3 Bridging Study in China and Russia)

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Table 6: Key Efficacy Results for Studies of Abiraterone Acetate in Subjects with mCRPC Study Number Treatment Median Overall Median Time to Median Number of Subjects (Analysis Survival PSA Progression Radiographic PFS % of Subjects with Population) (Months) (Months) (Months) PSA Responsea Abiraterone acetate Not reached Not reached Not assessed 50 N=157 (ITT) Placebo (ITT) Not reached 3.8 Not assessed 21 N=156

JNJ-212082-JPN-201 (Phase 2) Abiraterone acetate Not reached Not assessed 10.9 Week 12: 60 N=48 (Full Analysis Set) Studies in Subjects With or Without Previous Chemotherapy for mCRPC COU-AA-BE (Phase 1) Abiraterone acetate Not assessed 8.7 Not assessed 48 N=31 (PSA-evaluable) ` COU-AA-006 (Phase 1b) Abiraterone acetate 28.6 5.6 Not assessed 46 N=33 (All Treated) Study in Subjects With Non-Metastatic CRPC 212082PCR2005 (Phase 2) Abiraterone acetate Not assessed 28.7 Not reached 87c N=122 (PSA-evaluable) AA=abiraterone acetate; EXT=extension; ITT=intent to treat; mCRPC=metastatic castration-resistant prostate cancer; PFS=progression-free survival; PR=partial response; PSA=prostate-specific antigen; RECIST=Response Evaluation Criteria in Solid Tumors; SD=stable disease a PSA response was defined as a decline in PSA of 50% from baseline and is based on all PSA assessments during the study, unless otherwise noted. Week 12 response rate is based on PSA assessments at Week 12. b For Study COU-AA-001/001 EXT, the dataset analyzed includes all subjects receiving 1,000 mg abiraterone acetate with or without concomitant glucocorticoid. c During the Core Treatment Phase (Cycles 1 to 6)

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4.3.1. Other Efficacy Results in Phase 1/2 and Phase 2 Studies

4.3.1.1. Bone Scan Flare and Discordance with PSA and Clinical Response A barrier to development of therapies to treat CRPC has been the lack of suitable surrogate markers of response to treatment and an exaggerated reliance on serum PSA changes.50 Changes in bone scan images can serve as important markers of disease response and progression. However, misinterpretation of bone scans can occur because of the transient “flare” phenomenon in the context of treatment response, thereby leading to a false determination of disease progression. The discordance between the frequency of bone scans and PSA responses due to bone flare misinterpreted as disease progression in the first 8 to 12 weeks of therapy was assessed in Study COU-AA-002 (Appendix B.1), a multicenter, open-label study.50 In this study, bone flare was prospectively defined as discordant results after 3 months of therapy based on the combination of an interpreting radiologist’s report indicating “disease progression,” in the context of a 50% or more decline in PSA levels, which on subsequent reevalution 3 months later, showed scan improvement or stability.

Of the 33 subjects participating, 23 subjects were evaluable for bone scan flare. Disease progression was indicated in the radiologist’s report for 12 (52%) subjects and 11 of the 12 subjects subsequently showed improvement or stability. As prospectively defined, bone scan flare was observed in 11 (48%) of the evaluable subjects. These data highlight the importance of recognizing this phenomenom in order to avoid premature discontinuation of an efficacious therapy. This early study also confirmed that clinical responses to treatment with abiraterone acetate and prednisone were frequent and durable, with scan improvement or stability 3 months later.

4.3.1.2. Neoadjuvant Studies of Abiraterone Acetate in Prostate Cancer Study COU-AA-201 (Appendix B.3) was designed to determine the effects of adding abiraterone acetate plus prednisone to leuprolide acetate (LHRHa in this study), in the neoadjuvant (ie, prior to radical prostatectomy) setting. Two treatment groups were examined: 24 weeks of LHRHa in combination with abiraterone acetate plus prednisone (Group 1) versus 12 weeks of LHRHa monotherapy followed by 12 weeks of LHRHa in combination with abiraterone acetate plus prednisone (Group 2).

The primary efficacy endpoint included prostate tissue testosterone and dihydrotestosterone (DHT) concentrations measured at Week 12. The difference of the mean prostate tissue testosterone concentrations between the 2 treatment groups at Week 12 was statistically significant (p=0.0216). The mean DHT concentrations were significantly lower in Group 1 subjects than that in Group 2 subjects (p<0.0001).

The secondary efficacy endpoints included prostate tissue concentrations of testosterone and DHT at Week 24, tissue concentrations of DHEA and androstenedione at Week 12 and Week 24, serum concentration of other androgens, pathologic complete or near complete responses at prostatectomy, and PSA response rate (≤0.2 ng/mL) at Week 12 and Week 24. Mean prostate tissue concentrations of testosterone and DHT at Week 24 were not statistically different

34 Approved, Date: 26 August 2015 JNJ-212082 (abiraterone acetate) Investigator's Brochure - Edition 12 between treatment groups (p=0.1423 for testosterone and p=0.6639 for DHT). Mean prostate tissue concentrations of DHEA and androstenedione at Week 12 were statistically significant between treatment groups (p<0.0001 for DHEA and androstenedione), but were not significantly different at Week 24 (p=0.5767 for DHEA and p=0.5061 for androstenedione). Mean serum concentrations of testosterone at Week 12 were statistically significant between the 2 treatment groups (p<0.0001). Serum concentrations of testosterone (Week 24) and DHT (Week 12 and Week 24) were not statistically different between treatment groups.

The pathologic complete response rates after 24 weeks were not statistically different (p=0.3427) between the 2 treatment groups. The complete or near complete response rate was significantly different (35% for Group 1 and 15% for Group 2; p=0.0799; relative risk=2.259 [1.018, 5.015]). A significantly higher (p<0.0001) PSA response rate (≤0.2 ng/mL) at Week 12 was observed in Group 1 (87%) compared with Group 2 (4%). At 24 weeks, the PSA response rate (≤0.2 ng/mL) for Group 1 was 87% and was 82% for Group 2, and was not significantly different (p=0.2319).

In Study COU-AA-203 (Appendix B.3), 2 treatment groups were examined: 12 weeks of LHRHa (leuprolide or goserelin) monotherapy or in combination with abiraterone acetate plus prednisone (AA+LHRHa). This study did not meet its primary endpoint of proportion of subjects with pathological stage ≤pT2 when compared between the 2 treatment groups: 38.1% versus 54.5%, respectively, (p=0.2148). However, the PSA response rate (≤0.2 ng/mL) in the AA+LHRHa group was significantly higher compared with the LHRHa group, 93.2% vs. 14.3% respectively, (p<0.0001).

4.3.1.3. Non-metastatic Prostate Cancer Study 212082PCR2005 (Appendix B.4) is a Phase 2, multicenter, open-label, single-arm study of abiraterone acetate plus prednisone in subjects with advanced prostate cancer without radiographic evidence of metastatic disease.

Eligible subjects were those who were receiving GnRH monotherapy for at least 6 months or had undergone and had a serum testosterone level of <50 ng/dL (<2 nM), with either a rising PSA level of ≥10 ng/mL or PSA doubling time (PSADT) of ≤10 months, and an Eastern Cooperative Oncology Group (ECOG) performance status of ≤2 at screening. One hundred thirty-one subjects were enrolled, ages 48 to 90 years (median 72 years), with non-metastatic prostate cancer. The median duration of treatment (abiraterone acetate 1,000 mg plus prednisone 5 mg) was 17.9 months (range: 0.1 to 40.7 months) with a median of 20.0 cycles started.

During the Core Treatment Phase (Cycles 1-6), 87% of evaluable subjects (95% CI: 81%, 93%) achieved a ≥50% PSA reduction (primary endpoint) (p<0.0001). As well, 91% of evaluable subjects achieved a ≥30% PSA reduction, 60% achieved a ≥90% PSA reduction, and 22% achieved a PSA level of <0.20 ng/mL. The median time to PSA progression was 28.7 months.

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4.3.1.4. Combination of Abiraterone Acetate with Docetaxel in Prostate Cancer Study COU-AA-206 (Appendix B.1) is an open-label, uncontrolled, multicenter, Phase 1b study designed to determine the maximum safe dose combination of abiraterone acetate and docetaxel plus prednisone in chemotherapy-naïve men with mCRPC.

Subjects were sequentially enrolled into 1 of 3 treatment groups: Cohort 1: docetaxel 60 mg/m2 + abiraterone acetate 500 mg/day + prednisone 10 mg/day (n=7); Cohort 2: docetaxel 75 mg/m2 + abiraterone acetate 500 mg/day + prednisone 10 mg/day (n=8); and Cohort 3: docetaxel 75 mg/m2 + abiraterone acetate 1,000 mg/day + prednisone 10 mg/day (n=7).

It was determined that the approved doses of docetaxel 75 mg/m2 every 3 weeks, abiraterone acetate 1,000 mg/day, and prednisone 10 mg/day could be administered in combination to patients with mCRPC.

Of the 22 subjects treated, 14 subjects (63.6%) had a confirmed PSA response (>90% reduction from baseline). A confirmed PSA response (>50% reduction) was observed for 16 subjects (72.7%). The median time to PSA progression was 22.9 months. Of the 10 subjects with measurable disease at baseline, 6 subjects attained a partial response. The median time to radiographic progression was estimated to be 11.7 months.

4.3.1.5. Breast Cancer Study 212082BCA2001 (Appendix B.3) is a Phase 2, randomized, open-label study to assess the safety and efficacy of abiraterone acetate plus prednisone (AAP) and abiraterone acetate plus prednisone plus exemestane (AAPE), each compared with exemestane (E) alone, in postmenopausal women with metastatic breast cancer progressing after letrozole or anastrozole therapy.

Patients were randomly assigned in a 1:1:1 ratio to: (1) abiraterone acetate 1,000 mg/day plus prednisone 5 mg/day (AAP, n=89), (2) abiraterone acetate 1,000 mg/day plus prednisone 5 mg/day combined with exemestane 25 mg/day (AAPE, n=106), or (3) exemestane 25 mg/day (n=102). The distribution of subjects by baseline disease characteristics was balanced across treatment groups.

There was no significant difference observed between the exemestane and AAP or AAPE groups in any of the efficacy endpoints (PFS, OS, overall response rate, clinical benefit rate, or change in ECOG score). Based on the results from this analysis, no further development in this indication is planned.

4.3.2. Efficacy Results in Phase 3 Studies

4.3.2.1. COU-AA-301 (Appendix B.6) Study COU-AA-301 was the pivotal multinational, randomized, double-blind, placebo-controlled Phase 3 study comparing abiraterone acetate plus predisone with placebo plus

36 Approved, Date: 26 August 2015 JNJ-212082 (abiraterone acetate) Investigator's Brochure - Edition 12 prednisone in mCRPC subjects who had disease progression on or after docetaxel-based chemotherapy.

At randomization, subjects were stratified on the basis of ECOG performance status (0 or 1 versus 2) and pain (absent versus present). Overall survival was the primary endpoint. Other efficacy endpoints included time to PSA progression, radiographic progression-free survival (rPFS), PSA response, and objective response by Response Evaluation Criteria in Solid Tumors (RECIST). Patient-reported outcomes were assessed based on the Brief Pain Inventory-Short Form (BPI-SF) and Functional Assessment of Cancer Therapy-Prostate (FACT-P) instruments.

One thousand one hundred ninety-five subjects were randomized (2:1) with 791 subjects in the abiraterone acetate plus prednisone group and 398 subjects in the placebo plus prednisone group. At study entry, 89% of the subjects had an ECOG performance status of 0 or 1, and 44% of the subjects had pain. The median duration of treatment was in the abiraterone acetate plus prednisone group was 7.4 months and was 3.6 months in the placebo plus prednisone group.

The efficacy results are based on the clinical cutoff for the final analysis of OS, which occurred on 20 September 2010. After a median follow-up of 20.2 months, 775 (97% of the planned number of events for final analysis) deaths were observed (501 [63%] in the abiraterone acetate plus prednisone group and 274 [69%] in the placebo plus prednisone group). The cutoff for this analysis also occurred before the first subject in the placebo plus prednisone group crossed over to receive abiraterone acetate. Treatment with abiraterone acetate plus prednisone reduced the risk of death by 26% compared with placebo plus prednisone (HR=0.740; 95% CI: 0.638, 0.859; p<0.0001). The median OS was 15.8 months in the abiraterone acetate plus prednisone group and 11.2 months for the placebo plus prednisone group.19

The results for other efficacy endpoints (time to PSA progression, rPFS, PSA response and objective response by RECIST) at the time of the final analysis (20 September 2010) were consistent with the interim analysis (22 January 2010) demonstrating an improvement with abiraterone acetate plus prednisone compared with placebo plus prednisone (Table 7).13,19

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Table 7: Summary of Other Efficacy Endpoints (Study COU-AA-301) AA Placebo Hazard Ratio (95% CI; N=797) (95% CI; N=398) (95% CI) p value Time to PSA progression (months)a 8.5 (8.3, 11.1) 6.6 (5.6, 8.3) 0.63 (0.52, 0.78) <0.0001 Radiographic progression-free survival (months)a 5.6 (5.6, 6.5) 3.6 (2.9, 5.5) 0.66 (0.58, 0.76) <0.0001 RR: 5.27 PSA response (%)b 235 (29.5%) 22 (5.5%) 95% CI: 3.46, 8.02 <0.0001 Objective response by RECIST (%)c 118 (14.8%) 13 (3.3%) -- <0.0001 AA=abiraterone acetate; CI=confidence interval; PSA=prostate specific antigen; PSAWG=Prostate Specific Antigen Working Group; RECIST=Response Evaluation Criteria in Solid Tumors; RR=relative risk Data are median (95% CI) or number (%). a Calculated from date of randomization to date of PSA progression (per PSAWG criteria) or date of radiographically documented disease progression or death. b Proportion of subjects with PSA decline of 50% or higher according to PSAWG criteria, unstratified analysis. c Additional, not secondary endpoint Source: Fizazi19

Patient-reported outcomes Abiraterone acetate plus prednisone provided significant benefits in reducing fatigue, pain relief, pain palliation, and in the delay of occurrence of skeletal-related events.39,54 Clinical benefit was also demonstrated with improved and delayed declines in functional status assessed by the FACT-P instrument.(Harland)28

The last patient completed Study COU-AA-301 on 01 October 2012. The sponsor stopped the study, and all ongoing subjects were rolled over into Study 212082PCR3010, a Phase 3b multicenter, open-label abiraterone acetate long-term safety study, which is designed to collect long-term follow-up safety data from subjects in completed abiraterone acetate studies.

4.3.2.2. COU-AA-302 (Appendix B.6) Study COU-AA-302 was the pivotal multinational, randomized, double-blind, placebo-controlled Phase 3 study comparing abiraterone acetate plus predisone with placebo plus prednisone in mCRPC subjects who were asymptomatic or mildly symptomatic and had disease progression on ADT.

At randomization, subjects were stratified on the basis of ECOG performance status (0 versus 1). Radiographic progression-free survival and OS were the primary endpoints. Secondary efficacy endpoints included time to opiate use for cancer-related pain, time to cytotoxic chemotherapy, time ECOG performance status deterioration by by ≥1 grade, and time to PSA progression. Patient-reported outcomes were assessed based on the BPI-SF and FACT-P instruments.

One thousand eighty-eight subjects were randomized (1:1) with 546 subjects in the abiraterone acetate plus prednisone group and 542 subjects in the placebo plus prednisone group. At study entry, 76% of the subjects had an ECOG performance status grade of 0. The median duration of treatment in the abiraterone acetate plus prednisone group was 13.8 months and was 8.3 months in the placebo plus prednisone group.

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The data for the primary co-endpoint of rPFS provided in this document is based on the clinical cutoff date of 20 December 2010 for rPFS (Independent Review).51 Results are also presented based on the Investigator Review of rPFS at the time of the planned third interim analysis of OS at ~55% (actual 56%) of death events with a clinical cutoff of date of 22 May 2012 (hereafter referred as the updated analysis). The data presented for most of the secondary endpoints are also based on this updated analysis. The results for the final analysis of the co-primary endpoint of OS and the secondary endpoint of time to opiate use for cancer-related pain are based on a clinical cutoff date of 31 March 2014.

The study met its co-primary endpoint of rPFS at the prespecified significance level required to demonstrate efficacy for the independent review of rPFS analysis. Among the 1,088 randomized subjects assessed by the independent reviewers, 401 had radiographic disease progression or died: 150 (28%) in the abiraterone acetate plus prednisone group and 251 (46%) in the placebo plus prednisone group. Treatment with abiraterone acetate decreased the risk of radiographically documented disease progression or death by 58% compared with placebo (HR=0.425; 95% CI: 0.347, 0.522: p<0.0001). The median time radiographic disease progression or death was not reached in the abiraterone acetate plus prednisone group and was 8.3 months (95% CI: 8.12, 8.54) in the placebo plus prednisone group.51

At the time of the updated analysis of rPFS based on Investigator Review, 644 progression or death events had occurred (292 [54%] in the abiraterone acetate plus prednisone group and 352 [65%] in the placebo plus prednisone group). The results remained consistent with the primary analysis based on Independent Review presented above. Treatment with abiraterone acetate reduced the radiographically documented disease progression or death by 48% compared with placebo (HR=0.525; 95%CI: 0.449, 0.615). The median time to radiographic disease progression or death was 16.5 months in the abiraterone acetate plus prednisone group and 8.3 months in the placebo plus prednisone group

The median follow-up for OS was 49.2 months at the time of the final analysis. At that time, 741 death events were observed (354 [65%] in the abiraterone acetate plus prednsione group and 387 [71%] in the placebo plus prednisone group). This represents 96% of the planned 773 death events required for the final analysis.

Treatment with abiraterone acetate resulted in an estimated 19.4% decrease in the risk of death compared with the placebo group (HR=0.806; 95% CI: 0.697, 0.931; p=0.0033). The result of this analysis crossed the boundary for statistical significance specified in the protocol (O’Brien-Fleming efficacy boundary nominal significance level of 0.0384). The median OS was 34.7 months in the abiraterone acetate plus prednisone group and 30.3 months in the placebo plus prednisone group. At 48 months, the event-free rates were 0.34 and 0.25 for the abiraterone acetate and placebo groups, respectively.

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Secondary Endpoints A summary of the updated data for the secondary endpoints is provided in Table 8. The results for all secondary endpoints favored abiraterone acetate plus prednisone treatment and demonstrate the clinical benefit of the delay in radiographic disease progression.

Table 8: Summary of Efficacy Data for the Secondary Endpoints (Study COU-AA-302) AA Placebo HR (95% CI) p-valuea Median (months) (N=546) (N=542) Time to opiate use for cancer pain 33.4 23.4 0.721 (0.614, 0.846) <0.0001 Time to initiation of cytotoxic chemotherapy 26.5 16.8 0.607 (0.514, 0.717) < 0.0001 Time to deterioration of ECOG performance status by ≥ 1 grade 12.3 10.9 0.825 (0.721, 0.944) 0.0052 Time to PSA progression based on PCWG2 criteria 11.1 5.6 0.501 (0.432, 0.581) < 0.0001 AA=abiraterone and prednisone treatment; ECOG=Eastern Cooperative Oncology Group; HR=hazard ratio; PCWG2=Prostate Cancer Working Group 2; PSA=prostate-specific antigen a p value from log-rank test

Patient-reported Outcomes Patient-reported outcomes as assessed using the BPI-SF and FACT-P instruments were significantly improved in the abiraterone acetate group compared with the placebo group. In the updated analysis, treatment with abiraterone acetate reduced the risk of average pain intensity progression by 17% compared with placebo (HR=0.828; 95% CI: 0.679, 0.1.009; p=0.0612). The median time to average pain intensity progression was 26.7 months in the abiraterone acetate group and 18.4 months in the placebo group, a delay in median time to average pain intensity progression by >8 months in the abiraterone acetate group compared with the placebo group.

A summary of all FACT-P subscale results for the updated analysis is presented in Table 9.

Table 9: Summary of FACT-P Subscale Results (Study COU-AA-302: ITT Population) FACT-P Subscale Median (95% CI) Time to Progression Hazard ratio of p-value (months) AA/Placebo (95% CI) AA Placebo FACT-P (Total Score) 12.65 (11.07, 14.00) 8.31 (7.39, 10.61) 0.791 (0.672, 0.931) 0.0046 PCS 11.10 (8.64, 13.80) 5.78 (5.49, 8.31) 0.716 (0.610, 0.840) < 0.0001 TOI 13.86 (11.99, 16.49) 9.26 (8.31, 11.07) 0.768 (0.651, 0.907) 0.0018 FACT-G 16.56 (13.83, 19.35) 11.07 (8.51, 14.00) 0.761 (0.639, 0.908) 0.0023 PWB 14.78 (13.63, 16.82) 11.07 (9.10, 13.80) 0.763 (0.643, 0.906) 0.0019 SFWB 18.40 (13.83, 24.80) 16.59 (11.07, NE) 0.947 (0.782, 1.147) 0.5774 EWB 22.54 (17.35, 27.89) 14.16 (13.34, 19.45) 0.734 (0.605, 0.891) 0.0017 FWB 13.34 (11.01, 15.74) 8.35 (6.47, 10.12) 0.768 (0.652, 0.905) 0.0016 AA=abiraterone acetate; CI=confidence interval; EWB=Emotional Well Being; FACT-G=Functional Assessment of Cancer Therapy-General; FACT-P; Functional Assessment of Cancer Therapy-Prostate; FWB=Functional Well Being; ITT=intent to treat; NE=not evaluable; PCS=Prostate Cancer Scale; PWB=Physical Well Being; SFWB=Social/Family Well Being; TOI=Total Outcome Index

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4.3.2.3. Bridging Studies: ABI-PRO-3001 and ABI-PRO-3002 Study ABI-PRO-3001 (Appendix B.6) is the Phase 3 bridging study to COU-AA-301 in Chinese subjects with mCRPC who have failed docetaxel-based chemotherapy.

Study ABI-PRO-3002 (Appendix B.6) is the Phase 3 bridging study to COU-AA-302 in chemotherapy-naïve Asian and Russian subjects with mCRPC.

Available efficacy results for both of these studies are summarized in Table 6.

4.4. Summary of Safety in Studies with Abiraterone Acetate Safety data for the 2 large randomized, double-blind, placebo-controlled Phase 3 abiraterone acetate studies, COU-AA-301 and COU-AA-302 are presented by study and integrated safety data. The safety populations for the individual and integrated datasets are defined as any subject who received at least part of a 1,000 mg daily dose of abiraterone acetate or placebo. The integrated safety population includes 2,267 subjects with mCRPC: 1,331 subjects treated with abiraterone acetate and prednisone (791 subjects from Study COU AA-301 and 542 subjects from Study COU AA 302) and 934 control subjects treated with placebo and prednisone (394 subjects from Study COU-AA-301 and 540 subjects from Study COU-AA-302). Conclusions about the safety of abiraterone acetate with prednisone for the treatment of mCRPC are based primarily on data from these 2,267 subjects.

Summaries of other Phase 3 studies (the bridging study evaluations ABI-PRO-3001 and ABI-PRO-3002 and the expanded access study, 212082PCR3001) and key Phase 2 studies are presented separately.

All AEs presented are treatment-emergent, defined as those events occurring or worsening in severity from the start of treatment to within 30 days after the last dose of study medication.

4.4.1. Summary of Adverse Events in Studies COU-AA-301 and COU-AA-302 The clinical cutoff for the COU-AA-301 safety data is 20 September 2010 and for the COU-AA-302 safety data is 20 December 2011. For Study COU-AA-301, 16% of subjects in the abiraterone acetate group and 5% of subjects in the placebo group were ongoing; for Study COU-AA-302, 31% and 16%, respectively were ongoing. For the 2 studies, the median treatment duration for the abiraterone acetate plus prednisone group was approximately twice as long compared with the placebo plus prednisone group; the median duration of treatment for both treatment groups was approximately twice as long in Study COU-AA-302 compared with Study COU-AA-301 (see Sections 4.3.2.1 and 4.3.2.2).

An overview of AEs is provided in Table 10. Cumulative safety data for Study COU-AA-301 obtained at completion of study was consistent with safety data at the 20 September 2010 cutoff. Similarly, for Study COU-AA-302, safety data at the time of the final analysis of OS (clinical cutoff of 31 March 2014 with 96% of death events; median follow-up=49.2 months) was

41 Approved, Date: 26 August 2015 JNJ-212082 (abiraterone acetate) Investigator's Brochure - Edition 12 consistent with the safety data discussed below. With longer term follow-up no new safety findings were noted for these 2 studies.

Table 10: Overall Safety Profile (Integrated Safety Population) COU-AA-301 COU-AA-302 Combined AA Placebo AA Placebo AA Placebo (N=791) (N=394) (N=542) (N=540) (N=1333) (N=934) Treatment-Emergent Adverse 784 (99.1%) 390 (99.0%) 537 (99.1%) 524 (97.0%) 1321 914 (97.9%) Events (TEAEs) a (99.1%) Drug-related b 610 (77.1%) 305 (77.4%) 424 (78.2%) 413 (76.5%) 1034 718 (76.9%) (77.6%)

Grade 3-4 TEAEs 478 (60.4%) 240 (60.9%) 258 (47.6%) 225 (41.7%) 736 (55.2%) 465 (49.8%) Drug-related b 182 (23.0%) 76 (19.3%) 122 (22.5%) 91 (16.9%) 304 (22.8%) 167 (17.9%)

Serious TEAEs a 335 (42.4%) 172 (43.7%) 178 (32.8%) 142 (26.3%) 513 (38.5%) 314 (33.6%) Drug-related b 88 (11.1%) 41 (10.4%) 59 (10.9%) 54 (10.0%) 147 (11.0%) 95 (10.2%) Grade 3-4 288 (36.4%) 148 (37.6%) 150 (27.7%) 117 (21.7%) 438 (32.9%) 265 (28.4%) Drug-related Grade 3-4 b 76 (9.6%) 33 (8.4%) 53 (9.8%) 39 (7.2%) 129 (9.7%) 72 (7.7%)

TEAEs Leading to Treatment 162 (20.5%) 93 (23.6%) 55 (10.1%) 49 (9.1%) 217 (16.3%) 142 (15.2%) Discontinuation c Drug-related b 43 (5.4%) 27 (6.9%) 29 (5.4%) 23 (4.3%) 72 (5.4%) 50 (5.4%)

TEAEs Leading to Death 105 (13.3%) 61 (15.5%) 20 (3.7%) 12 (2.2%) 125 (9.4%) 73 (7.8%) Drug-related b 8 (1.0%) 11 (2.8%) 5 (0.9%) 4 (0.7%) 13 (1.0%) 15 (1.6%)

All deaths within 30 days of last 97 (12.3%) 55 (14.0%) 18 (3.3%) 8 (1.5%) 115 (8.6%) 63 (6.7%) dose Underlying Disease 64 (8.1%) 41 (10.4%) 7 (1.3%) 3 (0.6%) 71 (5.3%) 44 (4.7%) Other 29 (3.7%) 14 (3.6%) 10 (1.8%) 4 (0.7%) 39 (2.9%) 18 (1.9%) Unknown 4 (0.5%) 0 1 (0.2%) 1 (0.2%) 5 (0.4%) 1 (0.1%) a Grade 5 event is not included. b Adverse events reported to be unlikely related, possibly related, or related to AA/Placebo or Prednisone/Prednisolone are classified as drug-related. AEs with missing relationship are considered as drug- related AEs. c Discontinuation of study medication includes discontinuation of AA/Placebo and/or Prednisone/Prednisolone or both.

Most Common Adverse Events A summary of AEs reported in at least 10% of subjects in any treatment group is provided in Appendix D.2. For the combined treatment groups, the most frequently reported AEs were fatigue (44%), back pain (33%), nausea (28%), arthralgia (30%), constipation (26%), bone pain (24%), peripheral edema (26%), hot flush (21%), and diarrhea (21%). Most events were of Grade 1 or 2 toxicity. Noteworthy exceptions include muscle spasms, upper respiratory tract infection, hypertension, and increased alanine aminotransferase (ALT), all of which were reported at higher rates for Study COU-AA-302 compared with Study COU-AA-301.

4.4.1.1. Adverse Events of Special Interest Adverse events of special interest with abiraterone acetate therapy, include fluid retention/edema, hypokalemia, hypertension, cardiac disorders, and hepatotoxicity (labeled as

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“LFT abnormalities” in the table). Adverse events of special interest are summarized in Appendix D.3.

Adverse events of special interest were reported in 818 (61%) subjects in the combined abiraterone acetate group and 451 (48%) subjects in the combined placebo group. In Study COU-AA-301, these events were reported in 59% of subjects in the abiraterone acetate group and 46% of subjects in the placebo group. In Study COU-AA-302, AEs of special interest were reported in 66% and 50% of subjects, respectively.

Events of fluid retention/edema were reported for 33% of subjects in the abiraterone acetate group and 24% of subjects in the placebo group in Study COU-AA-301, and 28% and 24%, respectively, in Study COU-AA-302. The preferred term peripheral edema accounted for most of these events. With standardization for duration of exposure, the rate of fluid retention/edema events was higher for the abiraterone acetate group in Study COU-AA-301 (exposure-standardized rates expressed as events per 100 subject-years of 68.4 for the abiraterone acetate group and 68.1 for the placebo group) but lower for the abiraterone acetate group in Study COU-AA-302 (38.2 and 43.7, respectively).

Events of hypokalemia were reported in 18% of subjects in the abiraterone acetate group and 9% of subjects in the placebo group for Study COU-AA-301; for Study COU-AA-302, these proportions were 17% and 13%, respectively. With standardization for duration of exposure, the difference remained more pronounced for Study COU-AA-301 (exposure-standardized rates expressed as events per 100 subject-years of 42.2 for the abiraterone acetate group and 27.6 for the placebo group) as compared with Study COU-AA-302 (23.5 and 22.1, respectively).

Proportions of subjects experiencing events of hypertension were higher for Study COU-AA-302 (22% of subjects in the abiraterone acetate group and 13% of subjects in the placebo group) as compared with Study COU-AA-301 (11% of subjects in the abiraterone acetate group and 8% of subjects in the placebo group). The preferred term hypertension accounted for most of these events. With standardization for duration of exposure, the difference remained more pronounced for Study COU-AA-302 (exposure-standardized rates expressed as events per 100 subject-years of 23.5 for the abiraterone acetate group and 19.5 for the placebo group) as compared with Study COU-AA-301 (18.6 and 18.0, respectively).

The incidence of hepatotoxicity events was lower in Study COU-AA-301 (11% of subjects in the abiraterone acetate group and 9% of subjects in the placebo group) compared with Study COU-AA-302 (18% and 11%, respectively). With standardization for duration of exposure, a higher rate of hepatotoxicity events was noted in the placebo group in Study COU-AA-301 (exposure-standardized rates expressed as events per 100 subject-years of 32.1 for the abiraterone acetate group and 43.6 for the placebo group); the opposite was true for Study COU-AA-302 (54.6 and 31.1, respectively). All hepatotoxicity-related events completely resolved with dose reduction, dose interruption or treatment discontinuation.

Hy’s Law criteria were applied to Studies COU-AA-301 and COU-AA-302 to assess the incidence of severe hepatotoxicity. Hy’s Law criteria required the following: peak

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ALT 3 x upper limit of normality (ULN) or aspartate aminotransferase (AST) 3 x ULN and total bilirubin 2 x ULN at any time postbaseline, with alkaline phosphatase (ALP) 2 x ULN, and lacking an underlying clinical condition, which could explain the combination of increased aminotransferases and total bilirubin.

Due to the prevalence of elevated ALP in these 2 studies, liver function test (LFT) abnormalities were also assessed using the electronic tool for drug-induced serious hepatotoxicity (eDISH) methodology, which uses the same criteria as those for Hy’s Law, except that ALP concentrations are excluded.

One subject in Study COU-AA-302 had LFT abnormalities that met Hy’s Law laboratory criteria; however, an underlying clinical condition that the investigator confirmed was entirely due to compression of the biliary tract and not due to study therapies, explained the laboratory abnormalities and was responsible for the hepatotoxicity.

Of the 14 subjects that had LFT abnormalities meeting eDISH criteria for hepatotoxicity but had underlying conditions that precluded meeting Hy’s Law criteria, 7 subjects were from Study COU-AA-301 (4 subjects in the abiraterone acetate group and 3 subjects in the placebo group) and 7 subjects were from Study COU-AA-302 (5 subjects and 2 subjects, respectively). In summary, no cases of Hy’s Law were reported in Studies COU-AA-301 and COU-AA-302.

A higher rate of cardiac disorder events was noted for the abiraterone acetate group, relative to the placebo group, within each of the 2 individual studies: 16% for the abiraterone acetate group and 12% for the placebo group within Study COU-AA-301, and 17% and 14% for these groups within Study COU-AA-302. With standardization for duration of exposure, the rate of cardiac disorder events was higher for the abiraterone acetate group in Study COU-AA-301 (exposure-standardized rates expressed as events per 100 subject-years of 32.0 for the abiraterone acetate group and 27.0 for the placebo group) but lower for the abiraterone acetate group in Study COU-AA-302 (24.6 and 25.3, respectively).

4.4.1.2. Deaths, Serious Adverse Events and Other Significant Adverse Events

4.4.1.2.1. Serious Adverse Events The incidence of serious adverse events (SAEs) in the integrated safety population reported in at least 1% of subjects as of 20 December 2011 in any group is summarized in Appendix D.4.

For the combined treatment groups, SAEs were reported in 513 (38%) subjects in the abiraterone acetate group and 314 (34%) subjects in the placebo group. The 5 most frequently reported SAEs across the 2 studies were spinal cord compression, anemia, , pulmonary embolism, and bone pain. All other SAEs were reported in 2% of subjects in either combined treatment group.

Serious adverse events were reported for a lower proportion of abiraterone acetate-treated subjects versus placebo-treated subjects in Study COU-AA-301 (42% versus 44%), but a higher proportion of abiraterone acetate-treated subjects versus placebo-treated subjects in

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Study COU-AA-302 (33% versus 26%). A review of Appendix D.4 identified hematuria as reported for a greater proportion of subjects in the abiraterone acetate treatment group of Study COU-AA-302 compared with the Study COU-AA-301. Within Study COU-AA-302, the incidence reporting hematuria in the abiraterone acetate group was at least double compared with the placebo group (2% versus 1% respectively).

Grade 3 or 4 SAEs were reported for a lower proportion of abiraterone acetate-treated subjects versus placebo-treated subjects in Study COU-AA-301 (36% versus 38%), but a higher proportion of abiraterone acetate-treated subjects versus placebo-treated subjects in Study COU-AA-302 (28% versus 22%).

4.4.1.2.2. Deaths As of the 20 September 2010 clinical cutoff date for Study COU-AA-301, 12% of abiraterone acetate-treated subjects and 14% of placebo-treated subjects had died within 30 days of the last dose of study medication. As of the 20 December 2011 clinical cutoff date for Study COU-AA-302, 3% of abiraterone acetate-treated subjects and 1% of placebo-treated subjects had died within 30 days of the last dose of study medication.

In Study COU-AA-301, deaths were most often attributed to underlying disease (8% in the abiraterone acetate group and 10% in the placebo group). In the pre-chemotherapy population of Study COU-AA-302, deaths were most often attributed not to underlying disease but rather to ‘Other’ reasons (2% in the abiraterone acetate group and 1% in the placebo group). For the 10 abiraterone acetate-treated subjects in Study COU-AA-302 with ‘Other’ cause of death, the verbatim reasons provided included: aspiration pneumonia; respiratory failure due to pneumonia; hypothermia; myocardial infarction; respiratory infection; suicide; pulmonary infection; necrosis (ileum, jejunum); ischemic bowel; and respiratory infection. For the 4 placebo-treated subjects in Study COU-AA-302 with ‘Other’ cause of death, the verbatim reasons provided included: cardiac complications; cerebrovascular accident; exacerbation of chronic obstructive pulmonary disease; and heart attack.

4.4.1.2.3. Adverse Events Leading to Discontinuation of Treatment For the combined treatment groups, 217 (16%) subjects in the abiraterone acetate group and 142 (15%) subjects in the placebo group experienced an AE leading to discontinuation of study drug. The 5 most frequently reported AEs leading to discontinuation of study drug for the combined treatment groups were disease progression, spinal cord compression, back pain, ALT increased, and AST increased. Disease progression was the most commonly reported AE leading to treatment discontinuation in Study COU-AA-301 (6% of subjects in the abiraterone acetate group and 5% of subjects in the placebo group). In Study COU-AA-302, ALT increased was the most commonly reported AE leading to treatment discontinuation (1.7% of subjects in the abiraterone acetate group and 0.2% of subjects in the placebo group).

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4.4.2. Bridging Studies

Study 212082PCR2007 (Appendix B.3) Study 212082PCR2007 was a bridging evaluation study (based on studies COU-AA-004 and COU-AA-301) in subjects from Korea and Taiwan. Eighty-two subjects (52 from Korea and 30 from Taiwan) were included in the safety analysis. At the time of clinical cutoff (CCO) for the final analysis (16 December 2014), the median duration of treatment was 7.8 months. The safety profile in Korean and Taiwanese subjects was consistent with the safety profiles of Study COU-AA-301 and Study COU-AA-004.

Study ABI-PRO-3001 (Appendix B.6) Two hundred fourteen subjects (143 in the abiraterone acetate group and 71 in the placebo group) were included in the safety analysis. At the time of the CCO for the final analysis (30 April 2014), the median duration of treatment was 7.4 months in the abiraterone acetate group and 3.9 months in the placebo group. The safety profile of abiraterone acetate plus prednisone in Study ABI-PRO-3001 was consistent with the safety profile of Study COU-AA- 301. No new or unexpected safety signals were observed in the study.

Study ABI-PRO-3002 (Appendix B.6) An interim analysis of efficacy and safety for Study ABI-PRO-3002 was conducted after ~50% of the time to PSA progression events had occurred (CCO 18 March 2013). Three hundred thirteen subjects (157 in the abiraterone acetate group and 156 in the placebo group) were included in the safety analysis. The median duration of treatment was 3.8 months in the abiraterone acetate group and 3.4 months in the placebo group.

The safety profile of abiraterone acetate plus prednisone in Study ABI-PRO-3002 was consistent with the safety profile of Study COU-AA-302. The incidence of AEs was generally lower in Study ABI-PRO-3002 compared with Study COU-AA-302, which may, in part, be reflective of the shorter duration of follow-up in Study ABI-PRO-3002. No new or unexpected safety signals were observed in the study.

4.4.3. Food Safety Study

Study 212082PCR2008 (Appendix B.3) At the time of the clinical cutoff for the final analysis (29 May 2013), 25 subjects had received treatment with abiraterone acetate (7 in Cohort 1 [low fat] and 18 in Cohort 2 [high fat]. The median treatment duration was 420 days (range 84 to 571 days) in Cohort 1 and 154 days (range 44 to 415 days) in Cohort 2. No new or unexpected safety signals were observed in the study.

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4.4.4. Expanded Access Study

Study 212082PCR3001 (Appendix B.6) At the time of the final analysis (CCO 30 September 2013) 2,314 subjects had received at least 1 dose of study drug; treatment was ongoing for 215 subjects. The median duration of treatment was 4.9 months.

For this study, Grade 1 and 2 AEs were only to be reported if they were considered by the investigator to be medically significant (eg, requiring medical intervention, leading to dose reduction or treatment discontinuation). The most frequently reported Grade 3 or 4 AE was increased blood alkaline phosphatase level in 6% of subjects. All other Grade 3 or 4 AEs were reported in <5% of subjects. Grade 3 or 4 AEs of special interest were infrequent: liver function test abnormalities (8%), hypertension (4%), cardiac disorders (2%), hypokalemia, fluid retention/edema and osteoporosis/osteoporosis-related fractures (each in 1% of subjects).

In addition, 2 non-fatal cases of hepatotoxicity meeting Hy’s Law criteria were reported. In each case, the onset occurred within the first 2 months of treatment, and the subjects recovered after discontinuation of abiraterone acetate.

4.4.5. Safety in Subjects with Non-metastatic Prostate Cancer The study population for Studies COU-AA-201 and COU-AA-203 was men with localized high-risk prostate cancer (see Section 1.1). The safety profile of abiraterone acetate and prednisone (5 mg orally once daily) plus LHRHa in subjects with localized prostate cancer is consistent with the known side effects associated with abiraterone acetate in patients with mCRPC. No new safety signals were identified.

Study COU-AA-201 (Appendix B.3) In Study COU-AA-201, of 58 subjects in the safety population, 54 (93%) subjects completed the study. Two subjects discontinued due to AEs, 1 subject withdrew consent, and subject discontinued with reason “other”.

The most frequently reported AEs in the Group 1 and Group 2 treatment groups were hot flush (80% and 96%, respectively), AST increased (47% and 54%, respectively), ALT increased (40% and 57%, respectively), fatigue (43% and 57%, respectively). Hypokalemia was reported in 21% and 20% of subjects, respectively. Most of these events were Grade 1 or 2 in severity. Grade 3 ALT increased was reported in 10% of subjects in Group 1 and 7% of subjects in Group 2. Grade 3 hypokalemia was reported in 3% of subjects in Group 1 and 7% of subjects in Group 2. One subject experienced Grade 4 depression (Group 1); no other Grade 4 events were reported. No deaths were reported within 30 days of the last dose of study drug.

Study COU-AA-203 (Appendix B.3) In Study COU-AA-203, 65 subjects were enrolled and completed the 3 months of treatment.

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The most frequently reported AEs in the AA+LHRHa and LHRHa groups were hot flush (84% and 86%, respectively), anemia (52% and 38%, respectively), ALT increased (50% and 33%, respectively), AST increased (39 and 33%, respectively), and fatigue (43% and 48%, respectively). Most of the AEs were of Grade 1 severity. In the AA+LHRHa group, Grade 3 ALT and AST increases were reported in 16% and 2% of subjects, respectively. Other AEs of special interest reported in more than 5% of subjects in either treatment group included hypertension (AA+LHRHa: 23%, LHRHa: 14%), hyperbilirubinemia (AA+LHRHa: 18%, LHRHa: 5%), and hypokalemia (AA+LHRHa group only, 11%; Grade 3, 2%). Grade 3 hypertension was reported in 14% and 10% of subjects in the AA+LHRHa and LHRHa groups, respectively. No Grade 4 AEs were reported. No deaths were reported within 30 days of the last dose of study drug.

Study 212082PCR2005 (Appendix B.4) In Study 212082PCR2005, as of the CCO date (03 November 2014), 131 subjects were enrolled and 111 (85%) completed the Core Treatment Phase (Cycles 1 to 6). The median duration of treatment was 17.9 months. The most frequently reported Grade 3-4 AEs were hypertension (22%), hypokalemia ( 6%), hematuria, and pneumonia (each 4%). Grade 3 or higher AEs of special interest were reported in 49 subjects (37%); most (34%) were Grade 3. One subject experienced Grade 4 AEs of special interest (arrythmia and cardiorespiratory arrest) and 3 subjects experienced Grade 5 AEs of special interest (congestive cardiac failure, coronary artery disease and myocardial infarction).

4.4.6. Combination of Abiraterone Acetate With Other Drugs in Men With Prostate Cancer

4.4.6.1. Abiraterone Acetate and Prednisone With Docetaxel Study COU-AA-206 (Appendix B.1): At the time of the clinical cutoff (20 March 2014), 22 subjects had received combination treatment with abiraterone acetate; 7 in Cohort 1 (abiraterone acetate 500 mg/day + docetaxel 60 mg/m2/day + prednisone 10 mg/day), 8 in Cohort 2 (abiraterone acetate 500 mg/day + docetaxel 75 mg/m2/day + prednisone 10 mg/day), and 7 in Cohort 3 (abiraterone acetate 1,000 mg/day + docetaxel 75 mg/m2/day + prednisone 10 mg/day). The median treatment duration was 10 months.

The approved doses of docetaxel 75 mg/m2 every 3 weeks, abiraterone acetate 1,000 mg/day, and prednisone 10 mg/day could be administered in combination to patients with mCRPC. No new safety signals were observed.

4.4.7. Study COU-AA-BMA At the time of the clinical cutoff for the final analysis (28 August 2012), 57 subjects had received treatment with abiraterone acetate. The median treatment duration was 7.6 months (range: 0.1 to 58.6 months). No new or unexpected safety signals were observed in the study.

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4.4.8. Japanese Phase 2 Studies

Study JNJ-212082-JPN-201 At the time of the clinical cutoff for the final analysis (8 October 2014), 48 subjects had received treatment with abiraterone acetate. The median treatment duration was 14.1 months. No new or unexpected safety signals were observed in the study.

Study JNJ-212082-JPN-202 At the time of the clinical cutoff for the final analysis (15 October 2014), 47 subjects had received treatment with abiraterone acetate. The median treatment duration was 8.3 months. No new or unexpected safety signals were observed in the study.

4.4.9. Breast Cancer

Study 212082BCA2001 At the time of the clinical cutoff for the final analysis (20 September 2013) the median treatment duration was 3.7 months in the exemestane (E), abiraterone acetate + prednisone (AAP) and abiraterone acetate + prednisone + exemestane (AAPE) groups.

The most frequently reported AEs (ie, in ≥20% of subjects in any treatment group) were fatigue (25% E, 25% AAP, 19% AAPE); nausea (18% E, 23% AAP, 19% AAPE); hypokalemia (5% E, 22% AAP, 13% AAPE); and (7% E, 13% AAP, 20% AAPE). The most commonly reported Grade 3-4 AEs were hypokalemia (2% E, 3% AAP, 6% AAPE); hypertension (3% E, 1% AAP, 6% AAPE), and AST increased (4% E, 2% AAP, 5% AAPE). Three subjects experienced AEs leading to death (1 stress cardiomyopathy in the E group, 1 hyperbilirubinemia and 1 transaminase increased in the AAPE group).

The frequency and clinical pattern of toxicity in this study of women with breast cancer were similar to the safety profile of abiraterone acetate in patients with prostate cancer.

4.5. Marketing Experience As of 27 April 2015, abiraterone acetate is authorized in 100 countries worldwide (including the EU, and US) for the treatment of men with mCRPC (indications vary). Based on the 43,431,956 grams distributed worldwide, the estimated postmarketing exposure for abiraterone acetate from launch to 30 April 2015 is 118,992 person-years (6,204,565 person-weeks).

The Company has included rhabdomyolysis/myopathy as an ADR identified during postmarketing experience in the reference safety information (Core Company Data Sheet, CCDS). The incidence of rhabdomyolysis/myopathy is estimated to be 0.52%.

Based on postmarketing surveillance, as of 01 October 2014, 26 cases of rhabdomyolysis/myopathy (all non-fatal) were identified from the Company’s safety database (SCEPTRE). Rhabdomyolysis and myopathy were analyzed together because of similar etiology and pathophysiology and frequent difficulty in differentiating clinically with overlaping

49 Approved, Date: 26 August 2015 JNJ-212082 (abiraterone acetate) Investigator's Brochure - Edition 12 diagnostic criteria (eg, creatine phosphokinase). Moreover, the search criteria applied for regulatory purposes (Medical Dictionary for Regulatory Activities [MedDRA]) use the same standardized search query for both entities, eg, MedDRA Standard Medical Query rhabdomyolysis/myopathy. Therefore, both conditions were considered together in determining the frequency.

Although hepatoxicity is an important identified risk with the use of abiraterone acetate, severe cases have been rarely reported. Since the previous IB (Edition 11), 3 postmarketing cases from Japan reported hepatotoxicity meeting the criteria for Hy’s Law; 2 life-threatening cases of fulminant hepatitis and 1 fatal case of hepatic failure. The Company could not rule out a possible causal relationship with abiraterone acetate. In 2 of the cases, the hepatotoxicity may in part be explained by a delay in, and insufficient frequency of, liver function tests and bilirubin monitoring.

Postmarketing surveillance of spontaneously reported AEs is ongoing. The surveillance of spontaneous cases of AEs reported with the use of abiraterone acetate indicates that the safety profile of the drug in postmarketed use is consistent with what is known about the drug’s overall established safety profile from clinical studies.

5. SUMMARY OF DATA AND GUIDANCE FOR INVESTIGATORS

Description of Abiraterone Acetate Tablets The chemical name of the drug substance abiraterone acetate is (3β)-17-(3-pyridinyl)androsta- 5,16-dien-3-yl acetate. The molecular weight of the drug substance is 391.55.

The investigational drug product can be supplied as oral immediate release tablets of 250-mg strength (film coated or uncoated) or 500-mg strength (film coated). The formulations should be stored as stated on the label.

Tablet formulation information is presented in Section 2.3.

Dosage and Administration The recommended dosage of abiraterone acetate is 1,000 mg as a single daily dose that must not be taken with food. It should be taken at least 2 hours after eating and no food should be eaten for at least 1 hour after taking abiraterone acetate. The tablets should be swallowed whole with water.

Abiraterone acetate is used with low-dose prednisone or prednisolone. The recommended dosage of prednisone or prednisolone is 10 mg or per protocol.

How Supplied The container/closure system for tablets consists of a HDPE bottle with a child-resistant polypropylene cap.

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Handling Based on its mechanism of action, abiraterone acetate may harm a developing fetus; therefore, women who are pregnant or women who may be pregnant should not handle uncoated abiraterone acetate tablets without protection, eg, gloves (see also Pregnancy and Lactation).

Pharmacology Abiraterone acetate is converted in vivo to abiraterone, an androgen biosynthesis inhibitor. Specifically abiraterone selectively inhibits the enzyme 17α-hydroxylase/C17,20-lyase (CYP17). This enzyme is expressed in and is required for androgen biosynthesis in testicular, adrenal and prostatic tumor tissues. It catalyzes the conversion of pregnenolone and progesterone into testosterone precursors, DHEA and androstenedione, respectively, by 17α hydroxylation and cleavage of the C17,20 bond. CYP17 inhibition also results in increased production by the adrenals.

Androgen-sensitive prostatic carcinoma responds to treatment that decreases androgen levels. Androgen deprivation therapies, such as treatment with LHRHa or orchiectomy, decrease androgen production in the testes but do not affect androgen production by the adrenals or in the tumor. Treatment with abiraterone acetate decreases serum testosterone to undetectable levels (using commercial assays) when given with LHRHa (or orchiectomy).

Pharmacokinetics The PK of abiraterone and abiraterone acetate has been studied in healthy subjects, subjects with metastatic advanced prostate cancer and subjects without cancer with hepatic or renal impairment. Abiraterone acetate is rapidly converted in vivo to abiraterone, an androgen biosynthesis inhibitor.

Absorption Following oral administration of abiraterone acetate in the fasting state, the time to reach maximum plasma abiraterone concentration is approximately 2 hours.

In healthy subjects, a single-dose of abiraterone acetate with food, compared with administration after an overnight fast, results in up to a 17-fold increase in mean systemic exposure of abiraterone, depending on the fat content of the meal. Given the normal variation in the content and composition of meals, taking abiraterone acetate with meals has the potential to result in highly variable exposures. Therefore, abiraterone acetate must not be taken with food, and should be taken at least 2 hours after eating and no food should be eaten for at least 1 hour after taking abiraterone acetate. The tablets should be swallowed whole with water.

Distribution and Protein Binding The plasma protein binding of 14C-abiraterone in human plasma is 99.8%. The apparent volume of distribution is approximately 5,630 L, suggesting that abiraterone extensively distributes to peripheral tissues.

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Bioavailability Abiraterone is rapidly absorbed and based on available data, oral bioavailability is very low.

Metabolism Following oral administration of 14C-abiraterone acetate as capsules, abiraterone acetate is hydrolyzed to abiraterone, which then undergoes metabolism including sulphation, hydroxylation and oxidation primarily in the liver. The majority of circulating radioactivity (approximately 92%) is found in the form of metabolites of abiraterone. Of 15 detectable metabolites, 2 main metabolites, abiraterone sulfate and N-oxide abiraterone sulfate, each represent approximately 43% of total radioactivity.

Elimination The mean half-life of abiraterone in plasma is approximately 15 hours based on data from healthy subjects. Following oral administration of 14C-abiraterone acetate, approximately 88% of the radioactive dose is recovered in feces and approximately 5% in urine. The major compounds present in feces are unchanged abiraterone acetate and abiraterone (approximately 55% and 22% of the administered dose, respectively).

Pharmacodynamics/Efficacy Abiraterone acetate decreases serum testosterone and other androgens to levels lower than those achieved by the use of LHRHa alone or by orchiectomy. This results from the selective inhibition of the CYP17 enzyme required for androgen biosynthesis. Prostate-specific antigen serves as a biomarker in patients with prostate cancer. In a Phase 3 clinical study of subjects who failed prior chemotherapy with docetaxel, 38% of subjects treated with abiraterone actate, versus 10% of subjects treated with placebo, had at least a 50% decline from baseline in PSA levels.

Metastatic Castration-resistant Prostate Cancer The efficacy of abiraterone acetate was established in 2 randomized, double-blind, placebo-controlled, multicenter Phase 3 clinical studies. The study population in Study COU-AA-301 had disease progression on or after receiving docetaxel-based chemotherapy.13,19 The study population of Study COU-AA-302 included subjects who were asymptomatic or mildly symptomatic with disease progression on ADT and who had not received docetaxel-based chemotherapy.51 In these 2 studies, subjects have ongoing medical castration (eg, LHRHa) or were surgically castrated. Abiraterone acetate was administered at a dose of 1,000 mg daily in combination with low-dose prednisone (or prednisolone) 5 mg twice daily. Control subjects received placebo and low dose prednisone (or prednisolone) 5 mg twice daily. Because changes in PSA serum concentration do not always predict clinical benefit, the subjects were maintained on study drugs until discontinuation criteria were met as specified for each study.

Study COU-AA-301  For Study COU-AA-301, the primary endpoint was OS. Treatment with abiraterone acetate plus prednisone prolonged OS in this patient population and reduced the risk of

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death by 26% compared with placebo plus prednisone (HR=0.740; 95% CI: 0.638, 0.859; p<0.0001). There was a 41% improvement in median survival 15.8 months in the abiraterone acetate group and 11.2 months in the placebo group).19  In addition to the observed improvement in OS for Study COU-AA-301, all secondary study endpoints favored abiraterone acetate.  Abiraterone acetate demonstrated an improvement over placebo in patient-reported pain outcomes and the time to first skeletal-reported event. Study COU-AA-302  Study COU-AA-302 had co-primary endpoints of rPFS and OS. Treatment with abiraterone acetate plus prednisone resulted in a 58% decrease in the risk of rPFS (Independent Radiology Review) compared with placebo plus prednisone (HR=0.425; 95% CI: 0.347, 0.522; p<0.0001). The median rPFS was not reached in the abiraterone acetate group and was 8.3 months in the placebo group. The results were similar and highly consistent between the independent and the investigator assessments of rPFS. The treatment effect for rPFS was statistically significant and consistently in favor of the abiraterone acetate group across all subgroups examined.  At the time of the final analysis for OS (96% of death events), treatment with abiraterone acetate plus prednisone resulted in an estimated 19.4% decrease in the risk of death compared with placebo plus prednisone (HR=0.806; 95% CI: 0.697, 0.931; p=0.0033). The result of this analysis crossed the boundary for statistical significance specified in the protocol (O’Brien Fleming efficacy boundary nominal significance level of 0.0384). The median OS was 34.7 months (95% CI: 32.72, 36.80) in the abiraterone acetate group and 30.3 months (95% CI: 28.65, 33.28) in the placebo group.  Results for all secondary endpoints including 2 endpoints that are clinically meaningful to patients (time to opiate use for cancer pain and time to cytotoxic chemotherapy) favored abiraterone acetate over placebo.  Abiraterone acetate treatment demonstrated an improvement over placebo in patient-reported pain outcomes and measures of functional status. Neoadjuvant Abiraterone Acetate Treatment (before radical prostatectomy) in High-Risk Localized Prostate Cancer Two studies of abiraterone acetate (1,000 mg orally daily) plus prednisone (5 mg orally daily) in combination with LHRHa as neoadjuvant therapy demonstrated that additional reductions in serum and intraprostatic androgens with abiraterone acetate treatment were associated with higher PSA declines.

Correlation Between Plasma and Intratumoral Testosterone Concentrations A correlation between plasma testosterone versus intratumoral testosterone concentrations has been evaluated in an open-label study.15 Sustained suppression of testosterone in both blood and bone marrow aspirate was demonstrated. Blood and bone marrow aspirate testosterone concentrations declined to picograms-per-milliliter levels following the treatment with abiraterone acetate and prednisone, and remained suppressed at progression.

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Bone Scan Flare and Discordance with Serum PSA and Clinical Response The discordance between the frequency of bone scans and PSA responses due to bone flare misinterpreted as disease progression in the first 8 to 12 weeks of therapy has been assessed in a Phase 2 multicenter, open-label study.50 In this study, bone flare was prospectively defined as discordant results after 3 months of therapy based on the combination of an interpreting radiologist’s report indicating “disease progression,” in the context of a 50% or more decline in PSA levels, which on subsequent reevalution 3 months later, showed scan improvement or stability. The conclusion from this study was that clinical responses to treatment with abiraterone acetate and prednisone were frequent and durable, with scan improvement or stability 3 months later.

Pharmacodynamic Effect of Spironolactone

Patients in pivotal clinical trials with abiraterone acetate were not allowed to use spironolactone as spironolactone binds to the androgen receptor and may increase PSA levels.

Indications and Use Abiraterone acetate is indicated in combination with prednisone or prednisolone for the treatment of patients with metastatic castration-resistant prostate cancer.

Contraindications Pregnancy or lactation

General Precautions and Warnings Hypertension, Hypokalemia and Fluid Retention due to Mineralocorticoid Excess Abiraterone acetate may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition. Co-administration of a suppresses adrenocorticotropic hormone drive, resulting in a reduction in the incidence and severity of these adverse reactions. Caution is required in treating subjects whose underlying medical conditions might be compromised by increases in blood pressure, hypokalemia, or fluid retention, eg, those with , recent myocardial infarction, or ventricular .

Abiraterone acetate should be used with caution in subjects with a history of . The safety of abiraterone acetate in subjects with left ventricular ejection fraction <50% or New York Heart Association (NYHA) Class II to IV heart failure has not been established. Before treatment with abiraterone acetate, hypertension must be controlled and hypokalemia must be corrected. Blood pressure, serum potassium, and fluid retention should be monitored at least monthly or per protocol.

Hepatotoxicity Marked increases in liver enzymes leading to drug discontinuation or dosage modification occurred in controlled clinical studies. Serum transaminase and bilirubin levels should be

54 Approved, Date: 26 August 2015 JNJ-212082 (abiraterone acetate) Investigator's Brochure - Edition 12 measured prior to starting treatment with abiraterone acetate, every 2weeks for the first 3 months of treatment, and monthly thereafter or per protocol. If clinical symptoms or signs suggestive of hepatotoxicity develop, serum transaminases, in particular serum ALT, should be measured immediately. If at any time the ALT rises >5 x ULN or the bilirubin rises >3 x ULN treatment with abiraterone acetate should be interrupted immediately and liver function closely monitored.

Re-treatment with abiraterone acetate may take place only after the return of liver function tests to the patient’s baseline and at a reduced dose level. For patients being retreated, serum transaminases and bilirubin should be monitored at a minimum of every 2 weeks for 3 months and monthly thereafter.

If subjects develop severe hepatotoxicity (ALT 20 x ULN) anytime while on therapy, abiraterone acetate should be discontinued and subjects should not be re-treated with abiraterone acetate.

There are no data on the clinical safety and efficacy of multiple doses of abiraterone acetate when administered to patients with moderate or severe hepatic impairment (Child Pugh Class B or C) (see Use in Renal/Hepatic Impairment/Failure).

Monitoring of LFTs and bilirubin as defined above in this Section is advised. Some cases of severe hepatotoxicity in Japanese patients may in part be explained by a delay in, and insufficient frequency of, LFT and bilirubin monitoring.

Corticosteroid Withdrawal and Coverage of Stress Situations Caution is advised and monitoring for adrenocortical insufficiency should occur if patients need to be withdrawn from prednisone or prednisolone. If abiraterone acetate is continued after are withdrawn, patients should be monitored for symptoms of mineralocorticoid excess.

Use with Chemotherapy Based on the results from the Phase 1b Study COU-AA-206, abiraterone acetate and docetaxel can be combined at their respective approved doses.

Drug Interactions In vitro, abiraterone was shown to inhibit the hepatic drug-metabolizing enzymes CYP1A2, CYP2D6, and CYP2C8. In a clinical study to determine the effects of abiraterone acetate (plus prednisone) on a single dose of the CYP1A2 substrate theophylline, no increase in systemic exposure of theophylline was observed.

In the same study to determine the effects of abiraterone acetate (plus prednisone) on a single dose of the CYP2D6 substrate dextromethorphan, the systemic exposure (AUC) of dextromethorphan was increased by approximately 200%. The AUC24 for dextrorphan, the active metabolite of dextromethorphan, increased approximately 33%.

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Caution is advised when abiraterone acetate is administered with drugs activated by or metabolized by CYP2D6, particularly with drugs that have a narrow therapeutic index. Dose reduction of narrow therapeutic index drugs metabolized by CYP2D6 should be considered.

In a CYP2C8 drug-drug interaction trial in healthy subjects, the AUC of pioglitazone was increased by 46% and the AUCs for M-III and M-IV, the active metabolites of pioglitazone, each decreased by 10%, when pioglitazone was given together with a single dose of 1,000 mg abiraterone acetate. Patients should be monitored closely for signs of toxicity related to a CYP2C8 substrate with a narrow therapeutic index if used concomitantly with abiraterone acetate.

In vitro, abiraterone and its 2 major metabolites (abiraterone sulfate and N-oxide abiraterone sulfate), inhibited OATP-mediated substrate uptake in hepatocytes. There are no clinical data available to confirm transporter-based interaction.

In a clinical PK interaction study of healthy subjects pretreated with a strong CYP3A4 inducer (rifampicin, 600 mg daily for 6 days) followed by a single dose of abiraterone acetate 1,000 mg, the mean plasma AUC∞ of abiraterone was decreased by 55%. Strong inducers of CYP3A4 (eg, phenytoin, carbamazepine, rifampicin, rifabutin, rifapentine, phenobarbital) during treatment with abiraterone acetate are to be avoided.

In a separate clinical PK interaction study of healthy subjects, coadministration of ketoconazole, a strong inhibitor of CYP3A4, had no clinically meaningful effect on the PK of abiraterone.

Carcinogenicity and Genotoxicity No increase in tumors was observed in a 6-month transgenic mouse GLP carcinogenicity. In a 2-year rat GLP carcinogenicity study, there was an increased incidence of testicular interstitial (Leydig) cell adenomas and carcinomas; however, this finding was considered rat-specific and related to the pharmacological activity of abiraterone acetate.

Abiraterone acetate and abiraterone were devoid of genotoxic potential in the standard panel of genotoxicity tests, including an in vitro bacterial reverse mutation assay (the Ames test), an in vitro mammalian chromosome aberration test (using human lymphocytes), and an in vivo rat micronucleus assay.

Pregnancy and Lactation Abiraterone is contraindicated in women who are or may potentially be pregnant (see Contraindications). There are no human data on the use of abiraterone acetate in pregnancy. Maternal use of a CYP17 inhibitor is expected to produce changes in hormonal levels that may affect the development of the fetus.

In an oral developmental toxicity study in the rat, abiraterone affected pregnancy.

It is not known whether abiraterone or its metabolites are present in semen. A condom is required if the subject is engaged in sexual activity with a pregnant woman. If the subject is

56 Approved, Date: 26 August 2015 JNJ-212082 (abiraterone acetate) Investigator's Brochure - Edition 12 engaged in sex with a woman of childbearing potential, a condom is required along with another effective contraceptive method.

To avoid inadvertent exposure, women who are pregnant or women who may be pregnant should not handle uncoated abiraterone acetate tablets without protection, eg, gloves. It is not known if either abiraterone acetate or its metabolites are excreted in human breast milk.

Antigenicity and Immunogenicity Antigenicity and immunogenicity were not evaluated.

Geriatric Use Of the subjects in the two Phase 3 studies of abiraterone acetate (Studies COU-AA-301 and COU-AA-302), the median age was 70 years for each combined treatment group, with 30.0% of subjects in the combined abiraterone acetate group and 29.2% of subjects in the combined placebo group 75 years of age. Subjects enrolled to Study COU-AA-302 were slightly older than subjects enrolled to Study COU-AA-301, as assessed by both median age and proportion of subjects 75 years of age. Demographic characteristics were otherwise comparable across the 2 individual studies. No overall differences in safety or effectiveness were observed between these elderly subjects and younger subjects.

Pediatric Use Abiraterone acetate is not indicated for pediatric use.

Use in Renal/Hepatic Dysfunction/Failure Administration of abiraterone acetate in subjects with renal impairment including severe renal impairment does not require dose reduction.

The PK of abiraterone was examined in subjects with pre-existing mild or moderate hepatic impairment (Child-Pugh Class A and B, respectively) and in healthy control subjects. Systemic exposure to abiraterone after a single oral 1,000 mg dose increased by approximately 11% and 260% in subjects with mild and moderate pre-existing hepatic impairment, respectively. The mean half-life of abiraterone was prolonged to approximately 18 hours in subjects with mild hepatic impairment and to approximately 19 hours in subjects with moderate hepatic impairment. No dosage adjustment was necessary for subjects with pre-existing mild hepatic impairment.

There are no data on the clinical safety and efficacy of multiple doses of abiraterone acetate when administered to patients with moderate or severe hepatic impairment (Child Pugh Class B or C). No dose adjustment can be predicted. Abiraterone acetate should be used with caution in patients with moderate hepatic impairment only if the benefit clearly outweighs the possible risk. Abiraterone acetate should not be used in patients with severe hepatic impairment.

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Adverse Drug Reactions The most common ADRs observed with abiraterone acetate are peripheral edema, hypokalemia, , ALT and AST increased, dyspepsia, hematuria, hypertension, and fractures. The incidence of cardiac disorders occurred at <5%.

Abiraterone acetate may cause hypertension, hypokalemia, and fluid retention as a pharmacodynamic consequence of its mechanism of action. Mineralocorticoid effects were seen more commonly in subjects treated with abiraterone acetate: fluid retention (peripheral edema) 26%, hypokalemia 21%, and hypertension 16%. In subjects treated with abiraterone acetate, Grades 3 and 4 hypokalemia and Grades 3 and 4 hypertension were observed in 3% and 2% of subjects, respectively. Mineralocorticoid effects in general, were successfully managed medically. Concomitant use of a corticosteroid reduces the incidence and severity of these ADRs.

Two Phase 3 studies were conducted. Study COU-AA-301 enrolled subjects with metastatic advanced prostate cancer who were using an LHRHa or were previously treated with orchiectomy. Abiraterone acetate was administered at a dose of 1,000 mg daily in combination with low dose prednisone or prednisolone (10 mg daily) in the active treatment arm; placebo plus low dose prednisone or prednisolone (10 mg daily) was given to control subjects. Subjects enrolled were intolerant to or had failed up to 2 prior chemotherapy regimens, 1 of which contained docetaxel. Study COU-AA-302 subjects also followed the same dosing regimen but were asymptomatic or mildly symptomatic and had not received chemotherapy prior to study treatment.

Median duration of treatment exposure was longer for the abiraterone acetate group versus the placebo group within Studies COU-AA-302 (13.8 months and 8.3 months, respectively) and COU-AA-301 (7.4 months and 3.6 months, respectively), and longer for both treatment groups in Study COU-AA-302 versus Study COU-AA-301.

Cardiovascular Effects Phase 3 studies excluded subjects with uncontrolled hypertension, clinically significant heart disease as evidenced by myocardial infarction, arterial thrombotic events in the past 6 months, severe or unstable , NYHA Class II to IV (Study COU-AA-302) or III or IV (Study COU-AA-301) heart disease or cardiac ejection fraction measurement of <50%. All subjects enrolled (both active and placebo-treated patients) were concomitantly treated with ADT, predominantly with the use of an LHRHa, which has been associated with diabetes, myocardial infarction, cerebrovascular accident, and sudden cardiac death. The incidence of cardiac disorder events were reported for 219 (16%) subjects in the combined abiraterone acetate group and 122 (13%) subjects in the combined placebo group.

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Other Effects Effects on the QT Interval In Study COU-AA-006, a cardiovascular safety study in subjects with metastatic advanced prostate cancer there were no significant effects of abiraterone acetate on the cardiac QT/QTc interval.

Overdosage and Abuse Potential Human experience of overdose with abiraterone acetate is limited. There is no specific to abiraterone acetate. In the event of an overdose, administration of abiraterone acetate should be stopped and general supportive measures undertaken, including monitoring for . Liver function also should be assessed.

In conclusion, the overall benefit-risk assessment for abiraterone acetate is favorable when used as recommended in the currently approved indication.

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6. REFERENCE SAFETY INFORMATION The sponsor’s medical experts evaluated safety data from clinical studies (See Appendix D) up to 27 April 2015 using the following definition of adverse drug reactions (ADRs) from the International Conference on Harmonisation (ICH) guideline entitled, E6: Good Clinical Practice, Consolidated Guideline30,31:

"In the preapproval clinical experience with a new medicinal product or its new usages, particularly as the therapeutic dose(s) may not be established, all noxious and unintended responses to a medicinal product related to any dose should be considered adverse drug reactions. The phrase “responses to a medicinal product” means that a causal relationship between a medicinal product and an adverse event is at least a reasonable possibility, ie, the relationship cannot be ruled out.

“Regarding marketed medicinal products: a response to a drug which is noxious and unintended and which occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of diseases or for modification of physiological function (see the ICH Guideline for Clinical Safety Data Management: Definitions and Standards for Expedited Reporting [ICH 1994]).”

The ADRs listed Table 11 below were classified according to frequency and system organ class. The frequency categories are defined in the footnote of the table as very common, common, uncommon, rare, and very rare.

Details of anticipated adverse events (adverse experiences [serious or non-serious]) that commonly occur in the study population, background regimen, or are known consequences of the underlying disease (disease-related) or condition under investigation (eg, symptoms, disease progression), have been provided separately in the protocols.

The integrated ADR summary (Table 11) comes from subjects who received 1,000 mg of abiraterone acetate. Appendix D.1 provides a summary of all AEs by toxicity grade where combined abiraterone acetate is at least 1% greater than combined placebo. Allergic alveolitis and rhabdomyolysis/myopathy were identified as ADRs during the postmarking experience.

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Table 11: Adverse Drug Reactions Associated with Abiraterone Acetate (ZYTIGA®)

Infections and infestations very common: urinary tract infection Endocrine disorders uncommon: Metabolism and nutrition disorders very common: hypokalaemia common: hypertriglyceridaemia Musculoskeletal and connective tissue disorders uncommon: rhabdomyolysis/myopathy Cardiac disorders common: cardiac failurea, angina pectoris, arrhythmia, , Vascular disorders very common: hypertension Gastrointestinal disorders common: dyspepsia Hepatobiliary disorders common: alanine aminotransferase increased, aspartate aminotransferase increased Renal and urinary disorders common: haematuria General disorders and administration site conditions very common: oedema peripheral Injury, poisoning and procedural complications common: fracturesb Respiratory, Thoracic and Mediastinal Disorders very rare: allergic alveolitis IB Edition 12, Effective Date: 26 August 2015 a Cardiac failure also includes congestive heart failure, left ventricular dysfunction and ejection fraction decreased b Fractures includes all fractures with the exception of pathological fracture The preferred terms presented in this table are ordered by seriousness within each frequency grouping. Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000).

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REFERENCES 1. Achyara M, Gonzalez M, DeVries R, et al. A phase I, open-label, single-dose mass balance study 14C-labeled abiraterone acetate in healthy male subjects. Xenobiotica 2013;43:379-389. 2. Achyara M, Bernard A, Gonzalez M, et al. Open-label, phase I, pharmacokinetic studies of abiraterone acetate in healthy men. Cancer Chemother Pharmacol 2012;69:1583-1590. 3. Attard G, Reid AHM, Yap T, et al. Phase I clinical trial of selective inhibitor CYP17 abiraterone acetate, confirms that castration-resistant prostate cancer commonly remains hormone driven. J Clin Onc 2008; 26 (28): 4563-4571. 4. Attard G, Reid AHM, A’Hern R et al. Selective inhibitor of CYP17 with abiraterone acetate is highly active in the treatment of castration-resistant prostate cancer. J Clin Onc 2009;27(23):3742-3748. 5. Barrie SE, Potter GA, Goddard PM, et al. Pharmacology of novel steroidal inhibitors of cytochrome P450(17) alpha (17 alpha-hydroxylase/C17-20 lyase). J Steroid Biochem Mol Biol 1994;50:267-273. 6. Bruchovsky N, Wilson JD. The conversion of testosterone to 5-alpha-androstan-17-beta-ol-3-one by rat prostate in vivo and in vitro. J Biol Chem 1968;243:2012-2021. 7. Cetin K, Beebe-Dimmer JL, Fryzek JP, Markus R, Carducci MA. Recent time trends in the epidemiology for stage IV prostate cancer in the United States: Analysis of data from the surveillance, epidemiology and end results program. Urology 2010;75:1396-1405. 8. Chang K-H, Li R, Kuri B, et al. A gain-of-function mutation in DHT synthesis in castration-resistant prostate cancer. Cell 2013;154:1074-1084. 9. Chi KN, Tolcher A, Lee P, et al. Effect of abiraterone acetate plus prednisone on the pharmacokinetics of dextromethorphan and theophylline in patient with metastatic castration-resistant prostate cancer. Cancer Chemother Pharmacol. 2013;71:237-244. 10. Chen CD, Welsbie DS, Tran C, et al. Molecular determinants of resistance to therapy. Nat Med 2004; 10:33-39. 11. Clegg N, Wongvipat J, Joseph J, et al. Discovery and development of ARN 509, a novel anti-androgen for the treatment of prostate cancer. Cancer Res 2012; 2:1-10. 12. Danila DC, Morris MJ, de Bono JS, et al. Phase II multicenter study of abiraterone acetate plus prednisone therapy in patients with docetaxel-treated castration-resistant prostate cancer. J Clin Oncol 2010;28:1496-1501. 13. de Bono JS, Logothethis CJ, Molina A, et al. Abiraterone and increased survival with metastatic prostate cancer. New England J Med 2011;364(21):1995-2005. 14. Duc I, Bonnet P, Duranti V, et al. In vitro and in vivo models for the evaluation of potent inhibitors of male rat 17alpha-hydroxylase/C17,20-lyase. J Steroid Biochem Mol Biol 2003;84:537-542. 15. Efstathiou E, Titus M, Tsavachidou D, et al. Effects of abiraterone on androgen signaling in castrate resistant prostate cancer in bone. J Clin Onc 2012;30(6): 637-643. 16. Efstathiou E, Titus M, Wen AS, et al. The effects of enzalutamide (ENZA) in combination with abiraterone acetate (AA) in patients with bone metastatic castration resistant prostate cancer (mCRPC). Presented at: European Cancer Congress 2013; September 27-October 1, 2013; Amsterdam, The Netherlands. Abstract 2854. 17. Eliassen AH, Missmer SA, Tworoger SS. Endogenous steroid hormone concentrations and risk of breast cancer among premenopausal women. J Natl Cancer Inst. 2006;98:1406. 18. Flamand V et al. Observational survey on variations of prostate cancer incidence by stage in the Nord-Pas-de- Calais region between 1998 and 2004. Prog Urol. 2008;18:53-9. 19. Fizazi, K, Scher HI, Molina A, et al. Abiraterone acetate for treatment of metastatic castration resistant prostate cancer: final overall survival analysis of the COU-AA-301 randomised, double-blind, placebo- controlled phase 3 study. Lancet Oncol 2012;13:983-989. 20. Gandaglia G, Karakiewicz PI, Briganti A, et al. Impact of the site of metastases on survival in patients with metastatic prostate cancer. Eur Urol (2014), http://dx.doi.org/10.1016/j.eururo.2014.07.020.

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21. Global Medical Safety Review of Cases Reporting Possible Increased Risk of Disease Progression in the Setting of Co-administration of Spironolactone and Abiraterone Acetate, 20 March 2015. Document ID No.: EDMS-ERI-97610155. 22. Gregory CW, He B, Johnson RT, Ford OH, Mohler JL, French FS, and Wilson EM. A mechanism for androgen receptor-mediated prostate cancer recurrence after androgen deprivation therapy. Cancer Res 2001; 61:4315-4319. 23. Gregory CW, Johnson RT, Jr, Mohler JL, et al. Androgen receptor stabilization in recurrent prostate cancer is associated with hypersensitivity to low androgen. Cancer Res 2001;612892-2898. 24. Hackenberg R and Schulz KD. Androgen receptor mediated growth control of breast cancer and endometrial cancer modulated by antiandrogen- and androgen-like . J Steroid Biochem Mol Bol 1996;56:113-117. 25. Haidar S, Ehmer PB and Hartmann RW. Novel steroidal pyrimidyl inhibitors of P450 17 (17 alpha- hydroxylase/C17-20-lyase). Arch Pharm (Weinheim) 2001;334:373-374. 26. Haidar S, Ehmer PB, Barassin S, et al. Effects of novel 17alpha-hydroxylase/C17, 20-lyase (P450 17, CYP 17) inhibitors on androgen biosynthesis in vitro and in vivo. J Steroid Biochem Mol Biol 2003;84:555-562. 27. Hankinson SE, Willett WC, Manson JE, et al. Plasma sex steroid hormone levels and risk of breast cancer in postmenopausal women. J Natl Cancer Inst 1998;90:1292-1299. 28. Harland S, Bono JSd, Haqq C, et al. Abiraterone acetate improves functional status in patients with metastatic castration-resistant prostate cancer post-docetaxel: results from the COU-AA-301 phase 3 study. Eur J Cancer. 2011;47:S484 29. Howard GCW et al. Patterns of referral, management and survival of patients diagnosed with prostate cancer in Scotland during 1988 and 1993: results of a national retrospective population-based audit. BJUI. 2001;87:339-347. 30. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH harmonized tripartite guideline.Clinical Safety Data Management: Definitions and Standards for Expedited Reporting, E2A, 27 October 1994. Available at: http://www.ich.org/fileadmin/Public_Web_Site/ ICH_Products/Guidelines/Efficacy/E2A/ Step4/E2A_Guideline.pdf. Accessed on 16 June 2015. 31. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH harmonized tripartite guideline. Guideline for Good Clinical Practice, E6(R1), 10 Jun 1996. Available at http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/ E6/E6_R1_Guideline.pdf;1-53. Accessed on 16 June 2015. 32. Ideyama Y, Kudoh M, Tanimoto K, et al. Novel inhibitor of cytochrome P450(17alpha) (17alpha- hydroxylase/C17-20 lyase), YM116, decreased prostatic weights by reducing serum concentrations of testosterone and adrenal androgens in rats. Prostate 1998;37:10-18. 33. Jack R et al. Prostate cancer incidence, stage at diagnosis, treatment and survival in ethnic groups in South- East England. BJUI. 2009;105:1226-1230. 34. Jarman M, Barrie SE and Llera JM. The 16,17-double bond is needed for irreversible inhibition of human cytochrome p45017alpha by abiraterone (17-(3-pyridyl)androsta-5, 16-dien-3beta-ol) and related steroidal inhibitors. J Med Chem 1998;41:5375-5381. 35. Jonsson E et al. Adenocarcinoma of the prostate in Iceland: a population-based study of stage, Gleason grade, treatment and long-term survival in males diagnosed between 1983 and 1987. Scandinavian Journal of Urology and Nephrology. 2006;40:265-271. 36. Kaaks R, Rinaldi S, Key TJ, et al. Postmenopausal serum androgens, oestrogens and breast cancer risk: The European prospective investigation into cancer and nutrition. Endocr Relat Cancer 2005;12:1071-1082. 37. Key T, Appleby P, Barnes I, Reeves G; Endogenous and Breast Cancer Collaborative Group. Endogenous sex hormones and breast cancer in postmenopausal women: Reanalysis of nine prospective studies. J Natl Cancer Inst 2002;94:606-616. 38. Labrie F, Dupont A, Belanger A, et al. New approach in the treatment of prostate cancer: complete instead of partial withdrawal of androgens. Prostate 1983;4:579-594.

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39. Logothetis C, Basch E, Molina A, et al. Effect of abiraterone acetate and prednisone compared with placebo and prednisone on pain control and skeletal-related events in patients with metastatic castration-resistant prostate cancer: exploratory analysis of data from the COU-AA-301 randomised trial. Lancet Oncol 2012;13:1210-1217. 40. Maggiolini M, Donze O, Jeannin E, et al. Adrenal androgens stimulate the proliferation of breast cancer cells as direct activators of . Cancer Res 1999;59:4864-4869. 41. Millikan RE, Wen S, Pagliaro LC, et al. Phase 3 trial of androgen ablation with or without three cycles of systemic chemotherapy for advanced prostate cancer. J Clin Oncol 2008;26:5936-5942. 42. Mohler JL, Gregory CW, Ford OH. III, et al. The androgen axis in recurrent prostate cancer. Clin Cancer Res 2004;10:440-448. 43. Montgomery B, Mostaghel E, Vesella R, et al. Maintenance of intratumoral androgens in metastatic prostate cancer: A mechanism for castration-resistant tumor growth. Cancer Res 2008;68:4447-4454. 44. Montgomery B, Mostaghel E, Nelson P, et al. Abiraterone suppresses castration resistant human prostate cancer growth in the absence of testicular and adrenal androgens. Am Assoc Cancer Res Special Conference 2009: Advances in Prostate Cancer Research, San Diego, CA, January 21-24. 45. O’Donnell A, Judson I, Dowsett M, et al. Hormonal impact of the 17alpha-hydroxylase/C(17,20)-lyase inhibitor abiraterone acetate (CB7630) in patients with prostate cancer. Br J Cancer 2004;90:2317-2325. 46. Ogawa Y, Hai E, Matsumoto K, et al. Androgen receptor expression in breast cancer: Relationship with clinicopathological factors and biomarkers. Int J Clin Oncol 2008;13:431-435. 47. Reid AH, Attard G, Danila DC, et al. Significant and sustained antitumor activity in post-docetaxel, castration-resistant prostate cancer with the CYP17 inhibitor abiraterone acetate. J Clin Oncol 2010;28:1489-1495. 48. Richards J, Lim AC, Hay CW, Taylor AE, Wingate A, Nowakowska K, et al. Interactions of abiraterone, eplerenone and prednisolone with wild-type and mutant androgen receptor: a rationale for increasing abiraterone exposure or combining with MDV3100. Cancer Res 2012;72(9):2176-2182. 49. Ryan CJ, Smith MR, Fong L, et al. Phase I clinical trial of the CYP17 inhibitor abiraterone acetate demonstrating clinical activity in patients with castration-resistant prostate cancer who received prior ketoconazole therapy. J Clin Oncol 2010;28:1481-1488. 50. Ryan CJ, Shah SK, Efstathiou E, et al. Phase II study of abiraterone acetate in chemotherapy-naiive metastatic castration-resistant prostate cancer displaying bone flare discordant with serologic response. Clin Can Res 2011;17:4854-4861. 51. Ryan CJ, Smith MR, de Bono JS, et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Eng J Med 2013;368:138-148. 52. Ryan CJ, Smith MR, Fizazi K, et al. Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men with metastatic castration-resistant prostate cancer (COU-AA-302): final overall survival analysis of a randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol 2015;16(2):152-160. 53. Saunders FJ. Some aspects of relation of structure of steroids to their prostate-stimulating effects. Natl Cancer Inst Monogr 1963;12:139-159. 54. Sternberg CN, Molina A, North S, et al. Effect of abiraterone acetate on fatigue in patients with metastatic castration-resistant prostate cancer after docetaxel chemotherapy. Ann Oncol 2013;24:1017-1025. 55. Stigliano A, Gandini O, Cerquetti L, et al. Increased metastatic lymph node 64 and CYP17 expression are associated with high stage prostate cancer. J Endocrinol 2007;194:55-61. 56. Tangen CM, Faulkner JR, Crawford Ed, Thompson IM, Hirano D, Eisenberger M, Hussain M. Ten-year survival in patients with metastatic prostate cancer. Clin Prostate Cancer 2003;2:41-45. 57. Taxotere (2010) Package Insert. Bridgewater, NJ: Sanofi-Aventis LLC; 2010. 58. Tolcher AW, Cooper J. Castration-resistant prostate cancer-hormone therapy redux. J Clin Oncol 2010;28:1447-1449. 64 Approved, Date: 26 August 2015 JNJ-212082 (abiraterone acetate) Investigator's Brochure - Edition 12

APPENDIX A Figure A.1: The Molecular Structure of Abiraterone Acetate

N

C18 C12 C17 C11 (E) (S) C13 C19 H C16 C1 (S) C9 C14 (S) C2 C15 O (R) C10 C8 (R) H H (S) C3 C7 C5 (Z) O C4 C6

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Appendix A.1: Single and Repeated Oral Dose GLP Toxicity Studies Study Species/Strain Dose Levels Major Findings Number/Sex Single Oral Dose Toxicity An acute gastric irritation study of Mice (MF1) Oral gavage 800 mg/kg -Animal deaths: control (4/10) and study treatment (2/10) groups (necropsy revealed CB7630 in mice 10M esophageal injury during dosing and infiltration of dosing material into the pleural cavity) -No treatment-related effects in the GI tract -No abnormalities in the viscera or in the general condition of the animals A single dose toxicity study of Rats (Wistar) Oral gavage 400 mg/kg -No animal deaths abiraterone acetate in rats 10 M -No visceral abnormalities (Day 14) -No changes in the condition or behaviors of the animals NOAEL for acute toxicity >400 mg/kg (2400 mg/m²) Repeated Oral Dose Toxicity A 28-day repeated-dose toxicity Mice (CByB6F1) Oral gavage, QD for 28 - No mortality and toxicokinetic study of TOX: 10 M + 10 F/ group; days - Decreased motor activity, ruffled fur and hunched appearance (only males, abiraterone acetate in mice TK: 24 M + 24 F/group (6 M 0, 125, 375, 750 or 1500 mg/kg/day) + 6 F in vhecile group)/ 1500 mg/kg/day - Increased BWG (all doses) and BW (≥ 750 mg/kg/day) - Decrease in RBC, HCT, HGB (only males, all doses except in the 375 mg/kg/day group) and other minor alterations in hematology at 1500 mg/kg/day (decrease in MCHC and increase in RDW, platelet count and platelet volume) - Increase in bilirubin, ALT, AST (1500 mg/kg/day) and other minor alterations in biochemistry from 125 mg/kg/day (decrease in potassium and phosphate, increase in ALP, cholesterol, total protein and albumin) - Liver (all doses): increased weights, centrilobular hypertrophy, subacute/periportal inflammation and/or necrosis - Spleen (males ≥ 750 mg/kg/day, females ≥ 375 mg/kg/day: increased weights and/or, extramedulary hematopoiesis - Testes (all doses): small, decreased weights, degeneration/atrophy and/or increased interstitial cells - Epididymides (1500 mg/kg/day): accumulation of cellular debris with oligospermia - Uterus (≥ 375 mg/kg/day): thinning and/or atrophy - Vagina (all doses): staging - Ovary (≥ 750 mg/kg/day): persistent corpus luteum

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Appendix A.1: Single and Repeated Oral Dose GLP Toxicity Studies Study Species/Strain Dose Levels Major Findings Number/Sex

A 26-week Mouse (Tg.rasH2) Oral gavage, QD for 26 - No increase in the incidence of neoplastic lesions up to 750 mg/kg/day (M/F Day 176 (6-month) repeated dose oral (25M+ 25F/group) weeks AUC0-24h 5690/6565 ng.h/mL) carcinogenicity study in Tg.rasH2 125/375/750 mg/kg/day - Liver, spleen, non-glandular stomach, pituitary, adrenal glands, male and female genital mice tracts were identified as target organs for non-neoplastic lesions - No treatment-related ophthalmic abnormalities A 28-day repeated-dose toxicity Rat (Wistar) Oral gavage, QD for 28 -No animal deaths and toxicokinetic study of 10 M/group days -Treatment-related clinical signs of small lesion and red staining at 400 mg/kg/day and abiraterone acetate in rats, 40/126/ 400 mg/kg/day poor condition at 126 mg/kg/day followed by a 28-day recovery -Lower RBC (126 and 400 mg/kg/day) and lower haematocit (126 mg/kg/day) on Day 56 period -Absolute and relative liver, spleen, and thymus weights higher at 126 and 400 mg/kg/day (400 mg/kg/d dose showed liver hypertrophy and vacuolation) -Testes (interstitial cell hyperplasia reduction in spermatogenesis and tubular atrophy) -Reversible (Day 56) seminal vesicle and prostate changes (atrophy) -Microscopic changes in the liver, testes and lungs at 400 mg/kg/day (only pigmented macrophage in the lung unresolved after the recovery period) -Day 28 abnormal liver function test with 126 and 400 mg/kg/day; normalized by Day 56 -At 400 mg/kg/day histopathological changes in reproductive tract, liver, adrenals and spleen but not observed after recovery period. TK: Cmax and exposure (AUC) did not increase in a linear fashion with dose -Plasma concentrations lower at Day 27 than Day 4

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Appendix A.1: Single and Repeated Oral Dose GLP Toxicity Studies Study Species/Strain Dose Levels Major Findings Number/Sex

A 28-day repeat dose toxicity Rat/Sprague-Dawley Oral gavage, QD for 28 -No animal deaths or clinical signs. study of abiraterone acetate, with (10 M/group) days -Minor alterations in hematology and clinical chemistry at 400 mg/kg/day (albumin, total a 28-day recovery period, in rats 40/126/ 400 mg/kg/day protein, ALP). -Absolute and relative liver, spleen and thymus weights increased at 126 and 400 mg/kg/day. (liver weight reversed following treatment cessation but not thymus weight). -At 400 mg/kg/d, the target organs for toxicity were the reproductive organs and the pituitary gland. -Absolute and relative testes, , and prostate weights decreased in a dose- dependent manner and correlated microscopically with Leydig cell -Hyperplasia and reduced spermatogenesis -Hyperplasia of Leydig’s cells and anterior pituitary -Decreased secretion of the prostate and seminal vesicles -Mammary gland atrophy reduced in frequency and severity at the end of observation period -Reduced spermatogenesis of the testes at all doses but fully reversed by the end of recovery phase -Testicular weight, but not of secondary sex organs, fully reversed after dosing stopped. -Mononuclear cell infiltration of the prostate observed at all dose levels. -Increased liver weight did not correlate with histopathological lesions - No lesions were identified in the liver, spleen, lung, thymus, or adrenals -Reversible absence of spermatozoa in the urine at 400 mg/kg/day -Testosterone levels reduced in a dose-dependent manner

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Appendix A.1: Single and Repeated Oral Dose GLP Toxicity Studies Study Species/Strain Dose Levels Major Findings Number/Sex A 28-day repeated dose toxicity Cynomolgus monkeys Oral gavage -No animal deaths study, with abiraterone acetate, in 3+2M QD for 28 days -No clinical signs or body weight changes the cynomolgus monkey with a 4- 3+2F 0, 2, 10, 50, 250, or -Reversible changes in bilirubin, glucose, cholesterol, and ALP (except for bilirubin, in week recovery phase 1000 mg/kg/day males, dosed at 250 and 1000 mg/kg/day) -Thymus and adrenal weights increased in males at doses of 10 mg/kg/d and higher -Liver weight increased at 250 mg/kg/d (males) and at 1000 mg/kg/d (males and females); testicular volume decreased at doses of 10 to 1000 mg/kg/day and testicular weight at doses of 50 to 1000 mg/kg/day (reversible) -Reversible changes in the adrenals, and partially reversible changes in the mammary glands of male animals -Changes in the reproductive organs -Reversible changes in several hormones, in males and females were observed -Reversible microscopic changes in the adrenals, mammary glands, and reproductive organs (prostate, seminal vesicles, ovaries, and uterus) -Testosterone levels variable but were reduced in 3 or 4 out of 5 animals in 250 and 1000 mg/kg/day groups -NOAEL was 1000 mg/kg/day for both male and female animals

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Appendix A.1: Single and Repeated Oral Dose GLP Toxicity Studies Study Species/Strain Dose Levels Major Findings Number/Sex 13-week repeated oral dose Sprague Dawley rats Oral gavage -Two rounds of treatment related early deaths in the 2000/750 mg/kg/day group studies with 4-week recovery 15+5 M QD for 13 weeks -Clinical signs of toxicity in animals given 2000/750 mg/kg/day included hunched period in rats, with abiraterone 15+5 F start dose: 250, 750 and appearance, swollen midline ventral abdomen, thin appearance, pale body, rough haircoat, acetate 2000 mg/kg/day red haircoat, and few feces (all abnormal clinical signs disappeared by Day 11 of the with dose reduction as of recovery phase); no treatment-related clinical signs for the low and mid dose animals Days 10 and 9 for M & F, -Lower body weight and food consumption mid and high dose male rats resp: 50, 250 and -Decreased RBC count at all dose levels (male rats) 750 mg/kg/day -Reversible (after recovery period) increase in total protein (albumin fraction)-male & female rats -Reversible (after recovery period) increased bilirubin and alkaline phosphatase -Reversible (after recovery period) decrease in cholesterol and triglyceride in both males and females -Reversible (after recovery period) increase in LH at all dose levels in male rats -Reversible (after recovery period) decrease in testosterone levels at 750/250 mg/kg/day -Increase in liver weight (males and females) at doses higher than 750/250 mg/kg/day -Increased weights of adrenal (males only), thymus (males and females), and pituitary (males only) glands at all dose levels (except for thymus weight in females at 250/50 mg/kg/day) -Reduced testes, prostate, seminal vesicle, epididymus, uterus at all dose levels and did not recover by the recovery phase sacrifice -Treatment-related microscopic findings at the dosing phase sacrifice in pituitary, mammary gland, seminal vesicles, prostate, testis, epididymus and heart of males; ovaries, uterus and cervix of females; and lung and liver (bile duct hyperplasia) of males and females. -Treatment-related adverse anatomic pathology changes present in animals at all doses -Because of higher incidence of minimal to slight bile duct hyperplasia, the NOAEL is undetermined but < 250/50 mg/kg/day for male and female rats -Plasma concentration of abiraterone acetate did not increase in a linear fashion with dose. Plasma concentrations were lower at Week 13 than Day 1

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Appendix A.1: Single and Repeated Oral Dose GLP Toxicity Studies Study Species/Strain Dose Levels Major Findings Number/Sex A 104-week Crl:CD(SD) rats Oral gavage, QD for 104 - Increase in the incidence of testicular interstitial cell adenomas in all treated male groups (2-year) repeated dose oral (65M+ 65F/group) weeks and interstitial cell carcinomas at 15 and 50 mg/kg/day carcinogenicity study in rats M:5/15/50 mg/kg/day - Lower overall mortality in all treated female groups as compared to vehicle. F:15/50/150 mg/kg/day - Dose dependent reduction in the incidence of pituitary adenomas and mammary tumours in females - Liver, adrenal glands and male and female genital tracts were identified as target organs for non-neoplastic lesions - Earlier onset of posterior subcapsular opacities in the lens in M (50 mg/kg/day, faint to moderate in severity in Weeks 50 and 79) and F (150 mg/kg/day, slight severity in Week 79). No treatment-related ophthalmic findings at the end of the study. - M Day 181 AUC0-24h 809 ng.h/mL (50 mg/kg/day) - F Day 181 AUC0-24h 830 ng.h/mL (150 mg/kg/day) 13-week repeated oral-dose Cynomolgus monkeys Oral gavage -No mortalities toxicity and toxicokinetic study, 4+3 M/F QD for 13 weeks -white colored vomit and feces with CB7630, in monkeys with a 4 M/F 250, 750 and -Reversible higher triglyceride and total bilirubin at all dose levels 4-week recovery period 4 M/F 2000 mg/kg/day -Lower cortisol, testosterone, DHEA, and higher ACTH, LH, , and 4+3 M/F progesterone levels-all dose -Clinical pathology findings reversible during the 4-week recovery phase -Increase in mean absolute liver weight was dose-responsive in males given 750 and 2000 mg/kg/d and all doses in females -Increase in weights of liver and gallbladder correlated with microscopic findings of minimal hepatocyte hypertrophy and minimal, slight or moderate bile duct hyperplasia -Bile duct hyperplasia partially reversible during the recovery period -Increase in mean adrenal weights in all animals Because of higher incidence of minimal to slight bile duct reaction, the NOAEL for abiraterone acetate is < 250 mg/kg/day for male and female cynomolgus monkeys Plasma concentration of abiraterone did not increase in a linear fashion with dose. Plasma concentrations were lower at Week 13 than Day 1. 26-Week Oral Gavage Toxicity Crl:CD(SD) Oral gavage Toxicity profile in line with that of the 13-week rat study. In addition, cataracts were seen and Toxicokinetic Study with 155 males QD for 26 weeks at the end of the treatment period at all dose levels in males (50 mg/kg/day) and from CB7630 in Rats with a 4-Week 155 females 0, 50, 150, 400 mg/kg/day 150 mg/kg/day in female rats and did not reverse after a 4-week recovery period. The Recovery Period NOAEL was not established for males, whereas it was 50 mg/kg/day in female rats. Cataract findings were considered to be rat specific as no cataracts were found in the monkey.

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Appendix A.1: Single and Repeated Oral Dose GLP Toxicity Studies Study Species/Strain Dose Levels Major Findings Number/Sex 39-Week Oral Gavage Toxicity Cynomolgus monkeys Oral gavage, Toxicity in line with the 13-week study and pharmacological action of the compound. Study with CB7630 in 22 female 0, 250, 500, NOAEL for male and female monkeys below lowest dose (i.e. below 250 mg/kg/day). Cynomolgus Monkeys with a 4- 22 male 1000 mg/kg/day Week Recovery Period Abbreviations: ACTH = adrenocorticotropic hormone; ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; AUC = area under the curve; BW = body weight; BWG = body weight gain; Cmax=maximum plasma concentration; DHEA= dehydroepiandrosterone; GI = gastrointestinal; GLP = good laboratory practice; HCT = hematocrit; HGB = hemoglobin; LH = luteinizing hormone; MCHC = mean corpuscular hemoglobin concentration; NOAEL = no observed adverse effect level; QD = once daily; RBC = red blood cell; RDW = red blood cell distribution width; TK=toxicokinetic; TOX=toxicity

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Appendix A.2: Reproductive and Developmental GLP Toxicity Studies Study Species/Strain Dose Levels Major Findings Number/Sex

Oral Fertility study of Rat (Sprague-Dawley) Oral gavage, QD for a 4- - Complete loss of fertility consistent with the pharmacology of abiraterone acetate JNJ-212082-AAA in the male rat 36 M/group week pre-pairing period - NOAEL was not established and throughout the pairing - Full recovery of male fertility after 8 weeks period; - Full recovery of sperm motility after 16 weeks (300 mg/kg/day) 30 or 300 mg/kg/day Oral Fertility study of Rat (Sprague-Dawley) Oral gavage, QD for a 2- - Difficulties in the establishment and maintenance of pregnancy consistent with the JNJ-212082-AAA in the female 48 F/ group week pre-pairing period, pharmacology of abiraterone acetate rat throughout the pairing - Fertility per se was unaffected at dose levels up to 300 mg/kg/day period until Day 7 of - NOAEL was not established pregnancy; - Full recovery of reproductive effects after 4 weeks 30 or 300 mg/kg/day Oral developmental toxicity Rat (Sprague-Dawley) Oral gavage, QD from - 3 females sacrificed/died during post-treatment period in 100 mg/kg/day group study with abiraterone acetate in 22 F/ group; GD6 to GD17 - Observations of red vaginal discharge (≥30 mg/kg/day) the rat 0, 10, 30 or - Dose-related reduction in body weight gain (all doses) 100 mg/kg/day - Dose-related increase in late resorptions and post-implantation loss (all doses) - Dose-related reduction in live fetuses (≥30 mg/kg/day) - Decreased fetal weight (100 mg/kg/day) - Dose-related reduction in ano-genital distance in male (all doses) and female fetuses (100 mg/kg/day) - Increase in incidence of minor abnormalities/variants indicative of slight developmental delay - Absence of any significant abnormalities in the fetus at external, visceral or skeletal examination - NOAEL was not established for dams or embryo-fetal development

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Appendix A.2: Reproductive and Developmental GLP Toxicity Studies Study Species/Strain Dose Levels Major Findings Number/Sex

Juvenile Toxicity Study in the rat Rat (Sprague-Dawley) Oral gavage, - Animals in 300 mg/kg/day dose group from either Day 10 or Day 18 of age were 15M+15F/ group (main phase) prematurely sacrificed. Hepatocyte hypertrophy/vacuolation were noted at 30M+30F/group QD from Day 10 of age to histopathological evaluation (recovery/reproductive phase) Day 28 (F) or Day 38 (M) - Treatment was well tolerated at doses up to and including 100 mg/kg/day 0, 10, 30, 100 and - Dose-dependent decrease in overall body weight gain was apparent in males and to a 300 mg/kg/day. lesser extent also in females. As a consequence of this reduced weight gain, ulna growth was shorter. QD from Day 18 of age to - Dose-related delay in the timing of sexual maturation in males but not in females Day 28 (F) or Day 38 (M) - Oestrous cycle length, pre-coital interval, mating performance and fertility, and litter 0, 300 mg/kg/day parameters were unaffected when treated males were paired with untreated females and vice-versa - Minor changes in erythrocyte parameters in males and females receving 100 mg/kg/day and a slight increase in reticulocytes in females - Slight increases in total protein and albumin in males and females at 30 and 100 mg/kg/day; as well as low triglyceride, cholesterol, glucose and creatinine concentrations in males - Decrease in percentage of motile sperm and reduction in testicular spermatid concentrations at 100 mg/kg/day - Treatment-related histopathological changes were apparent in the liver, pituitary, ovaries and the male reproductive tract of animals killed at the end of treatment. All of these treatment-related effects, with the exception of the liver changes, were attributable to the pharmacological action of abiraterone acetate - Adaptive hepatocellular hypertrophy was observed in the liver of males and females given 100 mg/kg/day - Seminiferous epithelium degeneration/tubular atrophy and interstitial cell hyperplasia in testes and reduced spermatozoa in the epididymides did not show recovery after the designated off-dose period at 100 mg/kg/day - Interstitial cell hyperplasia in the ovaries of females did not show recovery after the designated off-dose period at 100 mg/kg/day - Scattered hypertrophic cells in the pars distalis of the pituitary in males (all doses) - Cortical tubular basophilia/dilatation in females at 100 mg/kg/day. Interstitial fibrosis was also recorded in 5/15 females at 100 mg/kg/day - NOAEL for general toxicity: 30 mg/kg/day (M/F Day 38/28 AUC0-24h 312/94 ng.h/mL) - NOAEL for survival/reproductive capacity: 100 mg/kg/day

(M/F Day 38/28 AUC0-24h 523/590 ng.h/mL) Abbreviations: GD = gestation day; NOAEL=no observed adverse effect level; QD = once daily

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APPENDIX B

75 Approved, Date: 26 August 2015 JNJ-212082 (abiraterone acetate) Investigator's Brochure - Edition 12

Appendix B.1: Completed Phase 1 and Phase 1/2 Clinical Studies (as of 27 April 2015)a

Protocol Number Subject Population Dosing Regimen Objective(s) Study Title Number of Subjects Treated Duration References (if applicable) Study Description

Protocol COU-AA-001 Subjects with mCRPC after failure of Phase 1: escalating doses of abiraterone acetate at 250 mg,  To evaluate the safety, tolerability, and A Phase 1/2 Open Label Study of the 17α- ADT. 500 mg, 750 mg, 1,000 mg, and 2 g (administered as recommended dose of abiraterone acetate Hydroxylase/C17,20-Lyase Inhibitor, 250 mg capsules) orally once daily in the morning; administered orally Abiraterone Acetate in Subjects with Prostate N=54 Phase 2: abiraterone acetate 1,000 mg. As of study protocol Cancer Who Have Failed Hormone Therapy amendment 5, a regimen of low dose glucocorticoid, such Phase 1/2, open-label, single arm, as prednisolone/prednisone 5 mg twice daily or Attard 20083 single center dose-escalation study dexamethasone 0.5 mg once daily became mandatory in all Attard 20094 patients at disease progression.

Duration: 12 cycles, or until disease progression or unacceptable toxicity Protocol COU-AA-002 Subjects with mCRPC after failure of Phase 1: escalating doses of abiraterone acetate at 250 mg, Phase 1 A Phase I/II Open Label Dose Escalation ADT. 500 mg, 750 mg, and 1,000 mg (administered as 250 mg  To determine the maximum tolerated dose Study of the 17α Hydroxylase/C17,20 lyase Phase 1: N=33 tablets) orally once daily under fed or fasted conditions; (MTD) of abiraterone acetate administered Inhibitor, Abiraterone Acetate in Hormone Phase 2: abiraterone acetate 1,000 mg after an overnight orally on a continuous once-daily schedule Phase 2: N=33 Refractory Prostate Cancer fast. As of study protocol amendment 7, all subjects were Phase 2 Phase 1/2, open-label, single arm, required to receive low dose such as  To assess the proportion of patients achieving a 49 Ryan 2010 multicenter dose-escalation study prednisone 5 mg twice daily orally or dexamethasone >50% PSA decline during therapy Ryan 201150 (0.5 mg once daily) with abiraterone acetate.

Duration: until disease progression or unacceptable toxicity Protocol COU-AA-005 Healthy adult male subjects Abiraterone acetate 1,000 mg single dose was administered  To determine the bioequivalence of A Single-Dose, Open-Label, Randomized, N=120 as four 250 mg tablets orally under fasted conditions abiraterone acetate tablets manufactured by Two-Way Crossover Pivotal Bioequivalence according to the treatment sequence (AB or BA) on Days 1 commercial process vs. abiraterone acetate Study of Abiraterone Acetate Tablets Phase 1, single-dose, open-label, and 8 with an approximate 7-day washout period between tablets manufactured by clinical trial process Manufactured by Clinical Trial Process at Pii randomized, 2-way crossover study each single-dose treatment at a dose of 1,000 mg. (Treatment A) Versus Tablets Manufactured by Commercial Process at Patheon (Treatment Duration: 14 days B) in Healthy Male Subjects

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Appendix B.1: Completed Phase 1 and Phase 1/2 Clinical Studies (as of 27 April 2015)a

Protocol Number Subject Population Dosing Regimen Objective(s) Study Title Number of Subjects Treated Duration References (if applicable) Study Description

Protocol COU-AA-006 Subjects with mCRPC who failed Abiraterone acetate 1,000 mg administered as 4 x 250 mg  To evaluate the effects of abiraterone acetate A QT/QTc and Multi-dose PK Study of gonadotropin releasing hormone tablets orally once daily at least 1 hour before or 2 hours plus prednisone on cardiac QT/QTc interval Abiraterone Acetate (CB7630) Plus Prednisone (GnRH) therapy and have a PSA after a meal and prednisone 5 mg orally twice daily. by using PK and time-matched ECGs in in Patients with Metastatic Castration-Resistant ≥2 ng/mL, who were medically or patients with metastatic CRPC Prostate Cancer surgically castrated, and received no Duration: until disease progression or unacceptable toxicity more than 1 course of chemotherapy

N=33

Phase 1, open-label, single arm, multicenter study

Protocol COU-AA-007 Healthy adult male subjects Each subject received 3 capsules containing  To determine the metabolic disposition of 14 14 A Phase 1, Open-Label, Single Dose, Mass N=8 C-abiraterone acetate (1,000 mg; approximately 100 μCi). radio-labeled 1,000 mg C-abiraterone acetate Balance Study of 14C Labeled Abiraterone (approximately 100 μCi) in healthy normal Phase 1, open-label, single dose, Acetate in Healthy Male Subjects Duration: approximately 30 days for each subject including male subjects mass balance study the final follow-up phone call Acharya 20131

Protocol COU-AA-008 Healthy adult male subjects Single dose of abiraterone acetate 250 mg, 500 mg,  Pharmacokinetics profile after a single dose in A Phase 1, Single Dose, Open-Label, Dose N=33 750 mg, and 1,000 mg (administered as 250 mg tablets) healthy male subjects Escalation Pharmacokinetics Study of orally after overnight fast. Abiraterone Acetate in Healthy Male Subjects Phase 1, open-label, dose-escalation study Duration: The planned total duration of participation for a Acharya 20122 single subject was 22 days (including the follow-up phone call on Day 22).

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Appendix B.1: Completed Phase 1 and Phase 1/2 Clinical Studies (as of 27 April 2015)a

Protocol Number Subject Population Dosing Regimen Objective(s) Study Title Number of Subjects Treated Duration References (if applicable) Study Description

Protocol COU-AA-009 Healthy adult male subjects Abiraterone acetate administered orally at 1,000 mg with a  To characterize the effect of a standardized A Phase 1, Single Dose, Open-Label, N=36 7-day washout between each dosing period. Subjects were high-fat meal and standardized low-fat meal Three-Period, Crossover Study to Determine randomized to 1 of 6 treatment sequences (ABC, ACB, on the pharmacokinetics of abiraterone acetate the Effect of Food on the Pharmacokinetics of Phase 1, randomized, open-label, BAC, BCA, CAB, CBA): and its major metabolites Abiraterone Acetate in Healthy Male Subjects single dose, 6-sequence, 3-period, Treatment A: Abiraterone acetate tablets taken crossover study immediately after a high-fat meal Treatment B: Abiraterone acetate tablets taken immediately after a low-fat meal Treatment C: Abiraterone acetate tablets given in the fasted state

Duration: The planned total duration of participation for a single subject was 21 days. Protocol COU-AA-010 Healthy adult male subjects Abiraterone acetate 1,000 mg single dose administered  To determine the relative bioavailability of A Phase 1 Randomized, Open-Label, N=22 orally under fasted conditions as four 250 mg tablets abiraterone acetate 1,000 mg tablets compared Two-Period, Two-Sequence Crossover Study (Treatment A [reference]) and 1,000 mg oral liquid to abiraterone acetate 1,000 mg liquid to Determine the Relative Bioavailability of Phase 1, randomized, open-label, formulations in 30 mL olive oil (Treatment B [test]) formulation in healthy normal male subjects Abiraterone Acetate Tablets versus Oral single-center, 2-period, 2 sequence according to the treatment sequence (AB or BA) with an Formulated Abiraterone Acetate Liquid in crossover study approximate 7-day washout between dosing periods Healthy Male Subjects Duration: approximately 38 days to complete both study treatments. Protocol COU-AA-011 Adult male subjects without cancer Single dose of 1,000 mg abiraterone acetate (4 x 250 mg  To determine the pharmacokinetic profile of A Phase 1 Single Dose Open-Label and with mild, or moderate, hepatic tablets) given orally. abiraterone acetate and its major metabolite(s) Pharmacokinetic Study of Abiraterone Acetate impairment compared with matched after a single 1,000 mg oral dose in Male Subjects With Mild or Moderate control subjects with normal hepatic Duration: For each subject (excluding the Screening administration of abiraterone acetate in Hepatic Impairment Compared to Matched function period) was approximately 22 days, including the final subjects with mild or moderate hepatic Control Subjects With Normal Hepatic N=24 follow-up visit. impairment and in matched control subjects Function with normal hepatic function. Phase 1, single dose, open-label PK study

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Appendix B.1: Completed Phase 1 and Phase 1/2 Clinical Studies (as of 27 April 2015)a

Protocol Number Subject Population Dosing Regimen Objective(s) Study Title Number of Subjects Treated Duration References (if applicable) Study Description

Protocol COU-AA-012 Adult male subjects without cancer Single dose of abiraterone acetate 1,000 mg (4 x 250 mg  To determine the PK profile of abiraterone A Phase 1 Single Dose Open-Label and with impaired renal function on tablets) given orally after an overnight fast acetate and its major metabolite(s) after a Reduced/Staged Pharmacokinetic Study of stable hemodialysis compared with single 1,000 mg oral dose administration of Abiraterone Acetate in Male Subjects with matched control subjects with normal Duration: approximately 22 days for each subject, abiraterone acetate in subjects with impaired Impaired Renal Function Compared to renal function including the final follow-up visit. renal function and matched control subjects Matched Control Subjects with Normal Renal N=16 with normal renal function. Function Phase 1, single dose, open-label reduced/staged pharmacokinetic study Protocol COU-AA-014 Healthy adult male subjects Abiraterone acetate 1,000 mg, administered as 4 x 250 mg  To characterize the PK of abiraterone and A Single Dose, Open Label Crossover Study to N=18 tablets under fasted conditions; there was a 7-day washout abiraterone acetate Determine the Relative Bioavailability of between each dosing period. Subjects were randomized to  To determine the relative bioavailability of the Abiraterone Acetate Tablets Manufactured by 1 of 6 treatment sequences (ABCC, ACBB, BCAA, abiraterone acetate tablets manufactured by the Phase 1, randomized, open-label, the Commercial Process with Respect to the BACC, CABB, CBAA) commercial process with respect to the clinical single center, single-dose, 4-period Clinical Trial Process trial process (extra-period), 6-sequence, Duration: participation for a single subject was 28 days 3-treatment crossover study  To estimate the intra- and inter-subject variability in the PK parameters of abiraterone Protocol COU-AA-016 Healthy adult male subjects Four single doses of abiraterone acetate at 250 mg, 500 mg  To evaluate the pharmacokinetic dose- A Single-Dose, Randomized, Open-Label, N=32 (2x250 mg tablets), 750 mg (3x250 mg tablets), and proportionality of abiraterone after single oral Four-Way Crossover Study to Evaluate the 1,000 mg (4x250 mg tablets) orally after an overnight fast administration of abiraterone acetate at doses Effect of Dose on the Pharmacokinetics of on Study Days 1, 8, 15, and 22 according to the subject's of 250 mg, 500 mg, 750 mg, and 1000 mg in Phase 1, single-dose, randomized, Abiraterone in Healthy Male Subjects assigned treatment sequence. healthy male subjects under fasted conditions. open-label, 4-way crossover study

Protocol JNJ-212082-JPN-101 Healthy Japanese adult male subjects Subjects were randomly allocated to 6 sequences of  To evaluate the pharmacokinetic dose A Single-Dose, Randomized, Open-Label, N=30 3 dosing periods each. In each sequence subjects received proportionality of abiraterone in plasma after Three-period Crossover Study to Evaluate the 250 mg, 500 mg or 1,000 mg of abiraterone acetate. In single oral administration of abiraterone Pharmacokinetics of Abiraterone in Japanese each sequence the order of dosing was different. acetate tablet(s) at doses of 250 mg, 500 mg Healthy Adult Male Subjects Phase 1, single-dose, single center, and 1,000 mg in Japanese healthy adult male open-label, randomized, 3-period subjects. crossover study

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Appendix B.1: Completed Phase 1 and Phase 1/2 Clinical Studies (as of 27 April 2015)a

Protocol Number Subject Population Dosing Regimen Objective(s) Study Title Number of Subjects Treated Duration References (if applicable) Study Description

Protocol 212082HPL1001 Healthy adult male subjects Subjects were randomly allocated to 6 sequences. In each  To evaluate the PK and relative bioavailability A Single-dose, Open-label, Randomized, N=31 sequence subjects received single doses of abiraterone of the 2 abiraterone acetate suspension Crossover Study to Assess the Relative acetate 250 mg (2 suspension formulations and tablets) formulations compared to the abiraterone Bioavailability of Two Abiraterone Acetate under fasted conditions. acetate tablet formulation at a single dose of Suspension Formulations Compared to the Phase 1, single-center, randomized, 250 mg in healthy adult men under fasted Abiraterone Acetate Tablet Formulation Under open-label, 3-way crossover design conditions. Fasted Condition in Healthy Adult Subjects study.  The safety and tolerability of the 2 abiraterone acetate suspension formulations and the abiraterone acetate tablet formulation under fasted conditions were assessed. Protocol ABI-PRO-1016 Healthy Chinese adult male subjects Abiraterone acetate (250, 500 mg, or 1,000 mg) – To evaluate the PK of abiraterone after A Single-Dose, Randomized, Open-Label, N=15 administered on Day 1 of each period according to the single oral administration of abiraterone Three-Way Crossover Study to Evaluate the randomization schedule. acetate at doses of 250, 500, and 1,000 mg Pharmacokinetics of Abiraterone in Chinese Phase 1 randomized, open-label, in Chinese healthy male subjects under Healthy Male Subjects. 3-way crossover study of single fasted conditions. doses of abiraterone acetate (250, 500, and 1,000) mg – The safety and tolerability of single doses of abiraterone acetate tablets in Chinese healthy male subjects over the dose range were also assessed.

Protocol COU-AA-BE Men with mCRPC after failure of Abiraterone acetate 1,000 mg (administered as four 250 mg  To evaluate the pharmacokinetics of A Pharmacokinetics Study to Assess the Oral ADT capsules or tablets) orally under fed or fasted condition. As abiraterone acetate administered in capsule Administration of CB7630 (Abiraterone of protocol amendment 3, subjects entering Stage III of the formulation with that in tablet formulation Acetate) Capsule Formulation and Tablet N=31 study were to receive concomitant glucocorticoid under fasted and fed conditions in subjects Formulation in Subjects with Prostate Cancer treatment; either prednisolone/prednisone 5 mg twice daily with prostate cancer. Phase 1, open-label, multicenter, or dexamethasone 0.5 mg once daily. 2-arm study with a 4-stage design Duration: until disease progression, death, or availability of abiraterone acetate through healthcare provider(s), or the Sponsor’s decision to terminate development of abiraterone acetate

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Appendix B.1: Completed Phase 1 and Phase 1/2 Clinical Studies (as of 27 April 2015)a

Protocol Number Subject Population Dosing Regimen Objective(s) Study Title Number of Subjects Treated Duration References (if applicable) Study Description

Protocol COU-AA-001EXT Subjects who have completed clinical Allowed responding subjects to continue beyond 12 cycles  To provide access to abiraterone acetate for An Expanded Access Open Label Study of study COU-AA-001 at the same dose and regimen of abiraterone acetate patients who have completed 12 cycles of CB7630 (Abiraterone Acetate) in Patients with administered at the end of Study COU-AA-001, a regimen abiraterone acetate treatment and continue to Advanced Prostate Cancer who Have N=30 of low dose glucocorticoid, such as receive clinical benefit from such a treatment. Completed CB7630 Clinical Study prednisolone/prednisone 5 mg twice daily or COU-AA-001. An extended access open-label dexamethasone 0.5 mg once daily became mandatory in all single-center study of abiraterone patients at disease progression. acetate Duration: until disease progression, availability of abiraterone acetate through healthcare provider(s), or the Sponsor’s decision to terminate development of abiraterone acetate Protocol COU-AA-002 Men with CRPC who had no Phase 1: escalating doses of abiraterone acetate at 250 mg, Phase 1 A Phase I/II Open Label Dose of the 17α- previous chemotherapy for prostate 500 mg, 750 mg, and 1,000 mg (administered as 250 mg  To determine the maximum tolerated dose Hydroxylase/C17,20 Lyase Inhibitor, cancer and had ongoing gonadal tablets) orally once daily under fed or fasted conditions; (MTD) of abiraterone acetate administered Abiraterone Acetate in Patients With Prostate androgen deprivation therapy or Phase 2: abiraterone acetate 1,000 mg after an overnight orally on a continuous once-daily schedule Cancer Who Have Failed Hormone Therapy orchiectomy fast. As of study protocol amendment 7, all subjects were Phase 2 required to receive low dose glucocorticoids such as  To assess the proportion of patients achieving a Phase 1: 33 prednisone 5 mg twice daily orally or dexamethasone >50% PSA decline during therapy Phase 2: 33 (0.5 mg once daily) with abiraterone acetate.

Phase 1/2, open-label, single arm, Duration: until disease progression or unacceptable toxicity multicenter dose-escalation study Protocol COU-AA-015 Subjects with mCRPC with disease Group A: Abiraterone acetate (4 x 250 mg tablets orally  To evaluate the effects of multiple doses of An Abiraterone Acetate Plus Prednisone Drug- progression on or after once daily) plus prednisone (5-mg tablets twice daily) and abiraterone acetate plus prednisone on the Drug Interaction Study with docetaxel-based chemotherapy. received 2 single doses of dextromethorphan HBr (30 mg): pharmacokinetics of a single dose of Dextromethorphan and Theophylline in one on Cycle 1 Day -8 and one on Cycle 1 Day 8 under dextromethorphan HBr in subjects with Patients with Metastatic Castration-Resistant N=34 fasting conditions. metastatic CRPC Prostate Cancer Group B: Abiraterone acetate (4 x 250 mg tablets orally  To evaluate the effects of multiple doses of once daily) plus prednisone (5-mg tablets twice daily)and abiraterone acetate plus prednisone on the 9 Phase 1b, open–label, multicenter, Chi 2013 abiraterone acetate plus prednisone received 2 single doses of theophylline (100 mg): one on pharmacokinetics of a single dose of drug-drug interaction study with Cycle 1 Day -8 and one on Cycle 1 Day 8 under fasting theophylline in subjects with metastatic CRPC dextromethorphan (Group A) and conditions. theophylline (Group B) Duration: until disease progression.

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Appendix B.1: Completed Phase 1 and Phase 1/2 Clinical Studies (as of 27 April 2015)a

Protocol Number Subject Population Dosing Regimen Objective(s) Study Title Number of Subjects Treated Duration References (if applicable) Study Description

Protocol 212082HPL1002 Adult women with documented Abiraterone acetate oral suspension (100 mg, 250 mg, or  To determine the minimal dose of abiraterone An Open-Label, Multiple-Dose, Dose-Finding 21-hydroxylase deficiency who are 500 mg daily doses) administered first thing in the morning acetate required to decrease serum Study of Abiraterone Acetate in Adult Women taking contraceptives. on an empty stomach during 6-day Treatment Periods. No androstenedione to the age-appropriate range With 21-Hydroxylase Deficiency N=6 food should be consumed for at least 1 hour after the dose for adult women with 21-hydroxylase of abiraterone acetate is taken. deficiency. Phase 1, open-label, non-randomized, multiple-dose, intra-subject Daily hydrocortisone (8 mg/m2/day up to 20 mg/day in 3 sequential dose-escalation study divided doses) and fludrocortisone (approximately 0.1 mg daily) was taken at least 6 days prior to qualifying androstenedione draw and continued through the study. For subjects who have been on a stable dose of hydrocortisone which is lower than 8 mg/m2/day without signs of adrenal insufficiency for at least 3 months prior to the study, the same dose of hydrocortisone should be maintained. For subjects who have been receiving hydrocortisone divided into 2 doses per day, the same schedule should be maintained during the study. Hydrocortisone and fludrocortisone should be taken with food.

Duration: Normalization of androstenedione in at least 80% of subjects.

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Appendix B.1: Completed Phase 1 and Phase 1/2 Clinical Studies (as of 27 April 2015)a

Protocol Number Subject Population Dosing Regimen Objective(s) Study Title Number of Subjects Treated Duration References (if applicable) Study Description

Protocol 212082PCR1002 Healthy adult male subjects Period 1 (Days 1 to 4): a single oral dose of 1,000 mg  To assess the effects of repeated daily An Open-Label Drug-Drug Interaction Study (4 x 250 mg) abiraterone acetate tablets on Day 1 only administration of ketoconazole, a cytochrome to Assess the Effect of Ketoconazole on the N=20 Period 2 (Days 11 to 17): a daily oral dose of 400 mg P450 3A4 (CYP3A4) inhibitor, on the PK of Pharmacokinetics of Abiraterone (JNJ-589485) (2 x 200 mg) ketoconazole tablets on Days 11 to 16 at abiraterone following single-dose Following Administration of Abiraterone approximately the same clock time as the administration of administration of abiraterone acetate tablets in Acetate (JNJ 212082) Tablets in Healthy Male Phase 1 open-label, single center, abiraterone acetate on Day 1 and a single oral dose of healthy male subjects. Subjects 2-period, sequential design, 1,000 mg (4 x 250 mg) abiraterone acetate tablets on drug-drug interaction study of Day 14 only. Abiraterone acetate administered after an  To assess the safety of abiraterone acetate abiraterone acetate and ketoconazole overnight fast. tablets in healthy male subjects with and without co-administration of ketoconazole. Duration: Screening Phase (within 14 days before the first study drug administration) followed by an Open-label Treatment Phase consisting of 2 treatment periods. Successive drug administration was to be separated by a washout period of at least 10 days. End-of-study assessments were to be performed on Day 17 of Period 2 or upon early withdrawal. The study length was to be approximately 31 days.

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Appendix B.1: Completed Phase 1 and Phase 1/2 Clinical Studies (as of 27 April 2015)a

Protocol Number Subject Population Dosing Regimen Objective(s) Study Title Number of Subjects Treated Duration References (if applicable) Study Description

Protocol 212082PCR1003 Healthy adult male subjects Period 1 (Day 1): a single oral dose of 1,000 mg (4 x  To assess the effects of repeated daily An Open-Label Drug-Drug Interaction Study 250 mg) abiraterone acetate tablets on Day 1 only; Period 2 administration of rifampicin, a CYP3A4 to Assess the Effect of Rifampicin on the N=19 (Days 8 to 14): a daily oral dose of 600 mg (2 x 300 mg) inducer, on the PK of abiraterone following Pharmacokinetics of Abiraterone (JNJ-589485) rifampicin capsules on Days 8 to 13 at approximately the single-dose administration of abiraterone Following Administration of Abiraterone Phase 1 open-label, single center, same clock time as the administration of abiraterone acetate tablets in healthy male subjects. Acetate (JNJ 212082) Tablets in Healthy Male 2-period, sequential-design, acetate on Day 1 and a single oral dose of 1,000 mg  To assess the safety of abiraterone acetate Subjects drug-drug interaction study of (4 x 250 mg) abiraterone acetate tablets on Day 14 only. tablets in healthy male subjects with and abiraterone acetate and rifampicin Abiraterone acetate administered after an overnight fast. without co-administration of rifampicin.

Duration:Screening Phase (within 14 days before the first study drug administration) followed by an Open-label Treatment Phase consisting of 2 treatment periods. Successive drug administration was separated by a washout period of at least 7 days. End-of-study assessments were to be performed on Day 17 of Period 2 or upon early withdrawal. The total study length was to be approximately 31 days.

Protocol 212082PCR1004 Men between 35 and 80 years of age, Impaired subjects received 5 mL of 25 mg/mL suspension  To characterize the PK of abiraterone after An Open-Label Pharmacokinetic Study of inclusive, who did not have cancer which equated to a dose of 125 mg abiraterone acetate. administration of a single dose of the Abiraterone Acetate Suspension in Subjects and who had severe hepatic Healthy subjects received 80 mL of 25 mg/mL suspension abiraterone acetate suspension in subjects with with Severe Hepatic Impairment Compared to impairment (as described by the which equated to a dose of 2,000 mg abiraterone acetate. severe hepatic impairment and in matched Matched Control Subjects with Normal Child-Pugh Classification C) control subjects with normal hepatic function. Hepatic Function. (Cohort 1) and matched control  To assess the safety of abiraterone acetate healthy subjects with normal hepatic suspension in these subject populations. function (Cohort 2).

N=16

Phase 1 open-label single dose, PK study.

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Appendix B.1: Completed Phase 1 and Phase 1/2 Clinical Studies (as of 27 April 2015)a

Protocol Number Subject Population Dosing Regimen Objective(s) Study Title Number of Subjects Treated Duration References (if applicable) Study Description

Protocol 212082PCR1005 Healthy Caucasian and Japanese Abiraterone acetate 1,000 mg (4 x 250 mg tablets), orally  To assess the effect of timing of food intake on A Single-Dose, Open-Label, Randomized, adult male subjects within each treatment period. All treatment sequences the PK of abiraterone following single-dose 4-Way Crossover Study to Assess the Effect of followed a 10-hour overnight fast. administration of abiraterone acetate tablets in Timing of Food Intake on the N=51 (24 Caucasian and 27 Japanese Four treatment periods, separated by a washout period of at healthy male subjects. Pharmacokinetics of Abiraterone Following subjects) least 14 days. End-of-study assessments were to be  To characterize the PK following single-dose Single-Dose Administration of Abiraterone performed on Day 4 of Period 4 or upon early withdrawal. administration of abiraterone acetate tablets in Acetate Tablets in Healthy Caucasian and Phase 1 single-center, single-dose, The total study duration was approximately 74 days. healthy Caucasian and Japanese males. To Japanese Male Subjects open-label, randomized, 4-way monitor the safety of single-dose crossover study to assess the timing administration of abiraterone acetate tablets in of food intake on the PK of healthy male subjectsd. abiraterone following single dose administration of abiraterone acetate. Eligible subjects were to be randomized on Day 1 before dosing to 1 of 4 treatment sequences.

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Appendix B.1: Completed Phase 1 and Phase 1/2 Clinical Studies (as of 27 April 2015)a

Protocol Number Subject Population Dosing Regimen Objective(s) Study Title Number of Subjects Treated Duration References (if applicable) Study Description

Protocol 212082PCR1006 Healthy adult male subjects Treatment A: Four 250-mg abiraterone acetate uncoated  To evaluate the PK and relative bioavailability A Single-Dose, Open-Label, Randomized, tablets (current commercial formulation), administered as a of abiraterone after administration of 3 newly 4-Way Crossover Study to Assess the Relative N=32 (safety analysis set) single oral 1,000-mg dose under fasted conditions developed abiraterone acetate tablet Bioavailability of 3 New Abiraterone Acetate (reference drug) formulations (Treatments B, C, and D) and the Tablet Formulations With Respect to the Open-label, single center, Treatment B: Two 500-mg abiraterone acetate coated current commercial abiraterone acetate tablet Current Commercial Abiraterone Acetate randomized, 4-way crossover study reformulated tablets, administered as a single oral formulation (Treatment A) under fasted Tablet Under Fasted Conditions in Healthy of a single dose of 1,000 mg 1,000-mg dose under fasted conditions (test drug) conditions. Male Subjects abiraterone acetate under fasted Treatment C: Four 250-mg abiraterone acetate coated  To assess the safety and tolerability of the conditions. Subjects were randomly reformulated tablets, administered as a single oral 3 new formulations and the commercial assigned to 1 of 4 treatment 1,000-mg dose under fasted conditions (test drug) formulation. sequences to ensure they receive all Treatment D: Two 500-mg abiraterone acetate coated treatments, 1 in each period. reformulated tablets showing slower in vitro dissolution, administered as a single oral 1,000-mg dose under fasted conditions (test drug).

Duration of treatment: 47 days up to a maximum of 68 days (including screening)

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Appendix B.1: Completed Phase 1 and Phase 1/2 Clinical Studies (as of 27 April 2015)a

Protocol Number Subject Population Dosing Regimen Objective(s) Study Title Number of Subjects Treated Duration References (if applicable) Study Description

Protocol 212082PCR1010 Healthy adult male subjects Treatment A: Four 250-mg abiraterone acetate uncoated – To evaluate the PK and relative A Single-Dose, Open-Label, Randomized, 4- tablets (current commercial formulation), administered as a bioavailability of abiraterone after Period, 5-Treatment Crossover Study to N=32 (safety analysis set) single oral 1,000-mg dose under fasted conditions administration of 4 newly developed Assess the Relative Bioavailability of 4 New (reference drug) abiraterone acetate tablet formulations Abiraterone Acetate Tablet Formulations With Open-label, single center, Treatment B: Four 250-mg abiraterone acetate film-coated (Treatments B, C, D, and E) and the current Respect to the Current Commercial randomized, 4-period, 5-treatment tablets (new composition), administered as a single oral commercial abiraterone acetate tablet Abiraterone Acetate Tablet Under Fasted crossover study of a single dose of 1,000-mg dose under fasted conditions (test drug) formulation (Treatment A) under fasted Conditions in Healthy Male Subjects 1,000 mg abiraterone acetate under Treatment C: Two 500-mg abiraterone acetate film-coated conditions. fasted conditions. Subjects were tablets (new composition), administered as a single oral – To assess the safety and tolerability of the randomly assigned to 1 of 8 1,000-mg dose under fasted conditions (test drug) 4 new formulations and the commercial treatment sequences, where they Treatment D: Four 250-mg abiraterone acetate film-coated formulation. received 4 out of 5 treatments, 1 in tablets (same composition as current commercial each period. formulation), administered as a single oral 1,000-mg dose under fasted conditions (test drug) Treatment E: Two 500-mg abiraterone acetate film-coated tablets (same composition as current commercial formulation), administered as a single oral 1,000-mg dose under fasted conditions (test drug)

Duration of treatment: 47 days to a maximum of 68 days (including screening)

87 Approved, Date: 26 August 2015 JNJ-212082 (abiraterone acetate) Investigator's Brochure - Edition 12

Appendix B.1: Completed Phase 1 and Phase 1/2 Clinical Studies (as of 27 April 2015)a

Protocol Number Subject Population Dosing Regimen Objective(s) Study Title Number of Subjects Treated Duration References (if applicable) Study Description

Protocol 212082PCR1011 Healthy adult male subjects Period 1 (Day 1): a single oral dose of 15 mg pioglitazone -To evaluate the effects of abiraterone on the PK An Open-Label Drug-Drug Interaction Study on Day 1 to be given approximately between 7:00 and of pioglitazone, a CYP2C8 substrate, when to Assess the Effect of Abiraterone on the N=16 10:00 AM; Period 2 (Day 8): a single oral dose of 1,000 coadministered with abiraterone acetate. Pharmacokinetics of Pioglitazone Following mg (4 x 250 mg) abiraterone acetate tablets on Day 8; -To evaluate the PK of abiraterone when Administration of Abiraterone Acetate and Phase 1 single-center, open-label, followed 1 hour later by a single oral dose of 15 mg coadministered with a single dose of Pioglitazone HCl Tablets in Healthy Male 2-period, sequential-design, drug- pioglitazone. For each subject, all pioglitazone doses were pioglitazone, to evaluate effects of abiraterone on Subjects drug interaction study of abiraterone to be administered at approximately the same time across the pharmacokinetics of the pioglitazone acetate and pioglitazone. both treatment periods. Treatments administered after an metabolites, M-III and M-IV, and to assess the overnight fast of at least 10 hours. A medium-fat breakfast safety and tolerability of abiraterone acetate was provided within 5 minutes after the pioglitazone dose. tablets in healthy male subjects when Lunch was provided after the 4-hour PK blood sample was coadministered with pioglitazone. obtained. Noncarbonated water was allowed as desired with the exception of 2 hours before and 1 hour after the pioglitazone administration in Period 1 and 2 hours before and 1 hour after the abiraterone acetate dose in Period 2.

Duration of treatment was up to approximately 32 days. Protocol 212082PCR1007 Healthy adult male subjects Treatment A: 4 x 250-mg abiraterone acetate uncoated - To determine the bioequivalence of 2 A Single-Dose, Open-Label, Randomized, N=102 tablets (current commercial formulation) abiraterone acetate FCT formulations 3-Way Crossover Pivotal Study to Assess the Treatment B: 4 x 250-mg abiraterone acetate FCT (current (Treatments B and C) with respect to the current Bioequivalence of 2 Abiraterone Acetate Phase 1 single-center, open-label, 3- commercial formulation) commercial abiraterone acetate uncoated tablet Coated Tablet Formulations With Respect to way crossover study of a single dose Treatment C: 2 x 500-mg abiraterone acetate FCTs (new formulation (Treatment A) under fasted the Current Commercial Abiraterone Acetate of 1,000 mg abiraterone acetate. composition) conditions in healthy male subjects. Uncoated Tablet Formulation Under Fasted Subjects were randomly assigned to - To assess the safety profile of the 2 new FCT Conditions in Healthy Male Subjects 1 of 6 treatment sequences; each All treatments were administered as a single oral 1,000-mg formulations. subject received all treatments. dose under fasted conditions.

88 Approved, Date: 26 August 2015 JNJ-212082 (abiraterone acetate) Investigator's Brochure - Edition 12

Appendix B.1: Completed Phase 1 and Phase 1/2 Clinical Studies (as of 27 April 2015)a

Protocol Number Subject Population Dosing Regimen Objective(s) Study Title Number of Subjects Treated Duration References (if applicable) Study Description

Protocol 212082PCR1013 Healthy adult men Treatment A: 4 x 250-mg abiraterone acetate uncoated - To evaluate the relative bioavailability of A Single-Dose, Open-Label, Randomized, tablets (current commercial formulation), administered as a abiraterone following administration of 3 new Crossover Study to Assess the Relative N=32 single oral 1,000-mg dose under fasted conditions abiraterone acetate tablet concepts using SDD Bioavailability of 3 New Abiraterone Acetate Treatment B: 2 x 125-mg abiraterone acetate tablets compared with the current commercial Tablet Concepts With Respect to the Current Phase 1 single center-open-label, (HPMC P-HP50 based SDD formulation, ratio 1/3) abiraterone acetate tablet formulation in healthy Commercial Abiraterone Acetate Tablet in 4-period, 5-treatment crossover of a administered as a single 250-mg dose under fasted male subjects. Healthy Male Subjects single 1,000-mg dose of abiraterone conditions - To evaluate the food effect of 1 new abiraterone acetate. Subjects will be randomly Treatment C: 2 x 125-mg abiraterone acetate tablets acetate tablet concept using SDD. assigned to 1 of 8 treatment (HPMC-AS based SDD formulation, ratio 1/3), - To assess the safety and tolerability of single- sequences administered as a single 250-mg dose under fasted dose administrations of the new abiraterone conditions acetate tablet concepts Treatment D: 1 x 250 -mg abiraterone acetate tablets (HPMC P-HP50 based SDD formulation, ratio 1/1), administered as a single 250-mg dose under fasted conditions Treatment E: 2 x 125-mg abiraterone acetate tablets (HPMC P-HP50 based SDD formulation, ratio 1/3), administered as a single 250-mg dose under fed conditions Protocol COU-AA-206 Men with mCRPC who have shown Part I (dose-escalation): abiraterone acetate (500 mg up to  To determine a safe dose combination of A Phase 1b Safety Study of Abiraterone tumor progression as evidenced by 1,000 mg/day) + docetaxel (60 to 75 mg/m2) + prednisone abiraterone acetate and docetaxel plus Acetate (JNJ-212082) and Docetaxel in rising PSA or radiography. (5 mg twice daily). prednisone in subjects with mCRPC. Subjects with Metastatic Castration-Resistant Part II: MTD of abiraterone acetate plus Prostate Cancer (mCRPC) Planned: 38 subjects enrolled in order docetaxel+prednisone is expanded to collect safety to have 30 evaluable subjects information.

Phase 1b, open-label, uncontrolled, Duration: until disease progression (PSA, radiographic and multicenter, safety study of symptomatic) or unacceptable toxicity escalating dose levels of abiraterone acetate and docetaxel plus prednisone as combination therapy.

89 Approved, Date: 26 August 2015 JNJ-212082 (abiraterone acetate) Investigator's Brochure - Edition 12

Appendix B.1: Completed Phase 1 and Phase 1/2 Clinical Studies (as of 27 April 2015)a

Protocol Number Subject Population Dosing Regimen Objective(s) Study Title Number of Subjects Treated Duration References (if applicable) Study Description

Protocol JNJ-212082-JPN-102 Japanese men with CRPC after Abiraterone acetate (250 mg, 500 mg or 1,000 mg) once Pharmacodynamics and safety of abiraterone Phase 1 Study of JNJ-212082 (Abiraterone failure of ADT. daily orally administered from Cycle 1 Day 1 at least 1 acetate for determining the recommended dose of Acetate) in Chemotherapy-naive Patients with hour before a meal or 2 hours after a meal. Oral abiraterone acetate for Japanese subjects with Castration-Resistant Prostate Cancer N=27 prednisolone 5 mg twice daily started on Cycle 1 Day 8. mCRPC

Phase 1 multicenter, open-label, non- Duration: Until disease progression (incl. PSA randomized dose-escalation study progression), or unacceptable toxicity, or when moved to a planned extension study aA “completed” clinical study is defined as a study for which a final CSR is available (ie, CSR completed before the cutoff date) and no subjects are being followed up for overall survival. ADT=androgen deprivation therapy; ECG=electrocardiogram; FCT=film-coated tablet; mCRPC=metastatic castration-resistant prostate cancer; PK=pharmacokinetics; PSA=prostate-specific antigen

90 Approved, Date: 26 August 2015 JNJ-212082 (abiraterone acetate) Investigator's Brochure - Edition 12

Appendix B.2: Ongoing Phase 1 and Phase 1/2 Clinical Studies (as of 27 April 2015)

Protocol Number Subject Population Dosing Regimen Objective(s) Study Title Number of Subjects Planned Duration References (if applicable) Study Description

Protocol CR9304-21 Post-menopausal women with Phase 1: Phase 1 (An investigator initiated study being estrogen (ER) or androgen receptor Abiraterone acetate capsules/tablets administered orally in  To evaluate the safety and tolerability of conducted in the U.K.) (AR) positive, advanced or metastatic Phase 1 (dose escalation) at each of 4 dose levels: 250 mg, CB7630 administered orally continuously in a A Cancer Research UK Phase I/II Open Label breast carcinoma 500 mg, 1,000 mg and 2 g (in the absence of dose-limiting once-daily regimen in post-menopausal women Study to Evaluate the Safety, Endocrine N=55 toxicities) with advanced breast malignancy Effects, and Anti-tumour Activity of Phase 2  To recommend a trial dose for the Phase 2 Abiraterone Acetate (CB7630) in Patients with Based on the optimal endocrine effect, pharmacokinetics, Phase 2 Oestrogen (ER) or Androgen Receptor (AR) Phase 1/2, open label, multi-center and safety, abiraterone acetate dose will be recommended  To evaluate the clinical benefit rate in post- Positive Advanced or Metastatic Breast study. The Phase 1 dose escalation for the Phase 2 evaluation menopausal women with ER+ or AR+ER- Carcinoma part of the study will identify the advanced breast cancer at 24 weeks (i.e. 6 recommended dose for the Phase 2. Duration: 12 cycles unless (a) the subject asks to be cycles) The Phase 2 part of the study will withdrawn (b) there is evidence of disease progression or assess the efficacy of abiraterone (c) patient is experiencing unacceptable toxicity. acetate Subjects who are maintaining a response to therapy or who have stable disease at the end of the formal study period will be offered the opportunity to continue abiraterone acetate treatment at the discretion of the investigators.

Protocol ARN-509-004 Men with mCRPC Abiraterone acetate: 1,000 mg once daily on an empty To determine the MTD/recommended Phase 2 Phase 1b, Open-Label Study to Assess the stomach dosage of ARN-509 when administered in Safety, Tolerability, Pharmacokinetics, and N=9 to 21 Prednisone: 5 mg once daily with food combination with abiraterone acetate. Preliminary Anti-Tumor Activity of Ascending JNJ-56021927: dose escalation starting at 120 to 240 mg Doses of ARN-509 (JNJ-56021927) in Phase 1b, open-label ascending dose with an intermediate dose of 180 mg once daily (if 240 mg Combination with Abiraterone Acetate in study is not well tolerated) with or without food and at least 1 Patients with mCRPC hour after abiraterone acetate (except for Cycle 1 Day 36 where the timing should be exactly 1 hour after abiraterone acetate [timing recorded]). Treatment will continue until disease progression, unacceptable toxicity, noncompliance, withdrawal of consent, or other reasons as outlined in the protocol.

Duration: until disease progression. unacceptable toxicity

91 Approved, Date: 26 August 2015 JNJ-212082 (abiraterone acetate) Investigator's Brochure - Edition 12

Appendix B.2: Ongoing Phase 1 and Phase 1/2 Clinical Studies (as of 27 April 2015)

Protocol Number Subject Population Dosing Regimen Objective(s) Study Title Number of Subjects Planned Duration References (if applicable) Study Description

Protocol 56021927PCR1010 Adult men with mCRPC  Treatment 1: abiraterone acetate 1,000 mg (4 x 250  To evaluate the effect of JNJ-56021927 on A Phase 1b Drug-Drug Interaction, Safety and mg tablet) taken orally once daily from Cycle 1 Day 1 steady state abiraterone pharmacokinetics in Efficacy Study With JNJ-56021927 (ARN- N=26 onwards subjects with mCRPC during combination 509) and Abiraterone Acetate in Subjects With  Treatment 2: prednisone 5 mg (1 x 5 mg tablet) taken treatment of JNJ-56021927 with abiraterone Metastatic Castration-Resistant Prostate Phase 1b, multicenter, open-label, orally twice daily from Cycle 1 Day 1 onwards acetate and prednisone Cancer single sequence study in subjects  Treatment 3: JNJ-56021927 240 mg ( 8 x 30 mg with mCRPC to assess the softgel capsules) taken orally once daily from Cycle 1 pharmacokinetics of abiraterone Day 8 onwards acetate and its metabolites when dosed alone or in combination with Duration: until disease progression or unacceptable toxicity JNJ-56021927 (ARN-509) Abbreviations: ADT=androgen deprivation therapy;AR=androgen receptor; CSR= clinical study report; ER=estrogen receptor; CRPC=castration-resistant prostate cancer; mCRPC=castration- resistant prostate cancer; MTD = maximum tolerated dose; PSA =prostate specific antigen; SDD= spray-dried dispersion

92 Approved, Date: 26 August 2015 JNJ-212082 (abiraterone acetate) Investigator's Brochure - Edition 12

Appendix B.3: Completed Phase 2 Clinical Studies (as of 27 April 2015)

Protocol Number Subject Population Dosing Regimen Objective(s) Study Title Number of Subjects Treated Duration Study Description

Protocol COU-AA-003 Subjects with mCRPCand disease Abiraterone acetate 1,000 mg after an overnight fast.  To evaluate the anti-tumor effects of A Phase II Open Label Study of CB7630 progression on or after Following Amendment 2 of the study protocol, subjects were abiraterone acetate acetate in subjects with (Abiraterone Acetate) in Patients with docetaxel-based chemotherapy. to take low dose glucocorticoid such as castration-resistant prostate cancer (CRPC) Advanced Prostate Cancer Who Have Failed prednisolone/prednisone (5 mg twice daily) or who have failed docetaxel based Androgen Deprivation and COU-AA-003 dexamethasone (0.5 mg once daily). chemotherapy, as measured by the proportion Docetaxel-Based Chemotherapy N=47 During Study COU-AA-003EXT, subjects continued with the of subjects achieving a PSA decline of at COU-AA-003EXT least 50% (PSA response) according to 47 same dose and regimen of abiraterone acetate administered Reid 2010 N=5 during Study COU AA 003 if no dose reduction had prostate-specific antigen working group occurred. Subjects also continued concurrent (PSAWG) criteria COU-AA-003EXT COU-AA-003 prednisone/prednisolone (5 mg twice daily) or  To provide additional treatment of An Extended Study of CB7630 (Abiraterone Phase 2 open-label, single-arm, dexamethasone (0.5 mg once daily). abiraterone acetate (CB7630) to patients who Acetate) in Patients with Advanced Prostate multicenter study. have completed 12 cycles of abiraterone Subjects in COU-AA-003 were treated through 12 cycles, or Cancer Who Have Failed Androgen acetate treatment and continue to receive until documented disease progression, lack of disease Deprivation and Docetaxel-Based COU-AA-003EXT clinical benefit from such treatment. Chemotherapy Open-label, single-arm extension of response after 6 evaluable cycles of treatment, or Study COU-AA-003 in the United unacceptable toxicity. Kingdom. Study COU-AA-003EXT allowed responding subjects in the United Kingdom to continue beyond 12 cycles. Treatment was to continue until subject’s death, loss to follow-up, withdrawal of informed consent, sustained toxicity, disease progression, or the sponsor’s decision to terminate development of abiraterone acetate.

Protocol COU-AA-004 Subjects with mCRPC and disease Abiraterone acetate 1,000 mg (administered as four 250 mg  The proportion of patients achieving a PSA A Phase 2 Open Label Study of CB7630 progression on or after tablets) once daily after an overnight fast, and decline of > 50% (PSA Response) According (Abiraterone Acetate) and Prednisone in docetaxel-based chemotherapy. prednisone/prednisolone 5 mg orally twice daily to Prostate Specific Antigen Working Group Patients With Advanced Prostate Cancer who (PSAWG) criteria Have Failed Androgen Deprivation and N=58 Duration: 12 cycles, or until disease progression, or Docetaxel-Based Chemotherapy unacceptable toxicity Phase 2, open-label, multicenter, Danila 201012 single arm study

93 Approved, Date: 26 August 2015 JNJ-212082 (abiraterone acetate) Investigator's Brochure - Edition 12

Appendix B.3: Completed Phase 2 Clinical Studies (as of 27 April 2015)

Protocol Number Subject Population Dosing Regimen Objective(s) Study Title Number of Subjects Treated Duration Study Description

Protocol COU-AA-201 Subjects with localized high risk Group 1: Abiraterone acetate (1,000 mg) plus leuprolide  To compare serum and prostate tissue A Phase 2 Open-Label, Randomized, Multi- prostate cancer acetate and prednisone (5 mg) daily for 24 weeks. androgen levels after 12 weeks of treatment center Study of Neoadjuvant Abiraterone Group 2: Leuprolide acetate for 12 weeks, then abiraterone with either abiraterone acetate plus leuprolide Acetate (CB7630) Plus Leuprolide Acetate N=58 acetate plus leuprolide acetate and prednisone for a acetate, and prednisone or leuprolide acetate and Prednisone Versus Leuprolide Acetate Group 1: 30 subsequent 12 weeks alone Alone in Men With Localized High Risk Group 2: 28 After 24 weeks of treatment, both groups will undergo radical Prostate Cancer prostatectomy (open or robotic procedure). Phase 2 open-label, multi-center, randomized study Duration: 24 weeks Protocol COU-AA-203 Men with locally advanced prostate Abiraterone acetate (1,000 mg) plus prednisone (5 mg) daily  To assess the differences in proportion of A Randomized, Open-Label, Neoadjuvant cancer and LHRHa subjects with pathologic stage ≤ pT2 between Prostate Cancer Trial of Abiraterone Acetate LHRHa alone group the 2 groups. plus Prednisone and LHRHa Versus LHRHa N=65  Seconday objectives included: assessment of After 3 months of treatment, all subjects were to undergo Alone changes in biomarkers related to androgen radical prostatectomy. Abiraterone acetate + prednisone signaling and other cancer-related pathways, + LHRHa: 44 Duration: Approximately 3 months before radical proliferation, apoptosis, and candidate LHRHa: 21 prostatectomy. Treatment following prostatectomy resistance pathways between the 2 groups; determined by the current practice guidelines and assessment of the difference in rate of Phase 2 open-label, single center, individualized to subject needs. positive surgical margins between the 2 randomized study groups, assessment of the safety profile in a pre-operative setting. Protocol COU-AA-BMA Men with mCRPC Abiraterone acetate 1,000 mg (administered as four 250 mg  To explore the effect of abiraterone acetate on An Observational Study of Continuous Oral tablets) orally once daily at least 1 hour before and 2 hours levels of testosterone and DHT in the bone Dosing of an Irreversible CYP17 Inhibitor, N=57 after a meal and prednisone/prednisolone 5 mg orally twice marrow of patients with metastatic castration- Abiraterone Acetate (CB7630), in Castration- daily. resistant prostate cancer Resistant Prostate Cancer Subjects Evaluating Phase 2, open-label, single arm,  To evaluate the difference in bone marrow Androgens and Steroid Metabolites in Bone single center observational study Duration: until disease progression, unacceptable toxicity, androgen levels between subjects with and Marrow Plasma study termination, or subject choice to discontinue from the without baseline serum PSA decline study Efstathiou15

94 Approved, Date: 26 August 2015 JNJ-212082 (abiraterone acetate) Investigator's Brochure - Edition 12

Appendix B.3: Completed Phase 2 Clinical Studies (as of 27 April 2015)

Protocol Number Subject Population Dosing Regimen Objective(s) Study Title Number of Subjects Treated Duration Study Description

Protocol 212082PCR2008 Men with mCRPC Abiraterone acetate, 1,000 mg (four 250 mg tablets) orally  To establish the safety profile of oral An Open-Label Study to Determine the Short- Planned: N=25 once daily and prednisone 5 mg orally twice a day abiraterone acetate and oral prednisone Term Safety of Continuous Dosing of administered in the modified fasted state and after meals of following short-term administration after Abiraterone Acetate and Prednisone in various fat contents. standardized low-fat (7.3%) or high-fat meals Actual Cohort 1 (low fat 7.3%): Modified Fasting and Fed States to Subjects (56.5%) to subjects with mCRPC. 6 evaluable subjects (7 treated) With Metastatic Castration-Resistant Prostate Duration: Once subjects completed the food evaluation Cancer Cohort 2 (high fat 56.5%): period (Cycle 2 Day 1), subjects were to continue treatment  A secondary objective included secondary 18 evaluable and treated with abiraterone acetate and prednisone in the modified objective was to evaluate the exposure to Phase 2, open label, fasting state (no food for 2 hours before and 1 hour after abiraterone following short-term non-randomized, study at 2 sites in the dose). Once subjects completed Cycle 12, they were to administration of oral abiraterone acetate in Canada to assess the short-term enter the Long-Term-Extension (LTE) phase and were to be the modified fasting state and after safety of abiraterone acetate and followed every third Cycle until disease progression or standardized low-fat or high-fat meals to prednisone administered after meals unacceptable toxicity. subjects with mCRPC. of various fat contents to subjects with mCRPC.

Protocol 212082BCA2001 Postmenopausal women with ER+, Abiraterone acetate 1,000 mg/day (four 250 mg tablets) must  To assess the safety and efficacy of Randomized, Open-Label Study of HER2- metastatic breast cancer be taken on an empty stomach. No food should be consumed abiraterone acetate plus prednisone and Abiraterone Acetate (JNJ 212082) plus progressing after letrozole or for at least 2 hours before the dose of abiraterone acetate is abiraterone acetate plus prednisone combined Prednisone with or without Exemestane in anastrozole therapy. taken and for at least 1 hour after the dose of abiraterone with exemestane, each compared with Postmenopausal Women with ER+ Metastatic Planned N=300 (~100 subjects per acetate is taken. Prednisone 5 mg/day should be taken daily exemestane alone, in postmenopausal women Breast Cancer Progressing after Letrozole or treatment group) with abiraterone acetate; if gastric intestinal upset occurs, with ER+ metastatic breast cancer Anastrozole Therapy prednisone may be taken with food and separately from progressing after letrozole or anastrozole abiraterone acetate. Exemestane 25 mg/day should be taken therapy. Phase 2, open-label, randomized, as a single tablet, preferably after a meal. parallel-group, multicenter study. Duration: disease progression, unacceptable toxicity, or death.

95 Approved, Date: 26 August 2015 JNJ-212082 (abiraterone acetate) Investigator's Brochure - Edition 12

Appendix B.3: Completed Phase 2 Clinical Studies (as of 27 April 2015)

Protocol Number Subject Population Dosing Regimen Objective(s) Study Title Number of Subjects Treated Duration Study Description

Protocol 212082PCR2007 Korean and Taiwanese men with Abiraterone acetate 1,000 mg (administered as four 250 mg  To determine the proportion of subjects Phase 2 Open Label Study of Abiraterone mCRPC cancer on or after tablets) orally once daily at least 1 hour before and 2 hours achieving a PSA decline ≥50% (PSA Acetate (JNJ-212082) and Prednisolone in docetaxel-based chemotherapy. after a meal and prednisone/prednisolone 5 mg orally twice response) according to protocol-specific Patients with Advanced Prostate Cancer Who N=82 daily. Prostate-Specific Antigen Working Group Have Failed Androgen Deprivation and (PSAWG) criteria. Docetaxel-Based Chemotherapy Phase 2, open-label, single-arm, Duration: until disease progression or unacceptable toxicity. multi-center bridging study at sites in Korea and Taiwan

Protocol JNJ-212082-JPN-201 Men with mCRPC who have not Abiraterone acetate 1,000 mg (administered as four 250 mg  To assess the proportion of subjects achieving A Phase 2 Study of JNJ-212082 (Abiraterone received prior cytotoxic tablets) orally once daily at least 1 hour before and 2 hours a PSA decline of ≥ 50% from baseline (PSA Acetate) in Metastatic Castration-Resistant chemotherapy. after a meal and prednisone/prednisolone 5 mg orally twice response) by 12 weeks of therapy according Prostate Cancer Patients Who Are daily. to PSAWG criteria in chemotherapy-naïve Chemotherapy-Naïve N=48 patients with mCRPC Duration: until disease progression or unacceptable toxicity Phase 2, open-label, single arm, multi center study Protocol JNJ-212082-JPN-202 Patients with mCRPC and disease Abiraterone acetate 1,000 mg (administered as four 250 mg  To assess the proportion of subjects achieving A Phase 2 Study of JNJ-212082 (Abiraterone progression on or after tablets) orally once daily at least 1 hour before and 2 hours a PSA decline of ≥ 50%from baseline (PSA Acetate) in Metastatic Castration-Resistant docetaxel-based chemotherapy after a meal and prednisone/prednisolone 5 mg orally twice response) by 12 weeks of therapy according Prostate Cancer Patients Who Have Received daily. to PSAWG criteria in patients with mCRPC Docetaxel-based Chemotherapy N=47 who have received docetaxel-based Duration: until disease progression or unacceptable toxicity chemotherapy Phase 2, open-label, single arm, multi center study a A “completed” clinical is defined as a study for which a final CSR is available (ie, CSR completed before the cutoff) and no subjects are being followed up for overall survival. AR=androgen receptor; DHT= dihydrotestosterone; ER=estrogen receptor; LHRHa= luteinizing hormone-releasing hormone analog; MTD = maximum tolerated dose; mCRPC =metastatic castration-resistant prostate cancer; PSA = prostate-specific antigen; PSAWG = prostate specific antigen working group; PK=pharmacokinetics; RECIST = response evaluation criteria in solid tumors

96 Approved, Date: 26 August 2015 JNJ-212082 (abiraterone acetate) Investigator's Brochure - Edition 12

Appendix B.4: Ongoing Phase 2 Clinical Studies (as of 27 April 2015)

Protocol Number Subject Population Study Title Number of Subjects Planned Dosing Regimen Primary Objective(s) Duration References (if applicable) Study Description

Protocol 212082PCR2005 Men with non-metastatic CRPC Abiraterone acetate, 1,000 mg (four 250 mg tablets) orally  To demonstrate that abiraterone acetate plus A Multicenter, Open-label, Single-arm, Phase N=110 once daily and prednisone 5 mg orally once daily prednisone effectively decreases PSA in 2 Study of Abiraterone Acetate Plus administered. Subjects were not to eat for at least 2 hours subjects with non-metastatic CRPC who have a Phase 2, prospective, open-label, Prednisone in Subjects with Advanced Prostate before and for at least 1 hour after taking abiraterone rising PSA despite castrate levels of Cancer Without Radiographic Evidence of single-arm, multicenter study of acetate. testosterone. Metastatic Disease abiraterone acetate plus prednisone in subjects with non-metastatic CRPC with a rising PSA despite castrate Duration: until radiographic evidence of disease levels of testosterone. progression whether or not they continue abiraterone acetate plus prednisone.

Protocol 212082PCR2023 Men with asymptomatic, All subjects will receive abiraterone acetate 1,000 mg once – To evaluate the safety of abiraterone acetate A Randomized Phase 2 Study Evaluating chemotherapy-naive mCRPC daily plus 1 of 4 steroid regimens: with 4 alternative steroid treatment strategies Abiraterone Acetate With Different Steroid Arm 1: abiraterone acetate plus prednisone 5 mg twice related to symptoms associated with Regimens for Preventing Symptoms daily mineralocorticoid excess toxicities (ie, Associated With Mineralocorticoid Excess in N=144 hypokalemia and/or hypertension) during the Asymptomatic, Chemotherapy-Naïve and Arm 2: abiraterone acetate plus prednisone 5 mg once daily first 24 weeks of treatment in asymptomatic, Metastatic Castration-Resistant Prostate Phase 2, randomized, open-label, Arm 3: abiraterone acetate plus prednisone 2.5 mg twice chemotherapy-naïve, mCRPC subjects Cancer (mCRPC) Patients parallel arm, multicenter daily Arm 4: abiraterone acetate plus dexamethasone 0.5 mg once daily

Duration; up to 156 weeks (39 cycles), or until the time of disease progression, unacceptable toxicity, or initiation of new anticancer treatment

Abbreviations: ER+=estrogen-receptor positive; HER2=human epidermal growth factor receptor 2; mCRPC=metastatic castration-resistant prostate cancer; PSA = prostate specific antigen; PSAWG = prostate specific antigen working group; PK=pharmacokinetics

97 Approved, Date: 26 August 2015 JNJ-212082 (abiraterone acetate) Investigator's Brochure - Edition 12

Appendix B.5: Completed Phase 3 Clinical Studies (as of 27 April 2015)

Protocol Number Subject Population Dosing Regimen Objective(s) Study Title Number of Subjects Duration References (if applicable) Study Description

Protocol COU-AA-301 Men with mCRPC and disease Abiraterone acetate 1,000 mg (administered as four 250 mg  To compare the clinical benefit of abiraterone A Phase 3, Randomized, Double-blind, progression on or after tablets) or 4 placebo tablets orally once daily at least 1 hour acetate plus prednisone with placebo plus Placebo-Controlled Study of Abiraterone docetaxel-based chemotherapy before or 2 hours after a meal, and prednisone/prednisolone prednisone in patients with mCRPC who have Acetate (CB7630) Plus Prednisone in Patients 5 mg orally twice daily failed 1 or 2 chemotherapy regimens, one of with Metastatic Castration-Resistant Prostate N=1,185 which contains docetaxel Cancer Who Have Failed Docetaxel-Based Abiraterone acetate group 791 Duration: until disease progression or unacceptable toxicity Chemotherapy Placebo group: 394

De Bono13 Phase 3, randomized, double-blind, Fizazi19 placebo-controlled, multinational, multicenter study Protocol COU-AA-302 Men with mCRPC after failure of Abiraterone acetate 1,000 mg (administered as four 250 mg  To compare the clinical benefit of abiraterone A Phase 3, Randomized, Double-Blind, ADT. tablets) or 4 placebo tablets orally once daily at least 1 hour acetate plus prednisone versus placebo plus Placebo-Controlled Study of Abiraterone before or 2 hours after a meal, and prednisone/prednisolone prednisone in patients with chemotherapy- Acetate (CB7630) Plus Prednisone in N=1,082 5 mg orally twice daily. naïve mCRPC who are asymptomatic or mildly Asymptomatic or Mildly Symptomatic symptomatic Patients With Metastatic Castration-Resistant Abiraterone acetate group: 542 Duration: until disease progression or unacceptable Prostate Cancer Placebo group: 540 toxicity.

Ryan51, Ryan52 Phase 3, randomized, double-blind, placebo-controlled, multinational, multicenter study

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Appendix B.6: Ongoing Phase 3 Clinical Studies (as of 27 April 2015)

Protocol Number Subject Population Dosing Regimen Objective(s) Study Title Number of Subjects Planned Duration References (if applicable) Study Description

Protocol 212082PCR3001 Men with mCRPC and disease Abiraterone acetate 1,000 mg (administered as four 250 mg  To collect additional safety data during An Open-Label Study of Abiraterone Acetate progression on or after tablets) orally once daily at least 1 hour before and 2 hours treatment with abiraterone acetate plus in Subjects with Metastatic Castration- docetaxel-based chemotherapy. after a meal and prednisone/prednisolone 5 mg orally twice prednisone who reside in areas in which Resistant Prostate Cancer Who Have daily. abiraterone acetate was not yet available Progressed After Taxane-Based Planned ~5,000 through local healthcare providers, and who Chemotherapy Duration: until disease progression or the subject otherwise are not eligible for enrollment into any Open-label extend access protocol. discontinued (eg, to receive marketed drug) available ongoing clinical study of abiraterone Data collection included SAEs, Grade acetate. 3 or higher AEs, including laboratory AEs. Protocol 212082PCR3011 Men ≥18 years of age with newly Abiraterone acetate 1,000 mg (four 250 mg tablets) or  The primary objective is to determine whether A Randomized, Double-blind, Comparative diagnosed (within 3 months prior to placebo will be taken orally once daily continuously, abiraterone acetate in combination with low- Study of Abiraterone Acetate Plus Low dose randomization) mHNPC, and concomitantly with oral low-dose prednisone 5 mg once dose prednisone and androgen deprivation Prednisone Plus Androgen Deprivation high-risk prognostic factors, and daily. Abiraterone acetate/placebo must be taken on an therapy is superior to androgen deprivation Therapy (ADT) Versus ADT Alone in Newly ECOG performance grade of 0, 1 or 2. empty stomach. No food should be consumed for at least therapy alone in improving survival in subjects Diagnosed Subjects With High Risk, High-risk prognosis is defined as 2 hours before the dose of abiraterone acetate/placebo is with mHNPC with high risk prognostic factors. Metastatic Hormone-Naive Prostate Cancer having at least 2 of the following 3 taken and for at least one1 hour after the dose of Secondary objectives are to evaluate the (mHNPC) risk factors: (1) Gleason score of ≥8; abiraterone acetate or placebo. clinically relevant improvements as well as the (2) presence of 3 or more lesions on safety of abiraterone acetate plus low-dose bone scan; (3) presence of visceral prednisone and androgen deprivation therapy metastasis. Treatment will continue until disease progression, compoared with androgen deprivation therapy withdrawal of consent, or the occurrence of unacceptable alone and to identify microRNA (miRNA) and Planned: ~1,270 toxicity. mRNA profiles predictive of abiraterone Abiraterone acetate group: ~635 acetate response or resistance in this patient Placebo group: ~635 population.

Phase 3 multinational, multicenter, randomized, double-blind, active-controlled study designed to determine if newly diagnosed subjects with mHNPC who have high-risk prognostic factors will benefit from the addition of abiraterone acetate and low-dose prednisone to ADT.

99 Approved, Date: 26 August 2015 JNJ-212082 (abiraterone acetate) Investigator's Brochure - Edition 12

Appendix B.6: Ongoing Phase 3 Clinical Studies (as of 27 April 2015)

Protocol Number Subject Population Dosing Regimen Objective(s) Study Title Number of Subjects Planned Duration References (if applicable) Study Description

Protocol ABI-PRO-3001 Men with mCRPC and disease Subjects randomized to the abiraterone acetate group will -The primary objective is to compare the clinical A Phase 3, Randomized, Double-blind, progression on or after receive a dose of 1,000 mg once daily. All subjects will be benefit, as measured by an improvement in time Placebo-Controlled Study of Abiraterone docetaxel-based chemotherapy. instructed to take 4 tablets (abiraterone acetate [250 mg per to prostate specific antigen (PSA) progression Acetate (JNJ-212082) Plus Prednisone in tablet] or placebo) orally (PO) on an empty stomach. No (TTPP), of abiraterone acetate plus prednisone Patients with Metastatic Castration-Resistant Planned number of subjects:~200 food should be consumed for at least 2 hours before the versus placebo plus prednisone in subjects with Prostate Cancer Who Have Failed Docetaxel- Abiraterone acetate group: ~133 dose of study drug is taken and for at least 1 hour after the mCRPC who have failed 1 or 2 chemotherapy Based Chemotherapy Placebo group: ~67 dose of study drug is taken. The tablets should be regimens, at least 1 of which contains docetaxel. swallowed whole with water. -Secondary Objectives are to characterize the Phase 3 bridging study (China) based Prednisone 5-mg orally, twice daily safety profile of abiraterone acetate with on Study COU-AA-301 concurrent prednisone in this patient population Subjects were to receive treatment until documented and to evaluate additional clinically relevant disease progression or unacceptable toxicity. improvements, including patient-reported outcomes (PRO), in mCRPC subjects treated with abiraterone acetate plus prednisone in comparison to placebo plus prednisone.

Protocol ABI-PRO-3002 Men with mCRPC and disease Abiraterone acetate 1,000 mg (administered as four 250 mg - The primary objective is to compare the clinical A Phase 3, Randomized, Double-Blind, progression on androgen deprivation tablets) or 4 placebo tablets orally once daily at least 1 hour benefit, as measured by an improvement in time Placebo-Controlled Study of Abiraterone therapy failure before or 2 hours after a meal, and prednisone/prednisolone to prostate specific antigen (PSA) progression Acetate (JNJ-212082) Plus Prednisone in 5 mg orally twice daily (TTPP), of abiraterone acetate plus prednisone Asymptomatic or Mildly Symptomatic N=313 versus placebo plus prednisone in subjects with Patients with Metastatic Castration-Resistant chemotherapy-naïve metastatic castration Prostate Cancer Abiraterone acetate group: 157 Subjects were to receive treatment until documented resistant prostate cancer (mCRPC) who are (China: 119; Russia: 35; Malaysia and disease progression or unacceptable toxicity or subject asymptomatic or mildly symptomatic. Secondary Thailand: 3) choice. objectives were to establish additional clinically Placebo group: 156 (China: 119; relevant improvements in prostate cancer subjects Russia: 34; Malaysis and Thailand:3) treated with abiraterone acetate in comparison to placebo and to characterize the safety profile of Phase 3 bridging study (China, Russia, abiraterone acetate with concurrent prednisone in Malaysia, and Taiwan) based on Study this subject population. COU-AA-302

100 Approved, Date: 26 August 2015 JNJ-212082 (abiraterone acetate) Investigator's Brochure - Edition 12

Appendix B.6: Ongoing Phase 3 Clinical Studies (as of 27 April 2015)

Protocol Number Subject Population Dosing Regimen Objective(s) Study Title Number of Subjects Planned Duration References (if applicable) Study Description

Protocol 212082PCR3010 The subjects enrolled in this study are Abiraterone acetate and low dose corticosteroids will be - To collect long term follow-up safety data A Phase 3b Multicenter, Open-label participating in an abiraterone acetate given orally as tablets according to the regimen established from subjects in completed abiraterone acetate Abiraterone Acetate Long-term Safety Study clinical study that is now considered in the prior abiraterone acetate clinical study (eg, studies for a maximum duration of 3 years complete and will have received at abiraterone acetate 1,000 mg once daily with prednisone from the protocol issue date of 9 April 2012. least 3 months of abiraterone acetate 5 mg orally twice daily). Lower doses of abiraterone and low dose corticosteroid treatment. acetate (500 mg or 750 mg daily) and lower doses of Eligibility criteria also include the corticosteroids are permitted per the regimen established in investigator's assessment that the prior study. continued abiraterone acetate therapy may provide clinical benefit. The Study treatment will continue until the investigator subjects should not have laboratory determines the subject is no longer receiving benefit from evaluations or medical conditions that continued treatment, or other reasons as described in the would preclude them from continuing protocol. to receive abiraterone acetate.

Estimated that ~300 subjects may participate. 56021927PCR3001 Men with chemotherapy-naive JNJ-56021927/placebo: 240 mg (4 x 60 mg tablets) daily - To compare the rPFS of JNJ 56021927 in A Phase 3 Randomized, Placebo-controlled mCRPC AA: 1,000 (4 x 250 mg tablets) daily combination with AAP to AAP alone in Double-blind Study of JNJ-56021927 in N=960 Prednisone: 10 mg (2 x 5 mg tablets) daily. subjects with chemotherapy-naïve mCRPC Combination with Abiraterone Acetate and JNJ-56021927 plus AAP (N=480) Prednisone Versus Abiraterone Acetate and Placebo plus AAP (N=480) Treatment will continue until disease progression, Prednisone in Subjects with Chemotherapy- unacceptable toxicity, death or the sponsor terminates the naive mCRPC Phase 3, randomized, placebo- study controlled, double-blind AAP=abiraterone acetate+prednisone/prednisolone; ADT= androgen deprivation therapy; AE=adverse event; ECOG=Eastern Cooperative Oncology Group; mCRPC=metastatic castration resistant prostate cancer; mHNPC=metastatic hormone-naïve prostate cancer; PRO=patient-reported outcomes; PSA=prostate-specific antigen; SAE=serious adverse event; TTPP=time to PSA progression

101 Approved, Date: 26 August 2015 JNJ-212082 (abiraterone acetate) Investigator's Brochure - Edition 12

Appendix B.7: Ongoing Phase 4 Clinical Studies (as of 27 April 2015)

Protocol Number Subject Population Dosing Regimen Objective(s) Study Title Number of Subjects Planned Duration References (if applicable) Study Description

ABI-C-14-JP-001-V03 Men with mCRPC who did not AA: 1,000 (4 x 250 mg tablets) once daily - To evaluate the response rate of ≥50% decline A Phase 4 Study of Abiraterone Acetate in sufficiently respond to initial Prednisone: 5 mg tablets twice daily (10 mg/day) of PSA from baseline by 12 weeks of therapy Metastatic Castration-Resistant Prostate combined androgen blockade therapy - To evaluate the safety of AA plus prednisone Cancer Patients Who Poorly Responded to the N=54 Treatment will continue until disease progression or 10 mg daily unacceptable toxicity is observed First-line Combined Androgen Blockade - To evaluate other secondary efficacy endpoints Therapy Phase 4, non-randomized, open-label, single-arm including PSA response, ORR, OS, and QoL outcomes

AA=abiraterone acetate; mCRPC=metastatic castration-resistant prostate cancer; ORR=overall response rate; OS=overall survival; PSA=prostate-specific antigen; QoL=quality of life

102 Approved, Date: 26 August 2015 JNJ-212082 (abiraterone acetate) Investigator's Brochure - Edition 12

APPENDIX C

103 Approved, Date: 26 August 2015 JNJ-212082 (abiraterone acetate) Investigator's Brochure - Edition 12 Appendix C.1: Pharmacokinetic Parameters for Abiraterone after a 1,000 mg Single or Daily Administration of Abiraterone Acetate under Fasting or Modified Fasting Conditions

Cmax (ng/mL) tmax(h) AUC (ng*h/mL) t1/2 (h) Study N Mean (SD) Median (Range) Mean (SD) Mean (SD) Healthy Subjects, Single Dose, Fasting Conditions COU-AA-005a 234 86.0 (47.5) 2 (1-8) 465 (212) 14.9 (4.1) COU-AA-008 8 112 (36.7) 1.8 (1-3) 617 (249) 12.7 (1.9) COU-AA-009 35 90.9 (65.3) 2 (1-4) 509 (338) 15.7 (3.7) COU-AA-010 19 101 (119) 2 (1-4) 583 (819) 15.4 (3.0) COU-AA-011 8 85.7 (46.6) 1.8 (1-3) 330 (166) 13.1 (4.2) COU-AA-012 8 104 (124) 1.5 (1-4) 497 (523) 19.0 (4.1) COU-AA-014b 64 93.4 (41.6) 2 (1-6) 529 (250) 15.2 (3.2) COU-AA-016c 57 120 (67.5) 2 (1-4) 610 (275) 16.2 (4.5) 212082PCR1002 20 131 (59.5) 1.8 (0.5-3) 682 (335) 14.8 (2.2) 212082PCR1003 19 138 (72.2) 1.5 (1-4) 747 (438) 16.3 (6.5) 212082PCR1005e 47 111 (62.1) 1.5 (1-6) 599 (271) 13.6 (3.4) 212082PCR1006 31 91.9 (51.0) 3 (1-6) 523 (275) 17.0 (3.68) 212082PCR1010 32 111 (64.3) 2 (1-8) 626 (347) 18.6 (5.53) POOLED 582 98.6 (60.1) 2 (0.5-8) 533 (310)d 15.0 (4.2) Healthy Subjects, Other Single Dose, Fasting Conditions COU-AA-007f 8 10.4 (5.50) 3 (1-3) 80.9 (44.0) 11.2 (3.9) JNJ-212082-JPN-101g 30 172.1 (150.3) 1.5 (1-4) 822 (616) 16.6 (6.9) ABI-PRO-1016h 15 106 (47) 1.5 (1-4) 424 (184) 13.3 (4.8) mCRPC Subjects Multiple Dose, Modified Fasting Conditions COU-AA-006i 33 207 (142) 2 (1-4) 965 (520) NA COU-AA-006j 33 226 (178) 2 (1-6) 993 (639) NA 212082PCR2008k 25 273 (214) 2 (0.5-8) 1,280 (874) NA POOLED 91 232 (177) 2 (0.5-8) 1,060 (681) NA

AUC=AUC∞ for single dose; AUC24h for multiple dose; Cmax=maximum observed plasma concentration; NA=not applicable or not available; SD=standard deviation; tmax= time to reach the maximum observed plasma concentration; t1/2= apparent elimination half-life Note: Fasting conditions is defined an overnight fast of at least 10 hours and a meal was given at 4 hours postdose. Modified fasting condition was defined as abiraterone acetate administration at least 2 hours after eating and no food was to be eaten for at least 1 hour after taking abiraterone acetate. a For Study COU-AA-005, abiraterone pharmacokinetic data from both Patheon commercial and Pii clinical abiraterone acetate tablets were included (n=119+115=234). b For Study COU-AA-014, abiraterone pharmacokinetic data from Patheon commercial, Pii clinical, and Pii commercial abiraterone acetate tablets were included (n=20+22+22=64). c For Study COU-AA-016, Pharmacokinetic data from the 750 mg dose was normalized to 1,000 mg and included (n=28+29=57). d Extrapolated parameters (AUC∞ and t1/2) are n=43 for 212082PCR1005; n=546 for pooled AUC∞ and for pooled t1/2 e Treatment A only f Study COU-AA-007 was not included in the overall pooled mean as this study was conducted using a non-micronized capsule formulation, while tablets were administered in all other studies listed. g Study was conducted in Japanese subjects h Study was conducted in Chinese subjects i Cycle 1 Day 8 j Cycle 2 Day 1 k Cycle 1 Day 7 only

104 Approved, Date: 26 August 2015 JNJ-212082 (abiraterone acetate) Investigator's Brochure - Edition 12

APPENDIX D

105 Approved, Date: 26 August 2015 JNJ-212082 (abiraterone acetate) Investigator's Brochure - Edition 12

Appendix D.1: Treatment-Emergent Adverse Events by Toxicity Grade where Combined AA is at least 1% Greater Than Combined Placebo Integrated Safety Population Receiving 1,000mg/day AA in All Clinical Trials COU-AA-301 AA Placebo (N=791) (N=394) System Organ Class Preferred Term Total Grade 1 Grade 2 Grade 3 Grade 4 Total Grade 1 Grade 2 Grade 3 Grade 4 Total no. of subjects with treatment- 784 (99.1%) 76 (9.6%) 230 (29.1%) 382 (48.3%) 96 (12.1%) 390 (99.0%) 46 (11.7%) 104 (26.4%) 194 (49.2%) 46 (11.7%) emergent adverse event

Musculoskeletal and connective tissue 599 (75.7%) 180 (22.8%) 240 (30.3%) 170 (21.5%) 8 (1.0%) 298 (75.6%) 77 (19.5%) 120 (30.5%) 94 (23.9%) 7 (1.8%) disorders Arthralgia 239 (30.2%) 96 (12.1%) 103 (13.0%) 40 (5.1%) 0 95 (24.1%) 33 (8.4%) 45 (11.4%) 17 (4.3%) 0 Musculoskeletal pain 134 (16.9%) 73 (9.2%) 38 (4.8%) 22 (2.8%) 1 (0.1%) 56 (14.2%) 25 (6.3%) 23 (5.8%) 8 (2.0%) 0 Groin pain 47 (5.9%) 27 (3.4%) 13 (1.6%) 7 (0.9%) 0 22 (5.6%) 8 (2.0%) 11 (2.8%) 3 (0.8%) 0 Musculoskeletal stiffness 18 (2.3%) 15 (1.9%) 2 (0.3%) 1 (0.1%) 0 2 (0.5%) 2 (0.5%) 0 0 0

General disorders and administration site 569 (71.9%) 222 (28.1%) 212 (26.8%) 129 (16.3%) 6 (0.8%) 268 (68.0%) 102 (25.9%) 98 (24.9%) 62 (15.7%) 5 (1.3%) conditions Fatigue 372 (47.0%) 147 (18.6%) 153 (19.3%) 70 (8.8%) 2 (0.3%) 174 (44.2%) 64 (16.2%) 69 (17.5%) 38 (9.6%) 3 (0.8%) Oedema peripheral 212 (26.8%) 143 (18.1%) 55 (7.0%) 13 (1.6%) 1 (0.1%) 75 (19.0%) 53 (13.5%) 19 (4.8%) 3 (0.8%) 0 Pyrexia 80 (10.1%) 51 (6.4%) 26 (3.3%) 3 (0.4%) 0 36 (9.1%) 22 (5.6%) 8 (2.0%) 5 (1.3%) 0 Disease progression 27 (3.4%) 1 (0.1%) 12 (1.5%) 12 (1.5%) 2 (0.3%) 6 (1.5%) 0 4 (1.0%) 2 (0.5%) 0

Gastrointestinal disorders 558 (70.5%) 270 (34.1%) 207 (26.2%) 73 (9.2%) 8 (1.0%) 267 (67.8%) 132 (33.5%) 99 (25.1%) 33 (8.4%) 2 (0.5%) Constipation 223 (28.2%) 125 (15.8%) 88 (11.1%) 10 (1.3%) 0 126 (32.0%) 73 (18.5%) 49 (12.4%) 4 (1.0%) 0 Diarrhoea 156 (19.7%) 99 (12.5%) 48 (6.1%) 8 (1.0%) 1 (0.1%) 58 (14.7%) 38 (9.6%) 14 (3.6%) 5 (1.3%) 0 Vomiting 191 (24.1%) 103 (13.0%) 67 (8.5%) 20 (2.5%) 1 (0.1%) 101 (25.6%) 63 (16.0%) 26 (6.6%) 12 (3.0%) 0 Dyspepsia 51 (6.4%) 38 (4.8%) 13 (1.6%) 0 0 15 (3.8%) 12 (3.0%) 3 (0.8%) 0 0 Dry mouth 59 (7.5%) 50 (6.3%) 9 (1.1%) 0 0 20 (5.1%) 17 (4.3%) 2 (0.5%) 1 (0.3%) 0

Metabolism and nutrition disorders 397 (50.2%) 165 (20.9%) 124 (15.7%) 99 (12.5%) 9 (1.1%) 170 (43.1%) 73 (18.5%) 52 (13.2%) 44 (11.2%) 1 (0.3%) Hypokalaemia 143 (18.1%) 99 (12.5%) 9 (1.1%) 31 (3.9%) 4 (0.5%) 36 (9.1%) 30 (7.6%) 3 (0.8%) 3 (0.8%) 0 Anorexia 143 (18.1%) 60 (7.6%) 71 (9.0%) 12 (1.5%) 0 75 (19.0%) 31 (7.9%) 31 (7.9%) 13 (3.3%) 0 Hyperglycaemia 57 (7.2%) 24 (3.0%) 19 (2.4%) 14 (1.8%) 0 21 (5.3%) 11 (2.8%) 4 (1.0%) 6 (1.5%) 0 Hyponatraemia 22 (2.8%) 10 (1.3%) 1 (0.1%) 10 (1.3%) 1 (0.1%) 7 (1.8%) 4 (1.0%) 0 3 (0.8%) 0

106 Approved, Date: 26 August 2015 JNJ-212082 (abiraterone acetate) Investigator's Brochure - Edition 12

Appendix D.1: Treatment-Emergent Adverse Events by Toxicity Grade where Combined AA is at least 1% Greater Than Combined Placebo Integrated Safety Population Receiving 1,000mg/day AA in All Clinical Trials COU-AA-302 AA Placebo (N=542) (N=540) System Organ Class Preferred Term Total Grade 1 Grade 2 Grade 3 Grade 4 Total Grade 1 Grade 2 Grade 3 Grade 4 Total no. of subjects with treatment- 537 (99.1%) 74 (13.7%) 205 (37.8%) 218 (40.2%) 40 (7.4%) 524 (97.0%) 104 (19.3%) 195 (36.1%) 195 (36.1%) 30 (5.6%) emergent adverse event

Musculoskeletal and connective tissue 392 (72.3%) 177 (32.7%) 171 (31.5%) 41 (7.6%) 2 (0.4%) 405 (75.0%) 184 (34.1%) 162 (30.0%) 59 (10.9%) 0 disorders Arthralgia 154 (28.4%) 91 (16.8%) 53 (9.8%) 10 (1.8%) 0 129 (23.9%) 78 (14.4%) 40 (7.4%) 10 (1.9%) 0 Musculoskeletal pain 78 (14.4%) 51 (9.4%) 23 (4.2%) 4 (0.7%) 0 78 (14.4%) 46 (8.5%) 26 (4.8%) 6 (1.1%) 0 Groin pain 36 (6.6%) 24 (4.4%) 10 (1.8%) 2 (0.4%) 0 22 (4.1%) 11 (2.0%) 7 (1.3%) 4 (0.7%) 0 Musculoskeletal stiffness 9 (1.7%) 8 (1.5%) 1 (0.2%) 0 0 6 (1.1%) 5 (0.9%) 1 (0.2%) 0 0

General disorders and administration site 351 (64.8%) 212 (39.1%) 112 (20.7%) 25 (4.6%) 2 (0.4%) 307 (56.9%) 183 (33.9%) 94 (17.4%) 29 (5.4%) 1 (0.2%) conditions Fatigue 212 (39.1%) 136 (25.1%) 64 (11.8%) 12 (2.2%) 0 185 (34.3%) 123 (22.8%) 53 (9.8%) 9 (1.7%) 0 Oedema peripheral 134 (24.7%) 101 (18.6%) 30 (5.5%) 2 (0.4%) 0 108 (20.0%) 73 (13.5%) 30 (5.6%) 5 (0.9%) 0 Pyrexia 47 (8.7%) 30 (5.5%) 13 (2.4%) 3 (0.6%) 0 32 (5.9%) 20 (3.7%) 11 (2.0%) 1 (0.2%) 0 Disease progression 4 (0.7%) 0 0 3 (0.6%) 1 (0.2%) 2 (0.4%) 0 1 (0.2%) 1 (0.2%) 0

Gastrointestinal disorders 347 (64.0%) 205 (37.8%) 116 (21.4%) 25 (4.6%) 1 (0.2%) 323 (59.8%) 208 (38.5%) 91 (16.9%) 20 (3.7%) 4 (0.7%) Constipation 125 (23.1%) 84 (15.5%) 39 (7.2%) 2 (0.4%) 0 103 (19.1%) 83 (15.4%) 17 (3.1%) 3 (0.6%) 0 Diarrhoea 117 (21.6%) 81 (14.9%) 31 (5.7%) 5 (0.9%) 0 96 (17.8%) 72 (13.3%) 19 (3.5%) 5 (0.9%) 0 Vomiting 69 (12.7%) 38 (7.0%) 26 (4.8%) 4 (0.7%) 0 58 (10.7%) 40 (7.4%) 18 (3.3%) 0 0 Dyspepsia 60 (11.1%) 47 (8.7%) 13 (2.4%) 0 0 27 (5.0%) 22 (4.1%) 4 (0.7%) 1 (0.2%) 0 Dry mouth 17 (3.1%) 17 (3.1%) 0 0 0 16 (3.0%) 14 (2.6%) 1 (0.2%) 1 (0.2%) 0

Metabolism and nutrition disorders 226 (41.7%) 113 (20.8%) 56 (10.3%) 52 (9.6%) 5 (0.9%) 216 (40.0%) 133 (24.6%) 44 (8.1%) 35 (6.5%) 4 (0.7%) Hypokalaemia 91 (16.8%) 73 (13.5%) 5 (0.9%) 12 (2.2%) 1 (0.2%) 68 (12.6%) 58 (10.7%) 0 10 (1.9%) 0 Anorexia 39 (7.2%) 25 (4.6%) 8 (1.5%) 6 (1.1%) 0 36 (6.7%) 27 (5.0%) 8 (1.5%) 1 (0.2%) 0 Hyperglycaemia 45 (8.3%) 16 (3.0%) 16 (3.0%) 12 (2.2%) 1 (0.2%) 41 (7.6%) 22 (4.1%) 9 (1.7%) 8 (1.5%) 2 (0.4%) Hyponatraemia 13 (2.4%) 3 (0.6%) 1 (0.2%) 8 (1.5%) 1 (0.2%) 14 (2.6%) 6 (1.1%) 1 (0.2%) 7 (1.3%) 0

107 Approved, Date: 26 August 2015 JNJ-212082 (abiraterone acetate) Investigator's Brochure - Edition 12

Appendix D.1: Treatment-Emergent Adverse Events by Toxicity Grade where Combined AA is at least 1% Greater Than Combined Placebo Integrated Safety Population Receiving 1,000mg/day AA in All Clinical Trials Pooled Phase 1/2 AA (N=347) System Organ Class Preferred Term Total Grade 1 Grade 2 Grade 3 Grade 4 Total no. of subjects with treatment- 345 (99.4%) 42 (12.1%) 120 (34.6%) 161 (46.4%) 22 (6.3%) emergent adverse event

Musculoskeletal and connective tissue 251 (72.3%) 110 (31.7%) 88 (25.4%) 52 (15.0%) 1 (0.3%) disorders Arthralgia 102 (29.4%) 58 (16.7%) 29 (8.4%) 15 (4.3%) 0 Musculoskeletal pain 53 (15.3%) 32 (9.2%) 16 (4.6%) 5 (1.4%) 0 Groin pain 20 (5.8%) 8 (2.3%) 7 (2.0%) 5 (1.4%) 0 Musculoskeletal stiffness 8 (2.3%) 7 (2.0%) 1 (0.3%) 0 0

General disorders and administration site 233 (67.1%) 94 (27.1%) 110 (31.7%) 27 (7.8%) 2 (0.6%) conditions Fatigue 177 (51.0%) 68 (19.6%) 85 (24.5%) 21 (6.1%) 2 (0.6%) Oedema peripheral 98 (28.2%) 72 (20.7%) 25 (7.2%) 1 (0.3%) 0 Pyrexia 31 (8.9%) 19 (5.5%) 9 (2.6%) 2 (0.6%) 0 Disease progression 1 (0.3%) 0 1 (0.3%) 0 0

Gastrointestinal disorders 203 (58.5%) 125 (36.0%) 59 (17.0%) 19 (5.5%) 0 Constipation 80 (23.1%) 64 (18.4%) 14 (4.0%) 1 (0.3%) 0 Diarrhoea 70 (20.2%) 48 (13.8%) 18 (5.2%) 4 (1.2%) 0 Vomiting 62 (17.9%) 36 (10.4%) 20 (5.8%) 6 (1.7%) 0 Dyspepsia 14 (4.0%) 11 (3.2%) 2 (0.6%) 0 0 Dry mouth 13 (3.7%) 12 (3.5%) 0 0 0

Metabolism and nutrition disorders 225 (64.8%) 125 (36.0%) 64 (18.4%) 34 (9.8%) 2 (0.6%) Hypokalaemia 121 (34.9%) 105 (30.3%) 5 (1.4%) 9 (2.6%) 2 (0.6%) Anorexia 56 (16.1%) 35 (10.1%) 18 (5.2%) 3 (0.9%) 0 Hyperglycaemia 80 (23.1%) 40 (11.5%) 29 (8.4%) 11 (3.2%) 0 Hyponatraemia 20 (5.8%) 12 (3.5%) 3 (0.9%) 5 (1.4%) 0

108 Approved, Date: 26 August 2015 JNJ-212082 (abiraterone acetate) Investigator's Brochure - Edition 12

Appendix D.1: Treatment-Emergent Adverse Events by Toxicity Grade where Combined AA is at least 1% Greater Than Combined Placebo Integrated Safety Population Receiving 1,000mg/day AA in All Clinical Trials All Clinical Trials Combined AA a Placebo (N=1680) (N=934) System Organ Class Preferred Term Total Grade 1 Grade 2 Grade 3 Grade 4 Total Grade 1 Grade 2 Grade 3 Grade 4 Diff b Total no. of subjects with treatment- 1666 192 (11.4%) 555 (33.0%) 761 (45.3%) 158 (9.4%) 914 (97.9%) 150 (16.1%) 299 (32.0%) 389 (41.6%) 76 (8.1%) 1.3 emergent adverse event (99.2%)

Musculoskeletal and connective tissue 1242 467 (27.8%) 499 (29.7%) 263 (15.7%) 11 (0.7%) 703 (75.3%) 261 (27.9%) 282 (30.2%) 153 (16.4%) 7 (0.7%) -1.3 disorders (73.9%) Arthralgia 495 (29.5%) 245 (14.6%) 185 (11.0%) 65 (3.9%) 0 224 (24.0%) 111 (11.9%) 85 (9.1%) 27 (2.9%) 0 5.5 Musculoskeletal pain 265 (15.8%) 156 (9.3%) 77 (4.6%) 31 (1.8%) 1 (0.1%) 134 (14.3%) 71 (7.6%) 49 (5.2%) 14 (1.5%) 0 1.4 Groin pain 103 (6.1%) 59 (3.5%) 30 (1.8%) 14 (0.8%) 0 44 (4.7%) 19 (2.0%) 18 (1.9%) 7 (0.7%) 0 1.4 Musculoskeletal stiffness 35 (2.1%) 30 (1.8%) 4 (0.2%) 1 (0.1%) 0 8 (0.9%) 7 (0.7%) 1 (0.1%) 0 0 1.2

General disorders and administration site 1153 528 (31.4%) 434 (25.8%) 181 (10.8%) 10 (0.6%) 575 (61.6%) 285 (30.5%) 192 (20.6%) 91 (9.7%) 6 (0.6%) 7.1 conditions (68.6%) Fatigue 761 (45.3%) 351 (20.9%) 302 (18.0%) 103 (6.1%) 4 (0.2%) 359 (38.4%) 187 (20.0%) 122 (13.1%) 47 (5.0%) 3 (0.3%) 6.9 Oedema peripheral 444 (26.4%) 316 (18.8%) 110 (6.5%) 16 (1.0%) 1 (0.1%) 183 (19.6%) 126 (13.5%) 49 (5.2%) 8 (0.9%) 0 6.8 Pyrexia 158 (9.4%) 100 (6.0%) 48 (2.9%) 8 (0.5%) 0 68 (7.3%) 42 (4.5%) 19 (2.0%) 6 (0.6%) 0 2.1 Disease progression 32 (1.9%) 1 (0.1%) 13 (0.8%) 15 (0.9%) 3 (0.2%) 8 (0.9%) 0 5 (0.5%) 3 (0.3%) 0 1

Gastrointestinal disorders 1108 600 (35.7%) 382 (22.7%) 117 (7.0%) 9 (0.5%) 590 (63.2%) 340 (36.4%) 190 (20.3%) 53 (5.7%) 6 (0.6%) 2.8 (66.0%) Constipation 428 (25.5%) 273 (16.3%) 141 (8.4%) 13 (0.8%) 0 229 (24.5%) 156 (16.7%) 66 (7.1%) 7 (0.7%) 0 1 Diarrhoea 343 (20.4%) 228 (13.6%) 97 (5.8%) 17 (1.0%) 1 (0.1%) 154 (16.5%) 110 (11.8%) 33 (3.5%) 10 (1.1%) 0 3.9 Vomiting 322 (19.2%) 177 (10.5%) 113 (6.7%) 30 (1.8%) 1 (0.1%) 159 (17.0%) 103 (11.0%) 44 (4.7%) 12 (1.3%) 0 2.1 Dyspepsia 125 (7.4%) 96 (5.7%) 28 (1.7%) 0 0 42 (4.5%) 34 (3.6%) 7 (0.7%) 1 (0.1%) 0 2.9 Dry mouth 89 (5.3%) 79 (4.7%) 9 (0.5%) 0 0 36 (3.9%) 31 (3.3%) 3 (0.3%) 2 (0.2%) 0 1.4

Metabolism and nutrition disorders 848 (50.5%) 403 (24.0%) 244 (14.5%) 185 (11.0%) 16 (1.0%) 386 (41.3%) 206 (22.1%) 96 (10.3%) 79 (8.5%) 5 (0.5%) 9.1 Hypokalaemia 355 (21.1%) 277 (16.5%) 19 (1.1%) 52 (3.1%) 7 (0.4%) 104 (11.1%) 88 (9.4%) 3 (0.3%) 13 (1.4%) 0 10 Anorexia 238 (14.2%) 120 (7.1%) 97 (5.8%) 21 (1.3%) 0 111 (11.9%) 58 (6.2%) 39 (4.2%) 14 (1.5%) 0 2.3 Hyperglycaemia 182 (10.8%) 80 (4.8%) 64 (3.8%) 37 (2.2%) 1 (0.1%) 62 (6.6%) 33 (3.5%) 13 (1.4%) 14 (1.5%) 2 (0.2%) 4.2 Hyponatraemia 55 (3.3%) 25 (1.5%) 5 (0.3%) 23 (1.4%) 2 (0.1%) 21 (2.2%) 10 (1.1%) 1 (0.1%) 10 (1.1%) 0 1

109 Approved, Date: 26 August 2015 JNJ-212082 (abiraterone acetate) Investigator's Brochure - Edition 12

Appendix D.1: Treatment-Emergent Adverse Events by Toxicity Grade where Combined AA is at least 1% Greater Than Combined Placebo Integrated Safety Population Receiving 1.000 mg/day AA in All Clinical Trials COU-AA-301 AA Placebo (N=791) (N=394) System Organ Class Preferred Term Total Grade 1 Grade 2 Grade 3 Grade 4 Total Grade 1 Grade 2 Grade 3 Grade 4 Hyperkalaemia 23 (2.9%) 10 (1.3%) 7 (0.9%) 6 (0.8%) 0 5 (1.3%) 2 (0.5%) 0 3 (0.8%) 0 Hypocalcaemia 24 (3.0%) 11 (1.4%) 12 (1.5%) 1 (0.1%) 0 11 (2.8%) 3 (0.8%) 4 (1.0%) 4 (1.0%) 0 Hypophosphataemia 25 (3.2%) 5 (0.6%) 7 (0.9%) 11 (1.4%) 2 (0.3%) 4 (1.0%) 0 1 (0.3%) 2 (0.5%) 1 (0.3%) Hypoalbuminaemia 6 (0.8%) 3 (0.4%) 3 (0.4%) 0 0 5 (1.3%) 1 (0.3%) 4 (1.0%) 0 0 Hypertriglyceridaemia 11 (1.4%) 9 (1.1%) 1 (0.1%) 1 (0.1%) 0 0 0 0 0 0 Hypomagnesaemia 8 (1.0%) 5 (0.6%) 1 (0.1%) 1 (0.1%) 1 (0.1%) 3 (0.8%) 3 (0.8%) 0 0 0

Infections and infestations 358 (45.3%) 111 (14.0%) 169 (21.4%) 69 (8.7%) 9 (1.1%) 137 (34.8%) 65 (16.5%) 50 (12.7%) 18 (4.6%) 4 (1.0%) Urinary tract infection 105 (13.3%) 35 (4.4%) 48 (6.1%) 22 (2.8%) 0 29 (7.4%) 8 (2.0%) 18 (4.6%) 3 (0.8%) 0 Upper respiratory tract infection 49 (6.2%) 25 (3.2%) 23 (2.9%) 1 (0.1%) 0 11 (2.8%) 8 (2.0%) 3 (0.8%) 0 0 Pneumonia 33 (4.2%) 2 (0.3%) 13 (1.6%) 15 (1.9%) 3 (0.4%) 9 (2.3%) 0 5 (1.3%) 4 (1.0%) 0 Sinusitis 10 (1.3%) 6 (0.8%) 4 (0.5%) 0 0 5 (1.3%) 2 (0.5%) 1 (0.3%) 2 (0.5%) 0 15 (1.9%) 1 (0.1%) 4 (0.5%) 7 (0.9%) 3 (0.4%) 2 (0.5%) 0 0 0 2 (0.5%)

Vascular disorders 266 (33.6%) 129 (16.3%) 106 (13.4%) 29 (3.7%) 2 (0.3%) 127 (32.2%) 72 (18.3%) 49 (12.4%) 5 (1.3%) 1 (0.3%) Hot flush 154 (19.5%) 104 (13.1%) 48 (6.1%) 2 (0.3%) 0 68 (17.3%) 47 (11.9%) 20 (5.1%) 1 (0.3%) 0 Hypertension 76 (9.6%) 24 (3.0%) 42 (5.3%) 10 (1.3%) 0 27 (6.9%) 10 (2.5%) 16 (4.1%) 1 (0.3%) 0 Haematoma 14 (1.8%) 12 (1.5%) 2 (0.3%) 0 0 4 (1.0%) 4 (1.0%) 0 0 0

Respiratory, thoracic and mediastinal 296 (37.4%) 183 (23.1%) 79 (10.0%) 24 (3.0%) 10 (1.3%) 120 (30.5%) 67 (17.0%) 28 (7.1%) 13 (3.3%) 11 (2.8%) disorders Dyspnoea 116 (14.7%) 63 (8.0%) 39 (4.9%) 12 (1.5%) 2 (0.3%) 49 (12.4%) 22 (5.6%) 17 (4.3%) 7 (1.8%) 2 (0.5%) 101 (12.8%) 82 (10.4%) 19 (2.4%) 0 0 32 (8.1%) 25 (6.3%) 7 (1.8%) 0 0

Investigations 260 (32.9%) 120 (15.2%) 87 (11.0%) 50 (6.3%) 3 (0.4%) 109 (27.7%) 50 (12.7%) 41 (10.4%) 13 (3.3%) 5 (1.3%) Aspartate aminotransferase increased 34 (4.3%) 14 (1.8%) 12 (1.5%) 7 (0.9%) 1 (0.1%) 16 (4.1%) 6 (1.5%) 5 (1.3%) 4 (1.0%) 1 (0.3%) Alanine aminotransferase increased 22 (2.8%) 9 (1.1%) 5 (0.6%) 8 (1.0%) 0 7 (1.8%) 3 (0.8%) 2 (0.5%) 1 (0.3%) 1 (0.3%) Blood alkaline phosphatase increased 37 (4.7%) 16 (2.0%) 8 (1.0%) 12 (1.5%) 1 (0.1%) 18 (4.6%) 3 (0.8%) 8 (2.0%) 6 (1.5%) 1 (0.3%) Blood creatinine increased 32 (4.0%) 14 (1.8%) 11 (1.4%) 6 (0.8%) 1 (0.1%) 10 (2.5%) 6 (1.5%) 4 (1.0%) 0 0

110 Approved, Date: 26 August 2015 JNJ-212082 (abiraterone acetate) Investigator's Brochure - Edition 12

Appendix D.1: Treatment-Emergent Adverse Events by Toxicity Grade where Combined AA is at least 1% Greater Than Combined Placebo Integrated Safety Population Receiving 1,000 mg/day AA in All Clinical Trials COU-AA-302 AA Placebo (N=542) (N=540) System Organ Class Preferred Term Total Grade 1 Grade 2 Grade 3 Grade 4 Total Grade 1 Grade 2 Grade 3 Grade 4 Hyperkalaemia 9 (1.7%) 4 (0.7%) 4 (0.7%) 1 (0.2%) 0 10 (1.9%) 2 (0.4%) 5 (0.9%) 3 (0.6%) 0 Hypocalcaemia 8 (1.5%) 4 (0.7%) 4 (0.7%) 0 0 3 (0.6%) 0 2 (0.4%) 0 1 (0.2%) Hypophosphataemia 10 (1.8%) 1 (0.2%) 4 (0.7%) 4 (0.7%) 1 (0.2%) 8 (1.5%) 0 1 (0.2%) 7 (1.3%) 0 Hypoalbuminaemia 4 (0.7%) 3 (0.6%) 1 (0.2%) 0 0 5 (0.9%) 5 (0.9%) 0 0 0 Hypertriglyceridaemia 7 (1.3%) 6 (1.1%) 1 (0.2%) 0 0 5 (0.9%) 5 (0.9%) 0 0 0 Hypomagnesaemia 5 (0.9%) 5 (0.9%) 0 0 0 5 (0.9%) 4 (0.7%) 1 (0.2%) 0 0

Infections and infestations 297 (54.8%) 106 (19.6%) 150 (27.7%) 39 (7.2%) 1 (0.2%) 210 (38.9%) 79 (14.6%) 98 (18.1%) 32 (5.9%) 1 (0.2%) Urinary tract infection 46 (8.5%) 10 (1.8%) 28 (5.2%) 8 (1.5%) 0 39 (7.2%) 15 (2.8%) 21 (3.9%) 3 (0.6%) 0 Upper respiratory tract infection 69 (12.7%) 45 (8.3%) 24 (4.4%) 0 0 43 (8.0%) 26 (4.8%) 17 (3.1%) 0 0 Pneumonia 11 (2.0%) 0 4 (0.7%) 7 (1.3%) 0 10 (1.9%) 0 6 (1.1%) 4 (0.7%) 0 Sinusitis 24 (4.4%) 13 (2.4%) 10 (1.8%) 1 (0.2%) 0 6 (1.1%) 3 (0.6%) 2 (0.4%) 1 (0.2%) 0 Sepsis 5 (0.9%) 0 1 (0.2%) 3 (0.6%) 1 (0.2%) 2 (0.4%) 0 0 2 (0.4%) 0

Vascular disorders 252 (46.5%) 130 (24.0%) 88 (16.2%) 30 (5.5%) 4 (0.7%) 182 (33.7%) 93 (17.2%) 59 (10.9%) 30 (5.6%) 0 Hot flush 121 (22.3%) 95 (17.5%) 25 (4.6%) 1 (0.2%) 0 98 (18.1%) 72 (13.3%) 26 (4.8%) 0 0 Hypertension 117 (21.6%) 45 (8.3%) 51 (9.4%) 21 (3.9%) 0 71 (13.1%) 27 (5.0%) 28 (5.2%) 16 (3.0%) 0 Haematoma 19 (3.5%) 17 (3.1%) 2 (0.4%) 0 0 6 (1.1%) 5 (0.9%) 1 (0.2%) 0 0

Respiratory, thoracic and mediastinal 201 (37.1%) 136 (25.1%) 38 (7.0%) 18 (3.3%) 8 (1.5%) 176 (32.6%) 123 (22.8%) 30 (5.6%) 15 (2.8%) 7 (1.3%) disorders Dyspnoea 64 (11.8%) 42 (7.7%) 8 (1.5%) 11 (2.0%) 2 (0.4%) 52 (9.6%) 32 (5.9%) 14 (2.6%) 4 (0.7%) 1 (0.2%) Cough 94 (17.3%) 76 (14.0%) 18 (3.3%) 0 0 73 (13.5%) 65 (12.0%) 7 (1.3%) 1 (0.2%) 0

Investigations 182 (33.6%) 75 (13.8%) 60 (11.1%) 40 (7.4%) 7 (1.3%) 142 (26.3%) 83 (15.4%) 35 (6.5%) 21 (3.9%) 3 (0.6%) Aspartate aminotransferase increased 58 (10.7%) 23 (4.2%) 19 (3.5%) 16 (3.0%) 0 26 (4.8%) 13 (2.4%) 8 (1.5%) 5 (0.9%) 0 Alanine aminotransferase increased 63 (11.6%) 13 (2.4%) 21 (3.9%) 26 (4.8%) 3 (0.6%) 27 (5.0%) 18 (3.3%) 5 (0.9%) 3 (0.6%) 1 (0.2%) Blood alkaline phosphatase increased 18 (3.3%) 6 (1.1%) 7 (1.3%) 5 (0.9%) 0 23 (4.3%) 11 (2.0%) 8 (1.5%) 3 (0.6%) 1 (0.2%) Blood creatinine increased 16 (3.0%) 12 (2.2%) 3 (0.6%) 1 (0.2%) 0 15 (2.8%) 6 (1.1%) 7 (1.3%) 1 (0.2%) 1 (0.2%)

111 Approved, Date: 26 August 2015 JNJ-212082 (abiraterone acetate) Investigator's Brochure - Edition 12

Appendix D.1: Treatment-Emergent Adverse Events by Toxicity Grade where Combined AA is at least 1% Greater Than Combined Placebo Integrated Safety Population Receiving 1,000mg/day AA in All Clinical Trials Pooled Phase 1/2 AA (N=347) System Organ Class Preferred Term Total Grade 1 Grade 2 Grade 3 Grade 4 Hyperkalaemia 18 (5.2%) 14 (4.0%) 3 (0.9%) 1 (0.3%) 0 Hypocalcaemia 13 (3.7%) 6 (1.7%) 7 (2.0%) 0 0 Hypophosphataemia 8 (2.3%) 0 5 (1.4%) 3 (0.9%) 0 Hypoalbuminaemia 30 (8.6%) 17 (4.9%) 13 (3.7%) 0 0 Hypertriglyceridaemia 17 (4.9%) 15 (4.3%) 2 (0.6%) 0 0 Hypomagnesaemia 19 (5.5%) 19 (5.5%) 0 0 0

Infections and infestations 133 (38.3%) 50 (14.4%) 49 (14.1%) 30 (8.6%) 4 (1.2%) Urinary tract infection 44 (12.7%) 17 (4.9%) 16 (4.6%) 10 (2.9%) 1 (0.3%) Upper respiratory tract infection 29 (8.4%) 19 (5.5%) 9 (2.6%) 1 (0.3%) 0 Pneumonia 12 (3.5%) 0 2 (0.6%) 9 (2.6%) 1 (0.3%) Sinusitis 5 (1.4%) 3 (0.9%) 2 (0.6%) 0 0 Sepsis 6 (1.7%) 0 1 (0.3%) 3 (0.9%) 2 (0.6%)

Vascular disorders 121 (34.9%) 63 (18.2%) 48 (13.8%) 9 (2.6%) 1 (0.3%) Hot flush 43 (12.4%) 33 (9.5%) 10 (2.9%) 0 0 Hypertension 70 (20.2%) 40 (11.5%) 24 (6.9%) 6 (1.7%) 0 Haematoma 2 (0.6%) 2 (0.6%) 0 0 0

Respiratory, thoracic and mediastinal 126 (36.3%) 79 (22.8%) 29 (8.4%) 14 (4.0%) 4 (1.2%) disorders Dyspnoea 59 (17.0%) 30 (8.6%) 20 (5.8%) 8 (2.3%) 1 (0.3%) Cough 36 (10.4%) 30 (8.6%) 6 (1.7%) 0 0

Investigations 160 (46.1%) 73 (21.0%) 40 (11.5%) 43 (12.4%) 3 (0.9%) Aspartate aminotransferase increased 51 (14.7%) 30 (8.6%) 17 (4.9%) 3 (0.9%) 1 (0.3%) Alanine aminotransferase increased 34 (9.8%) 22 (6.3%) 7 (2.0%) 5 (1.4%) 0 Blood alkaline phosphatase increased 54 (15.6%) 21 (6.1%) 7 (2.0%) 25 (7.2%) 1 (0.3%) Blood creatinine increased 18 (5.2%) 13 (3.7%) 5 (1.4%) 0 0

112 Approved, Date: 26 August 2015 JNJ-212082 (abiraterone acetate) Investigator's Brochure - Edition 12

Appendix D.1: Treatment-Emergent Adverse Events by Toxicity Grade where Combined AA is at least 1% Greater Than Combined Placebo Integrated Safety Population Receiving 1,000 mg/day AA in All Clinical Trials All Clinical Trials Combined AA a Placebo (N=1680) (N=934) System Organ Class Preferred Term Total Grade 1 Grade 2 Grade 3 Grade 4 Total Grade 1 Grade 2 Grade 3 Grade 4 Diff b Hyperkalaemia 50 (3.0%) 28 (1.7%) 14 (0.8%) 8 (0.5%) 0 15 (1.6%) 4 (0.4%) 5 (0.5%) 6 (0.6%) 0 1.4 Hypocalcaemia 45 (2.7%) 21 (1.3%) 23 (1.4%) 1 (0.1%) 0 14 (1.5%) 3 (0.3%) 6 (0.6%) 4 (0.4%) 1 (0.1%) 1.2 Hypophosphataemia 43 (2.6%) 6 (0.4%) 16 (1.0%) 18 (1.1%) 3 (0.2%) 12 (1.3%) 0 2 (0.2%) 9 (1.0%) 1 (0.1%) 1.3 Hypoalbuminaemia 40 (2.4%) 23 (1.4%) 17 (1.0%) 0 0 10 (1.1%) 6 (0.6%) 4 (0.4%) 0 0 1.3 Hypertriglyceridaemia 35 (2.1%) 30 (1.8%) 4 (0.2%) 1 (0.1%) 0 5 (0.5%) 5 (0.5%) 0 0 0 1.5 Hypomagnesaemia 32 (1.9%) 29 (1.7%) 1 (0.1%) 1 (0.1%) 1 (0.1%) 8 (0.9%) 7 (0.7%) 1 (0.1%) 0 0 1

Infections and infestations 788 (46.9%) 267 (15.9%) 368 (21.9%) 138 (8.2%) 14 (0.8%) 347 (37.2%) 144 (15.4%) 148 (15.8%) 50 (5.4%) 5 (0.5%) 9.8 Urinary tract infection 195 (11.6%) 62 (3.7%) 92 (5.5%) 40 (2.4%) 1 (0.1%) 68 (7.3%) 23 (2.5%) 39 (4.2%) 6 (0.6%) 0 4.3 Upper respiratory tract infection 147 (8.8%) 89 (5.3%) 56 (3.3%) 2 (0.1%) 0 54 (5.8%) 34 (3.6%) 20 (2.1%) 0 0 3 Pneumonia 56 (3.3%) 2 (0.1%) 19 (1.1%) 31 (1.8%) 4 (0.2%) 19 (2.0%) 0 11 (1.2%) 8 (0.9%) 0 1.3 Sinusitis 39 (2.3%) 22 (1.3%) 16 (1.0%) 1 (0.1%) 0 11 (1.2%) 5 (0.5%) 3 (0.3%) 3 (0.3%) 0 1.1 Sepsis 26 (1.5%) 1 (0.1%) 6 (0.4%) 13 (0.8%) 6 (0.4%) 4 (0.4%) 0 0 2 (0.2%) 2 (0.2%) 1.1

Vascular disorders 639 (38.0%) 322 (19.2%) 242 (14.4%) 68 (4.0%) 7 (0.4%) 309 (33.1%) 165 (17.7%) 108 (11.6%) 35 (3.7%) 1 (0.1%) 5 Hot flush 318 (18.9%) 232 (13.8%) 83 (4.9%) 3 (0.2%) 0 166 (17.8%) 119 (12.7%) 46 (4.9%) 1 (0.1%) 0 1.2 Hypertension 263 (15.7%) 109 (6.5%) 117 (7.0%) 37 (2.2%) 0 98 (10.5%) 37 (4.0%) 44 (4.7%) 17 (1.8%) 0 5.2 Haematoma 35 (2.1%) 31 (1.8%) 4 (0.2%) 0 0 10 (1.1%) 9 (1.0%) 1 (0.1%) 0 0 1

Respiratory, thoracic and mediastinal 623 (37.1%) 398 (23.7%) 146 (8.7%) 56 (3.3%) 22 (1.3%) 296 (31.7%) 190 (20.3%) 58 (6.2%) 28 (3.0%) 18 (1.9%) 5.4 disorders Dyspnoea 239 (14.2%) 135 (8.0%) 67 (4.0%) 31 (1.8%) 5 (0.3%) 101 (10.8%) 54 (5.8%) 31 (3.3%) 11 (1.2%) 3 (0.3%) 3.4 Cough 231 (13.8%) 188 (11.2%) 43 (2.6%) 0 0 105 (11.2%) 90 (9.6%) 14 (1.5%) 1 (0.1%) 0 2.5

Investigations 602 (35.8%) 268 (16.0%) 187 (11.1%) 133 (7.9%) 13 (0.8%) 251 (26.9%) 133 (14.2%) 76 (8.1%) 34 (3.6%) 8 (0.9%) 9 Aspartate aminotransferase increased 143 (8.5%) 67 (4.0%) 48 (2.9%) 26 (1.5%) 2 (0.1%) 42 (4.5%) 19 (2.0%) 13 (1.4%) 9 (1.0%) 1 (0.1%) 4 Alanine aminotransferase increased 119 (7.1%) 44 (2.6%) 33 (2.0%) 39 (2.3%) 3 (0.2%) 34 (3.6%) 21 (2.2%) 7 (0.7%) 4 (0.4%) 2 (0.2%) 3.4 Blood alkaline phosphatase increased 109 (6.5%) 43 (2.6%) 22 (1.3%) 42 (2.5%) 2 (0.1%) 41 (4.4%) 14 (1.5%) 16 (1.7%) 9 (1.0%) 2 (0.2%) 2.1 Blood creatinine increased 66 (3.9%) 39 (2.3%) 19 (1.1%) 7 (0.4%) 1 (0.1%) 25 (2.7%) 12 (1.3%) 11 (1.2%) 1 (0.1%) 1 (0.1%) 1.3

113 Approved, Date: 26 August 2015 JNJ-212082 (abiraterone acetate) Investigator's Brochure - Edition 12

Appendix D.1: Treatment-Emergent Adverse Events by Toxicity Grade where Combined AA is at least 1% Greater Than Combined Placebo Integrated Safety Population Receiving 1,000mg/day AA in All Clinical Trials COU-AA-301 AA Placebo (N=791) (N=394) System Organ Class Preferred Term Total Grade 1 Grade 2 Grade 3 Grade 4 Total Grade 1 Grade 2 Grade 3 Grade 4 Blood albumin decreased 5 (0.6%) 4 (0.5%) 1 (0.1%) 0 0 1 (0.3%) 0 1 (0.3%) 0 0

Renal and urinary disorders 258 (32.6%) 124 (15.7%) 72 (9.1%) 52 (6.6%) 9 (1.1%) 119 (30.2%) 60 (15.2%) 33 (8.4%) 25 (6.3%) 1 (0.3%) Haematuria 73 (9.2%) 38 (4.8%) 23 (2.9%) 12 (1.5%) 0 34 (8.6%) 18 (4.6%) 7 (1.8%) 9 (2.3%) 0 Nocturia 52 (6.6%) 43 (5.4%) 8 (1.0%) 1 (0.1%) 0 17 (4.3%) 13 (3.3%) 4 (1.0%) 0 0

Skin and subcutaneous tissue disorders 209 (26.4%) 150 (19.0%) 54 (6.8%) 4 (0.5%) 1 (0.1%) 89 (22.6%) 59 (15.0%) 29 (7.4%) 1 (0.3%) 0 Rash 31 (3.9%) 19 (2.4%) 11 (1.4%) 1 (0.1%) 0 15 (3.8%) 13 (3.3%) 2 (0.5%) 0 0 Dry skin 20 (2.5%) 17 (2.1%) 3 (0.4%) 0 0 3 (0.8%) 2 (0.5%) 1 (0.3%) 0 0 Skin lesion 13 (1.6%) 12 (1.5%) 1 (0.1%) 0 0 5 (1.3%) 3 (0.8%) 2 (0.5%) 0 0

Injury, poisoning and procedural 197 (24.9%) 107 (13.5%) 55 (7.0%) 32 (4.0%) 3 (0.4%) 60 (15.2%) 35 (8.9%) 20 (5.1%) 3 (0.8%) 2 (0.5%) complications Contusion 62 (7.8%) 55 (7.0%) 7 (0.9%) 0 0 22 (5.6%) 20 (5.1%) 2 (0.5%) 0 0 Fall 32 (4.0%) 23 (2.9%) 5 (0.6%) 4 (0.5%) 0 9 (2.3%) 6 (1.5%) 2 (0.5%) 0 0

Blood and lymphatic system disorders 232 (29.3%) 53 (6.7%) 104 (13.1%) 60 (7.6%) 15 (1.9%) 123 (31.2%) 21 (5.3%) 65 (16.5%) 30 (7.6%) 7 (1.8%) Anaemia 198 (25.0%) 40 (5.1%) 96 (12.1%) 53 (6.7%) 9 (1.1%) 110 (27.9%) 17 (4.3%) 61 (15.5%) 26 (6.6%) 6 (1.5%)

Hepatobiliary disorders 23 (2.9%) 9 (1.1%) 5 (0.6%) 8 (1.0%) 1 (0.1%) 14 (3.6%) 6 (1.5%) 1 (0.3%) 6 (1.5%) 1 (0.3%) Hyperbilirubinaemia 12 (1.5%) 5 (0.6%) 3 (0.4%) 4 (0.5%) 0 8 (2.0%) 4 (1.0%) 0 3 (0.8%) 1 (0.3%)

114 Approved, Date: 26 August 2015 JNJ-212082 (abiraterone acetate) Investigator's Brochure - Edition 12

Appendix D.1: Treatment-Emergent Adverse Events by Toxicity Grade where Combined AA is at least 1% Greater Than Combined Placebo Integrated Safety Population Receiving 1,000 mg/day AA in All Clinical Trials COU-AA-302 AA Placebo (N=542) (N=540) System Organ Class Preferred Term Total Grade 1 Grade 2 Grade 3 Grade 4 Total Grade 1 Grade 2 Grade 3 Grade 4 Blood albumin decreased 0 0 0 0 0 0 0 0 0 0

Renal and urinary disorders 184 (33.9%) 104 (19.2%) 50 (9.2%) 30 (5.5%) 0 155 (28.7%) 79 (14.6%) 50 (9.3%) 24 (4.4%) 2 (0.4%) Haematuria 56 (10.3%) 40 (7.4%) 9 (1.7%) 7 (1.3%) 0 30 (5.6%) 21 (3.9%) 6 (1.1%) 3 (0.6%) 0 Nocturia 31 (5.7%) 20 (3.7%) 9 (1.7%) 2 (0.4%) 0 28 (5.2%) 18 (3.3%) 10 (1.9%) 0 0

Skin and subcutaneous tissue disorders 174 (32.1%) 145 (26.8%) 28 (5.2%) 1 (0.2%) 0 142 (26.3%) 117 (21.7%) 23 (4.3%) 2 (0.4%) 0 Rash 44 (8.1%) 39 (7.2%) 5 (0.9%) 0 0 20 (3.7%) 17 (3.1%) 3 (0.6%) 0 0 Dry skin 10 (1.8%) 9 (1.7%) 0 0 0 12 (2.2%) 10 (1.9%) 2 (0.4%) 0 0 Skin lesion 19 (3.5%) 17 (3.1%) 2 (0.4%) 0 0 5 (0.9%) 4 (0.7%) 1 (0.2%) 0 0

Injury, poisoning and procedural 189 (34.9%) 124 (22.9%) 46 (8.5%) 17 (3.1%) 2 (0.4%) 152 (28.1%) 97 (18.0%) 41 (7.6%) 11 (2.0%) 1 (0.2%) complications Contusion 72 (13.3%) 70 (12.9%) 2 (0.4%) 0 0 49 (9.1%) 42 (7.8%) 7 (1.3%) 0 0 Fall 32 (5.9%) 29 (5.4%) 3 (0.6%) 0 0 18 (3.3%) 15 (2.8%) 3 (0.6%) 0 0

Blood and lymphatic system disorders 76 (14.0%) 34 (6.3%) 23 (4.2%) 16 (3.0%) 3 (0.6%) 66 (12.2%) 24 (4.4%) 24 (4.4%) 16 (3.0%) 2 (0.4%) Anaemia 58 (10.7%) 26 (4.8%) 21 (3.9%) 9 (1.7%) 2 (0.4%) 50 (9.3%) 18 (3.3%) 23 (4.3%) 9 (1.7%) 0

Hepatobiliary disorders 22 (4.1%) 12 (2.2%) 4 (0.7%) 4 (0.7%) 2 (0.4%) 11 (2.0%) 5 (0.9%) 4 (0.7%) 1 (0.2%) 0 Hyperbilirubinaemia 13 (2.4%) 9 (1.7%) 1 (0.2%) 3 (0.6%) 0 7 (1.3%) 4 (0.7%) 2 (0.4%) 1 (0.2%) 0

115 Approved, Date: 26 August 2015 JNJ-212082 (abiraterone acetate) Investigator's Brochure - Edition 12

Appendix D.1: Treatment-Emergent Adverse Events by Toxicity Grade where Combined AA is at least 1% Greater Than Combined Placebo Integrated Safety Population Receiving 1,000 mg/day AA in All Clinical Trials Pooled Phase 1/2 AA (N=347) System Organ Class Preferred Term Total Grade 1 Grade 2 Grade 3 Grade 4 Blood albumin decreased 20 (5.8%) 17 (4.9%) 3 (0.9%) 0 0

Renal and urinary disorders 76 (21.9%) 40 (11.5%) 22 (6.3%) 14 (4.0%) 0 Haematuria 18 (5.2%) 8 (2.3%) 6 (1.7%) 3 (0.9%) 0 Nocturia 14 (4.0%) 8 (2.3%) 5 (1.4%) 1 (0.3%) 0

Skin and subcutaneous tissue disorders 90 (25.9%) 71 (20.5%) 19 (5.5%) 0 0 Rash 14 (4.0%) 10 (2.9%) 4 (1.2%) 0 0 Dry skin 19 (5.5%) 19 (5.5%) 0 0 0 Skin lesion 4 (1.2%) 3 (0.9%) 1 (0.3%) 0 0

Injury, poisoning and procedural 65 (18.7%) 33 (9.5%) 17 (4.9%) 14 (4.0%) 1 (0.3%) complications Contusion 29 (8.4%) 28 (8.1%) 1 (0.3%) 0 0 Fall 6 (1.7%) 0 5 (1.4%) 1 (0.3%) 0

Blood and lymphatic system disorders 91 (26.2%) 30 (8.6%) 38 (11.0%) 19 (5.5%) 3 (0.9%) Anaemia 70 (20.2%) 19 (5.5%) 39 (11.2%) 9 (2.6%) 3 (0.9%)

Hepatobiliary disorders 23 (6.6%) 20 (5.8%) 2 (0.6%) 1 (0.3%) 0 Hyperbilirubinaemia 19 (5.5%) 17 (4.9%) 2 (0.6%) 0 0

116 Approved, Date: 26 August 2015 JNJ-212082 (abiraterone acetate) Investigator's Brochure - Edition 12

Appendix D.1: Treatment-Emergent Adverse Events by Toxicity Grade where Combined AA is at least 1% Greater Than Combined Placebo Integrated Safety Population Receiving 1000mg/day AA in All Clinical Trials All Clinical Trials Combined AA a Placebo (N=1680) (N=934) System Organ Class Preferred Term Total Grade 1 Grade 2 Grade 3 Grade 4 Total Grade 1 Grade 2 Grade 3 Grade 4 Diff b Blood albumin decreased 25 (1.5%) 21 (1.3%) 4 (0.2%) 0 0 1 (0.1%) 0 1 (0.1%) 0 0 1.4

Renal and urinary disorders 518 (30.8%) 268 (16.0%) 144 (8.6%) 96 (5.7%) 9 (0.5%) 274 (29.3%) 139 (14.9%) 83 (8.9%) 49 (5.2%) 3 (0.3%) 1.5 Haematuria 147 (8.8%) 86 (5.1%) 38 (2.3%) 22 (1.3%) 0 64 (6.9%) 39 (4.2%) 13 (1.4%) 12 (1.3%) 0 1.9 Nocturia 97 (5.8%) 71 (4.2%) 22 (1.3%) 4 (0.2%) 0 45 (4.8%) 31 (3.3%) 14 (1.5%) 0 0 1

Skin and subcutaneous tissue disorders 473 (28.2%) 366 (21.8%) 101 (6.0%) 5 (0.3%) 1 (0.1%) 231 (24.7%) 176 (18.8%) 52 (5.6%) 3 (0.3%) 0 3.4 Rash 89 (5.3%) 68 (4.0%) 20 (1.2%) 1 (0.1%) 0 35 (3.7%) 30 (3.2%) 5 (0.5%) 0 0 1.6 Dry skin 49 (2.9%) 45 (2.7%) 3 (0.2%) 0 0 15 (1.6%) 12 (1.3%) 3 (0.3%) 0 0 1.3 Skin lesion 36 (2.1%) 32 (1.9%) 4 (0.2%) 0 0 10 (1.1%) 7 (0.7%) 3 (0.3%) 0 0 1.1

Injury, poisoning and procedural 451 (26.8%) 264 (15.7%) 118 (7.0%) 63 (3.8%) 6 (0.4%) 212 (22.7%) 132 (14.1%) 61 (6.5%) 14 (1.5%) 3 (0.3%) 4.1 complications Contusion 163 (9.7%) 153 (9.1%) 10 (0.6%) 0 0 71 (7.6%) 62 (6.6%) 9 (1.0%) 0 0 2.1 Fall 70 (4.2%) 52 (3.1%) 13 (0.8%) 5 (0.3%) 0 27 (2.9%) 21 (2.2%) 5 (0.5%) 0 0 1.3

Blood and lymphatic system disorders 399 (23.8%) 117 (7.0%) 165 (9.8%) 95 (5.7%) 21 (1.3%) 189 (20.2%) 45 (4.8%) 89 (9.5%) 46 (4.9%) 9 (1.0%) 3.5 Anaemia 326 (19.4%) 85 (5.1%) 156 (9.3%) 71 (4.2%) 14 (0.8%) 160 (17.1%) 35 (3.7%) 84 (9.0%) 35 (3.7%) 6 (0.6%) 2.3

Hepatobiliary disorders 68 (4.0%) 41 (2.4%) 11 (0.7%) 13 (0.8%) 3 (0.2%) 25 (2.7%) 11 (1.2%) 5 (0.5%) 7 (0.7%) 1 (0.1%) 1.4 Hyperbilirubinaemia 44 (2.6%) 31 (1.8%) 6 (0.4%) 7 (0.4%) 0 15 (1.6%) 8 (0.9%) 2 (0.2%) 4 (0.4%) 1 (0.1%) 1

Note: Table does not include Grade 5 events.Uncoded AE's are not included in this table and are listed separately. A subject who had multiple events per system organ class or preferred term is counted twice, once in the column for the worst reported severity among the events and once in the All Grades column. A subject who had events with missing toxicity grade is counted in the All Grades column but not listed separately. a Include subjects from all studies 301 (data cut-off of 20SEP2010), 302 (data cut-off of 20DEC2011), 006 and, 015 (data cut-off of 01DEC2011), and Phase 1/2 legacy studies (data from 001/001EXT, 002, 003/003EXT, 004, BMA, BE with data cut-off of 20SEP2011). b Diff is the difference in the percentages between the AA of all trials combined column and the Placebo of all trials combined column.

117 Approved, Date: 26 August 2015 JNJ-212082 (abiraterone acetate) Investigator's Brochure - Edition 12

Appendix D.2: Treatment-Emergent Adverse Events Reported in at Least 10% of Subjects in Any Group; Integrated Safety Population COU-AA-301 COU-AA-302 Combined MedDRA SOC Term AA Placebo AA Placebo AA Placebo MedDRA Preferred Term (N=791) (N=394) (N=542) (N=540) (N=1333) (N=934) Total no. subjects with a treatment- 784 (99.1%) 390 (99.0%) 537 (99.1%) 524 (97.0%) 1321 (99.1%) 914 (97.9%) emergent adverse event Musculoskeletal and connective tissue 599 (75.7%) 298 (75.6%) 392 (72.3%) 405 (75.0%) 991 (74.3%) 703 (75.3%) disorders Back pain 262 (33.1%) 141 (35.8%) 173 (31.9%) 173 (32.0%) 435 (32.6%) 314 (33.6%) Arthralgia 239 (30.2%) 95 (24.1%) 154 (28.4%) 129 (23.9%) 393 (29.5%) 224 (24.0%) Bone pain 216 (27.3%) 117 (29.7%) 106 (19.6%) 103 (19.1%) 322 (24.2%) 220 (23.6%) Pain in extremity 156 (19.7%) 82 (20.8%) 90 (16.6%) 85 (15.7%) 246 (18.5%) 167 (17.9%) Musculoskeletal pain 134 (16.9%) 56 (14.2%) 78 (14.4%) 78 (14.4%) 212 (15.9%) 134 (14.3%) Muscle spasms 74 (9.4%) 37 (9.4%) 75 (13.8%) 110 (20.4%) 149 (11.2%) 147 (15.7%) Muscular weakness 89 (11.3%) 37 (9.4%) 31 (5.7%) 40 (7.4%) 120 (9.0%) 77 (8.2%) General disorders and administration 569 (71.9%) 268 (68.0%) 351 (64.8%) 307 (56.9%) 920 (69.0%) 575 (61.6%) site conditions Fatigue 372 (47.0%) 174 (44.2%) 212 (39.1%) 185 (34.3%) 584 (43.8%) 359 (38.4%) Oedema peripheral 212 (26.8%) 75 (19.0%) 134 (24.7%) 108 (20.0%) 346 (26.0%) 183 (19.6%) Asthenia 122 (15.4%) 54 (13.7%) 43 (7.9%) 45 (8.3%) 165 (12.4%) 99 (10.6%) Pyrexia 80 (10.1%) 36 (9.1%) 47 (8.7%) 32 (5.9%) 127 (9.5%) 68 (7.3%) Gastrointestinal disorders 558 (70.5%) 267 (67.8%) 347 (64.0%) 323 (59.8%) 905 (67.9%) 590 (63.2%) Nausea 258 (32.6%) 130 (33.0%) 120 (22.1%) 118 (21.9%) 378 (28.4%) 248 (26.6%) Constipation 223 (28.2%) 126 (32.0%) 125 (23.1%) 103 (19.1%) 348 (26.1%) 229 (24.5%) Diarrhoea 156 (19.7%) 58 (14.7%) 117 (21.6%) 96 (17.8%) 273 (20.5%) 154 (16.5%) Vomiting 191 (24.1%) 101 (25.6%) 69 (12.7%) 58 (10.7%) 260 (19.5%) 159 (17.0%) Abdominal pain 102 (12.9%) 47 (11.9%) 37 (6.8%) 43 (8.0%) 139 (10.4%) 90 (9.6%) Dyspepsia 51 (6.4%) 15 (3.8%) 60 (11.1%) 27 (5.0%) 111 (8.3%) 42 (4.5%) Infections and infestations 358 (45.3%) 137 (34.8%) 297 (54.8%) 210 (38.9%) 655 (49.1%) 347 (37.2%) Urinary tract infection 105 (13.3%) 29 (7.4%) 46 (8.5%) 39 (7.2%) 151 (11.3%) 68 (7.3%) Upper respiratory tract infection 49 (6.2%) 11 (2.8%) 69 (12.7%) 43 (8.0%) 118 (8.9%) 54 (5.8%) Nasopharyngitis 51 (6.4%) 24 (6.1%) 58 (10.7%) 44 (8.1%) 109 (8.2%) 68 (7.3%)

118 Approved, Date: 26 August 2015 JNJ-212082 (abiraterone acetate) Investigator's Brochure - Edition 12

Appendix D.2: Treatment-Emergent Adverse Events Reported in at Least 10% of Subjects in Any Group; Integrated Safety Population COU-AA-301 COU-AA-302 Combined MedDRA SOC Term AA Placebo AA Placebo AA Placebo MedDRA Preferred Term (N=791) (N=394) (N=542) (N=540) (N=1333) (N=934) Metabolism and nutrition disorders 397 (50.2%) 170 (43.1%) 226 (41.7%) 216 (40.0%) 623 (46.7%) 386 (41.3%) Hypokalaemia 143 (18.1%) 36 (9.1%) 91 (16.8%) 68 (12.6%) 234 (17.6%) 104 (11.1%) Anorexia 143 (18.1%) 75 (19.0%) 39 (7.2%) 36 (6.7%) 182 (13.7%) 111 (11.9%) Decreased appetite 81 (10.2%) 35 (8.9%) 28 (5.2%) 30 (5.6%) 109 (8.2%) 65 (7.0%) Nervous system disorders 371 (46.9%) 184 (46.7%) 232 (42.8%) 210 (38.9%) 603 (45.2%) 394 (42.2%) 103 (13.0%) 42 (10.7%) 72 (13.3%) 66 (12.2%) 175 (13.1%) 108 (11.6%) Dizziness 89 (11.3%) 39 (9.9%) 70 (12.9%) 70 (13.0%) 159 (11.9%) 109 (11.7%) Vascular disorders 266 (33.6%) 127 (32.2%) 252 (46.5%) 182 (33.7%) 518 (38.9%) 309 (33.1%) Hot flush 154 (19.5%) 68 (17.3%) 121 (22.3%) 98 (18.1%) 275 (20.6%) 166 (17.8%) Hypertension 76 (9.6%) 27 (6.9%) 117 (21.6%) 71 (13.1%) 193 (14.5%) 98 (10.5%) Respiratory, thoracic and mediastinal 296 (37.4%) 120 (30.5%) 201 (37.1%) 176 (32.6%) 497 (37.3%) 296 (31.7%) disorders Cough 101 (12.8%) 32 (8.1%) 94 (17.3%) 73 (13.5%) 195 (14.6%) 105 (11.2%) Dyspnoea 116 (14.7%) 49 (12.4%) 64 (11.8%) 52 (9.6%) 180 (13.5%) 101 (10.8%) Investigations 260 (32.9%) 109 (27.7%) 182 (33.6%) 142 (26.3%) 442 (33.2%) 251 (26.9%) Weight decreased 94 (11.9%) 55 (14.0%) 33 (6.1%) 25 (4.6%) 127 (9.5%) 80 (8.6%) Aspartate aminotransferase increased 34 (4.3%) 16 (4.1%) 58 (10.7%) 26 (4.8%) 92 (6.9%) 42 (4.5%) Alanine aminotransferase increased 22 (2.8%) 7 (1.8%) 63 (11.6%) 27 (5.0%) 85 (6.4%) 34 (3.6%) Renal and urinary disorders 258 (32.6%) 119 (30.2%) 184 (33.9%) 155 (28.7%) 442 (33.2%) 274 (29.3%) Haematuria 73 (9.2%) 34 (8.6%) 56 (10.3%) 30 (5.6%) 129 (9.7%) 64 (6.9%) Injury, poisoning and procedural 197 (24.9%) 60 (15.2%) 189 (34.9%) 152 (28.1%) 386 (29.0%) 212 (22.7%) complications Contusion 62 (7.8%) 22 (5.6%) 72 (13.3%) 49 (9.1%) 134 (10.1%) 71 (7.6%) Psychiatric disorders 215 (27.2%) 106 (26.9%) 136 (25.1%) 117 (21.7%) 351 (26.3%) 223 (23.9%) Insomnia 90 (11.4%) 51 (12.9%) 73 (13.5%) 61 (11.3%) 163 (12.2%) 112 (12.0%) Blood and lymphatic system disorders 232 (29.3%) 123 (31.2%) 76 (14.0%) 66 (12.2%) 308 (23.1%) 189 (20.2%) Anaemia 198 (25.0%) 110 (27.9%) 58 (10.7%) 50 (9.3%) 256 (19.2%) 160 (17.1%) Note: Table does not include Grade 5 events

119 Approved, Date: 26 August 2015 JNJ-212082 (abiraterone acetate) Investigator's Brochure - Edition 12

Appendix D.3: Treatment-Emergent Adverse Events of Special Interest; Integrated Safety Population COU-AA-301 COU-AA-302 Combined Adverse Events of Special Interest AA Placebo AA Placebo AA Placebo MedDRA Preferred Term (N=791) (N=394) (N=542) (N=540) (N=1,333) (N=934) Total no. subjects with a treatment-emergent 463 (58.5%) 182 (46.2%) 355 (65.5%) 269 (49.8%) 818 (61.4%) 451 (48.3%) adverse event of special interest

Fluid Retention/edema 261 (33.0%) 94 (23.9%) 150 (27.7%) 127 (23.5%) 411 (30.8%) 221 (23.7%) Oedema peripheral 212 (26.8%) 75 (19.0%) 134 (24.7%) 108 (20.0%) 346 (26.0%) 183 (19.6%) Joint swelling 23 (2.9%) 5 (1.3%) 7 (1.3%) 10 (1.9%) 30 (2.3%) 15 (1.6%) Pleural effusion 18 (2.3%) 6 (1.5%) 4 (0.7%) 4 (0.7%) 22 (1.7%) 10 (1.1%) Pitting oedema 13 (1.6%) 7 (1.8%) 2 (0.4%) 5 (0.9%) 15 (1.1%) 12 (1.3%) Fluid retention 5 (0.6%) 3 (0.8%) 5 (0.9%) 4 (0.7%) 10 (0.8%) 7 (0.7%) Generalised oedema 5 (0.6%) 0 2 (0.4%) 2 (0.4%) 7 (0.5%) 2 (0.2%) Localised oedema 3 (0.4%) 5 (1.3%) 4 (0.7%) 1 (0.2%) 7 (0.5%) 6 (0.6%) Lymphoedema 3 (0.4%) 3 (0.8%) 3 (0.6%) 1 (0.2%) 6 (0.5%) 4 (0.4%) Ascites 4 (0.5%) 1 (0.3%) 1 (0.2%) 1 (0.2%) 5 (0.4%) 2 (0.2%) Local swelling 4 (0.5%) 4 (1.0%) 0 1 (0.2%) 4 (0.3%) 5 (0.5%) Oedema 4 (0.5%) 2 (0.5%) 0 0 4 (0.3%) 2 (0.2%) Joint effusion 3 (0.4%) 1 (0.3%) 0 0 3 (0.2%) 1 (0.1%) Muscle swelling 2 (0.3%) 0 0 0 2 (0.2%) 0 Swelling 2 (0.3%) 1 (0.3%) 0 0 2 (0.2%) 1 (0.1%) Bone swelling 0 0 1 (0.2%) 0 1 (0.1%) 0 Brain oedema 1 (0.1%) 1 (0.3%) 0 0 1 (0.1%) 1 (0.1%) Pericardial effusion 1 (0.1%) 0 0 0 1 (0.1%) 0 Hypervolaemia 0 1 (0.3%) 0 0 0 1 (0.1%) Testicular swelling 0 0 0 1 (0.2%) 0 1 (0.1%)

Hypokalemia 143 (18.1%) 36 (9.1%) 91 (16.8%) 68 (12.6%) 234 (17.6%) 104 (11.1%) Hypokalaemia 143 (18.1%) 36 (9.1%) 91 (16.8%) 68 (12.6%) 234 (17.6%) 104 (11.1%)

Hypertension 88 (11.1%) 32 (8.1%) 118 (21.8%) 71 (13.1%) 206 (15.5%) 103 (11.0%) Hypertension 76 (9.6%) 27 (6.9%) 117 (21.6%) 71 (13.1%) 193 (14.5%) 98 (10.5%) Blood pressure increased 11 (1.4%) 4 (1.0%) 0 0 11 (0.8%) 4 (0.4%) Diastolic hypertension 1 (0.1%) 0 0 0 1 (0.1%) 0 Hypertensive crisis 0 0 1 (0.2%) 0 1 (0.1%) 0 Orthostatic hypertension 1 (0.1%) 1 (0.3%) 0 0 1 (0.1%) 1 (0.1%) Pregnancy induced hypertension 0 0 1 (0.2%) 0 1 (0.1%) 0 Retinopathy hypertensive 1 (0.1%) 0 0 0 1 (0.1%) 0

120 Approved, Date: 26 August 2015 JNJ-212082 (abiraterone acetate) Investigator's Brochure - Edition 12 Appendix D.3: Treatment-Emergent Adverse Events of Special Interest; Integrated Safety Population COU-AA-301 COU-AA-302 Combined Adverse Events of Special Interest AA Placebo AA Placebo AA Placebo MedDRA Preferred Term (N=791) (N=394) (N=542) (N=540) (N=1,333) (N=934) LFT Abnormalities 89 (11.3%) 35 (8.9%) 97 (17.9%) 59 (10.9%) 186 (14.0%) 94 (10.1%) Aspartate aminotransferase increased 34 (4.3%) 16 (4.1%) 58 (10.7%) 26 (4.8%) 92 (6.9%) 42 (4.5%) Alanine aminotransferase increased 22 (2.8%) 7 (1.8%) 63 (11.6%) 27 (5.0%) 85 (6.4%) 34 (3.6%) Blood alkaline phosphatase increased 37 (4.7%) 18 (4.6%) 18 (3.3%) 23 (4.3%) 55 (4.1%) 41 (4.4%) Hyperbilirubinaemia 12 (1.5%) 8 (2.0%) 13 (2.4%) 7 (1.3%) 25 (1.9%) 15 (1.6%) Hypoalbuminaemia 6 (0.8%) 5 (1.3%) 4 (0.7%) 5 (0.9%) 10 (0.8%) 10 (1.1%) Gamma-glutamyltransferase increased 4 (0.5%) 3 (0.8%) 3 (0.6%) 3 (0.6%) 7 (0.5%) 6 (0.6%) Hepatic enzyme increased 1 (0.1%) 0 4 (0.7%) 0 5 (0.4%) 0 Hepatomegaly 5 (0.6%) 1 (0.3%) 0 1 (0.2%) 5 (0.4%) 2 (0.2%) Liver function test abnormal 0 1 (0.3%) 5 (0.9%) 0 5 (0.4%) 1 (0.1%) Jaundice 2 (0.3%) 1 (0.3%) 2 (0.4%) 1 (0.2%) 4 (0.3%) 2 (0.2%) Hypertransaminasaemia 0 0 3 (0.6%) 0 3 (0.2%) 0 Hepatotoxicity 1 (0.1%) 0 1 (0.2%) 0 2 (0.2%) 0 Abnormal faeces 1 (0.1%) 0 0 0 1 (0.1%) 0 Alanine aminotransferase abnormal 0 0 1 (0.2%) 0 1 (0.1%) 0 Cholestasis 1 (0.1%) 2 (0.5%) 0 0 1 (0.1%) 2 (0.2%) Hepatic pain 1 (0.1%) 1 (0.3%) 0 0 1 (0.1%) 1 (0.1%) Ischaemic hepatitis 1 (0.1%) 0 0 0 1 (0.1%) 0 Liver tenderness 1 (0.1%) 0 0 0 1 (0.1%) 0 Varices oesophageal 1 (0.1%) 0 0 1 (0.2%) 1 (0.1%) 1 (0.1%) Hepatic encephalopathy 0 1 (0.3%) 0 0 0 1 (0.1%) Hepatitis 0 1 (0.3%) 0 0 0 1 (0.1%) Hepatosplenomegaly 0 1 (0.3%) 0 0 0 1 (0.1%) Jaundice cholestatic 0 0 0 1 (0.2%) 0 1 (0.1%) Liver palpable subcostal 0 0 0 1 (0.2%) 0 1 (0.1%) Ocular icterus 0 0 0 1 (0.2%) 0 1 (0.1%)

Cardiac Disorders 126 (15.9%) 46 (11.7%) 93 (17.2%) 76 (14.1%) 219 (16.4%) 122 (13.1%) Arrhythmias 98 (12.4%) 34 (8.6%) 76 (14.0%) 67 (12.4%) 174 (13.1%) 101 (10.8%) Atrial fibrillation 23 (2.9%) 6 (1.5%) 22 (4.1%) 26 (4.8%) 45 (3.4%) 32 (3.4%) Tachycardia 26 (3.3%) 8 (2.0%) 11 (2.0%) 8 (1.5%) 37 (2.8%) 16 (1.7%) Syncope 13 (1.6%) 7 (1.8%) 10 (1.8%) 8 (1.5%) 23 (1.7%) 15 (1.6%) Palpitations 10 (1.3%) 3 (0.8%) 12 (2.2%) 7 (1.3%) 22 (1.7%) 10 (1.1%) Arrhythmia 9 (1.1%) 0 6 (1.1%) 4 (0.7%) 15 (1.1%) 4 (0.4%) Loss of consciousness 5 (0.6%) 1 (0.3%) 4 (0.7%) 0 9 (0.7%) 1 (0.1%) Bradycardia 4 (0.5%) 1 (0.3%) 4 (0.7%) 4 (0.7%) 8 (0.6%) 5 (0.5%) Cardio-respiratory arrest 6 (0.8%) 0 0 0 6 (0.5%) 0 Supraventricular tachycardia 2 (0.3%) 0 4 (0.7%) 1 (0.2%) 6 (0.5%) 1 (0.1%) Heart rate irregular 1 (0.1%) 0 4 (0.7%) 0 5 (0.4%) 0 Sinus tachycardia 3 (0.4%) 3 (0.8%) 2 (0.4%) 2 (0.4%) 5 (0.4%) 5 (0.5%)

121 Approved, Date: 26 August 2015 JNJ-212082 (abiraterone acetate) Investigator's Brochure - Edition 12 Appendix D.3: Treatment-Emergent Adverse Events of Special Interest; Integrated Safety Population COU-AA-301 COU-AA-302 Combined Adverse Events of Special Interest AA Placebo AA Placebo AA Placebo MedDRA Preferred Term (N=791) (N=394) (N=542) (N=540) (N=1,333) (N=934) Ventricular extrasystoles 1 (0.1%) 0 4 (0.7%) 2 (0.4%) 5 (0.4%) 2 (0.2%) Extrasystoles 1 (0.1%) 1 (0.3%) 3 (0.6%) 4 (0.7%) 4 (0.3%) 5 (0.5%) Syncope vasovagal 1 (0.1%) 1 (0.3%) 3 (0.6%) 2 (0.4%) 4 (0.3%) 3 (0.3%) Heart rate increased 3 (0.4%) 0 0 0 3 (0.2%) 0 Atrial flutter 0 1 (0.3%) 2 (0.4%) 2 (0.4%) 2 (0.2%) 3 (0.3%) Cardiac arrest 1 (0.1%) 2 (0.5%) 1 (0.2%) 1 (0.2%) 2 (0.2%) 3 (0.3%) Tachyarrhythmia 1 (0.1%) 0 1 (0.2%) 1 (0.2%) 2 (0.2%) 1 (0.1%) Arrhythmia supraventricular 1 (0.1%) 1 (0.3%) 0 1 (0.2%) 1 (0.1%) 2 (0.2%) Atrial tachycardia 1 (0.1%) 1 (0.3%) 0 1 (0.2%) 1 (0.1%) 2 (0.2%) Cardiac flutter 0 0 1 (0.2%) 2 (0.4%) 1 (0.1%) 2 (0.2%) Sudden death 1 (0.1%) 0 0 0 1 (0.1%) 0 Supraventricular tachyarrhythmia 0 0 1 (0.2%) 0 1 (0.1%) 0 Ventricular tachycardia 1 (0.1%) 0 0 0 1 (0.1%) 0 Electrocardiogram abnormal 0 0 0 1 (0.2%) 0 1 (0.1%) Supraventricular extrasystoles 0 1 (0.3%) 0 0 0 1 (0.1%)

Ischaemic Heart Disease 23 (2.9%) 10 (2.5%) 22 (4.1%) 18 (3.3%) 45 (3.4%) 28 (3.0%) Angina pectoris 11 (1.4%) 2 (0.5%) 14 (2.6%) 6 (1.1%) 25 (1.9%) 8 (0.9%) Myocardial infarction 7 (0.9%) 3 (0.8%) 4 (0.7%) 6 (1.1%) 11 (0.8%) 9 (1.0%) Coronary artery disease 1 (0.1%) 0 4 (0.7%) 2 (0.4%) 5 (0.4%) 2 (0.2%) Myocardial ischaemia 1 (0.1%) 1 (0.3%) 3 (0.6%) 6 (1.1%) 4 (0.3%) 7 (0.7%) Acute myocardial infarction 2 (0.3%) 1 (0.3%) 0 0 2 (0.2%) 1 (0.1%) Troponin I increased 1 (0.1%) 0 1 (0.2%) 0 2 (0.2%) 0 Angina unstable 0 1 (0.3%) 1 (0.2%) 2 (0.4%) 1 (0.1%) 3 (0.3%) Electrocardiogram ST segment depression 0 0 1 (0.2%) 0 1 (0.1%) 0 Ischaemic cardiomyopathy 0 0 1 (0.2%) 0 1 (0.1%) 0 Arteriosclerosis coronary artery 0 0 0 1 (0.2%) 0 1 (0.1%) Blood creatine phosphokinase increased 0 1 (0.3%) 0 0 0 1 (0.1%) Troponin increased 0 1 (0.3%) 0 0 0 1 (0.1%)

Cardiac Failure 24 (3.0%) 6 (1.5%) 11 (2.0%) 2 (0.4%) 35 (2.6%) 8 (0.9%) Cardiac failure congestive 8 (1.0%) 1 (0.3%) 5 (0.9%) 1 (0.2%) 13 (1.0%) 2 (0.2%) Ejection fraction decreased 7 (0.9%) 1 (0.3%) 1 (0.2%) 0 8 (0.6%) 1 (0.1%) Cardiac failure 3 (0.4%) 2 (0.5%) 3 (0.6%) 0 6 (0.5%) 2 (0.2%) Pulmonary oedema 6 (0.8%) 0 0 0 6 (0.5%) 0 Brain natriuretic peptide increased 1 (0.1%) 0 1 (0.2%) 0 2 (0.2%) 0 Dyspnoea paroxysmal nocturnal 2 (0.3%) 0 0 0 2 (0.2%) 0 Left ventricular dysfunction 1 (0.1%) 1 (0.3%) 1 (0.2%) 0 2 (0.2%) 1 (0.1%) Acute pulmonary oedema 1 (0.1%) 0 0 0 1 (0.1%) 0 Cardiac failure acute 0 0 1 (0.2%) 0 1 (0.1%) 0

122 Approved, Date: 26 August 2015 JNJ-212082 (abiraterone acetate) Investigator's Brochure - Edition 12 Appendix D.3: Treatment-Emergent Adverse Events of Special Interest; Integrated Safety Population COU-AA-301 COU-AA-302 Combined Adverse Events of Special Interest AA Placebo AA Placebo AA Placebo MedDRA Preferred Term (N=791) (N=394) (N=542) (N=540) (N=1,333) (N=934) Cardiogenic shock 1 (0.1%) 0 0 0 1 (0.1%) 0 Cardiomegaly 1 (0.1%) 0 0 1 (0.2%) 1 (0.1%) 1 (0.1%) Cor pulmonale 1 (0.1%) 0 0 0 1 (0.1%) 0 Orthopnoea 0 0 1 (0.2%) 0 1 (0.1%) 0 Right ventricular failure 0 0 1 (0.2%) 0 1 (0.1%) 0 Venous pressure jugular increased 0 1 (0.3%) 0 0 0 1 (0.1%)

123 Approved, Date: 26 August 2015 JNJ-212082 (abiraterone acetate) Investigator's Brochure - Edition 12

Appendix D.4: Treatment-Emergent Serious Adverse Events Reported in at Least 1% of Subjects in Any Group; Integrated Safety Population COU-AA-301 COU-AA-302 Combined MedDRA SOC Term AA Placebo AA Placebo AA Placebo MedDRA Preferred Term (N=791) (N=394) (N=542) (N=540) (N=1,333) (N=934) Total no. subjects with a treatment-emergent 335 (42.4%) 172 (43.7%) 178 (32.8%) 142 (26.3%) 513 (38.5%) 314 (33.6%) serious adverse event

Infections and infestations 73 (9.2%) 22 (5.6%) 45 (8.3%) 31 (5.7%) 118 (8.9%) 53 (5.7%) Pneumonia 19 (2.4%) 4 (1.0%) 7 (1.3%) 4 (0.7%) 26 (2.0%) 8 (0.9%) Urinary tract infection 16 (2.0%) 4 (1.0%) 8 (1.5%) 3 (0.6%) 24 (1.8%) 7 (0.7%) Sepsis 12 (1.5%) 2 (0.5%) 4 (0.7%) 2 (0.4%) 16 (1.2%) 4 (0.4%)

Nervous system disorders 55 (7.0%) 34 (8.6%) 30 (5.5%) 13 (2.4%) 85 (6.4%) 47 (5.0%) Spinal cord compression 22 (2.8%) 17 (4.3%) 5 (0.9%) 4 (0.7%) 27 (2.0%) 21 (2.2%)

Renal and urinary disorders 47 (5.9%) 26 (6.6%) 27 (5.0%) 25 (4.6%) 74 (5.6%) 51 (5.5%) Haematuria 11 (1.4%) 11 (2.8%) 10 (1.8%) 4 (0.7%) 21 (1.6%) 15 (1.6%) Hydronephrosis 12 (1.5%) 3 (0.8%) 2 (0.4%) 4 (0.7%) 14 (1.1%) 7 (0.7%) Urinary retention 8 (1.0%) 5 (1.3%) 4 (0.7%) 3 (0.6%) 12 (0.9%) 8 (0.9%) Renal failure acute 6 (0.8%) 5 (1.3%) 1 (0.2%) 0 7 (0.5%) 5 (0.5%)

Musculoskeletal and connective tissue 53 (6.7%) 39 (9.9%) 14 (2.6%) 18 (3.3%) 67 (5.0%) 57 (6.1%) disorders Bone pain 16 (2.0%) 13 (3.3%) 2 (0.4%) 4 (0.7%) 18 (1.4%) 17 (1.8%) Back pain 8 (1.0%) 11 (2.8%) 3 (0.6%) 4 (0.7%) 11 (0.8%) 15 (1.6%) Pain in extremity 4 (0.5%) 7 (1.8%) 1 (0.2%) 1 (0.2%) 5 (0.4%) 8 (0.9%) Arthralgia 2 (0.3%) 4 (1.0%) 1 (0.2%) 4 (0.7%) 3 (0.2%) 8 (0.9%)

Gastrointestinal disorders 49 (6.2%) 26 (6.6%) 16 (3.0%) 13 (2.4%) 65 (4.9%) 39 (4.2%) Vomiting 16 (2.0%) 9 (2.3%) 2 (0.4%) 0 18 (1.4%) 9 (1.0%)

124 Approved, Date: 26 August 2015 JNJ-212082 (abiraterone acetate) Investigator's Brochure - Edition 12

Appendix D.4: Treatment-Emergent Serious Adverse Events Reported in at Least 1% of Subjects in Any Group; Integrated Safety Population COU-AA-301 COU-AA-302 Combined MedDRA SOC Term AA Placebo AA Placebo AA Placebo MedDRA Preferred Term (N=791) (N=394) (N=542) (N=540) (N=1,333) (N=934) General disorders and administration site 47 (5.9%) 30 (7.6%) 13 (2.4%) 12 (2.2%) 60 (4.5%) 42 (4.5%) conditions Disease progression 12 (1.5%) 2 (0.5%) 2 (0.4%) 1 (0.2%) 14 (1.1%) 3 (0.3%) Fatigue 9 (1.1%) 6 (1.5%) 0 0 9 (0.7%) 6 (0.6%) Pyrexia 5 (0.6%) 9 (2.3%) 2 (0.4%) 3 (0.6%) 7 (0.5%) 12 (1.3%) Pain 1 (0.1%) 6 (1.5%) 0 1 (0.2%) 1 (0.1%) 7 (0.7%)

Cardiac disorders 26 (3.3%) 6 (1.5%) 29 (5.4%) 14 (2.6%) 55 (4.1%) 20 (2.1%) Atrial fibrillation 5 (0.6%) 3 (0.8%) 7 (1.3%) 8 (1.5%) 12 (0.9%) 11 (1.2%)

Metabolism and nutrition disorders 32 (4.0%) 14 (3.6%) 13 (2.4%) 6 (1.1%) 45 (3.4%) 20 (2.1%) Dehydration 12 (1.5%) 5 (1.3%) 5 (0.9%) 1 (0.2%) 17 (1.3%) 6 (0.6%)

Respiratory, thoracic and mediastinal 26 (3.3%) 18 (4.6%) 15 (2.8%) 21 (3.9%) 41 (3.1%) 39 (4.2%) disorders Pulmonary embolism 6 (0.8%) 10 (2.5%) 8 (1.5%) 11 (2.0%) 14 (1.1%) 21 (2.2%) Dyspnoea 9 (1.1%) 4 (1.0%) 2 (0.4%) 5 (0.9%) 11 (0.8%) 9 (1.0%)

Blood and lymphatic system disorders 31 (3.9%) 17 (4.3%) 7 (1.3%) 7 (1.3%) 38 (2.9%) 24 (2.6%) Anaemia 24 (3.0%) 14 (3.6%) 5 (0.9%) 5 (0.9%) 29 (2.2%) 19 (2.0%) Note: Table does not include Grade 5 events.

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125 Approved, Date: 26 August 2015