CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 209115Orig1s000 MULTI-DISCIPLINE REVIEW Summary / Clinical / Non-Clinical NDA/BLA Multi-disciplinary Review and Evaluation NDA 209115 Rubraca (rucaparib) 1 NDA/BLA Multi-disciplinary Review and Evaluation Application Type NDA Application Number(s) 209115 Priority or Standard Priority Submit Date(s) June 23, 2016 Received Date(s) June 23, 2016 PDUFA Goal Date February 23, 2017 Division/Office DOP1/OHOP Review Completion Date November 22, 2016 Established Name Rucaparib (Proposed) Trade Name RUBRACA Pharmacologic Class Poly (ADP-Ribose) Polymerase 1 inhibitor Code name AG-014669, PF-01367338, Applicant Clovis Oncology, Inc. Formulation(s) Oral tablet Dosing Regimen 600 mg PO BID Applicant Proposed Rubraca is indicated as monotherapy treatment of advanced ovarian Indication(s)/Population(s) cancer in patients with deleterious BRCA-mutated tumors, inclusive of both germline BRCA and somatic BRCA mutations (as detected by an FDA approved test), and who have been treated with two or more chemotherapies. Recommendation on Accelerated approval Regulatory Action Recommended Rubraca™ is indicated as monotherapy for the treatment of patients Indication(s)/Population(s) with deleterious BRCA mutation (germline and/or somatic) associated (if applicable) advanced ovarian cancer who have been treated with two or more chemotherapies. Select patients for therapy based on an FDA-approved companion diagnostic for Rubraca. 1-1 Version date: February 1, 2016 for initial rollout (NME/original BLA reviews) Reference ID: 40178304028244 NDA/BLA Multi-disciplinary Review and Evaluation NDA 209115 Rubraca (rucaparib) Contents 1 NDA/BLA Multi-disciplinary Review and Evaluation .......................................................................... 1-1 Reviewers of Multi-Disciplinary Review and Evaluation ............................................................................ 1-4 Additional Reviewers of Application .......................................................................................................... 1-4 Glossary ...................................................................................................................................................... 1-5 1 Executive Summary ............................................................................................................................ 1-7 1.1. Product Introduction .................................................................................................................. 1-7 1.2. Conclusions on the Substantial Evidence of Effectiveness ........................................................ 1-7 1.3. Benefit-Risk Assessment ............................................................................................................ 1-9 2 Therapeutic Context .......................................................................................................................... 2-1 2.1. Analysis of Condition.................................................................................................................. 2-1 2.2. Analysis of Current Treatment Options ..................................................................................... 2-2 3 Regulatory Background ...................................................................................................................... 3-1 3.1. U.S. Regulatory Actions and Marketing History ......................................................................... 3-1 3.2. Summary of Presubmission/Submission Regulatory Activity .................................................... 3-1 4 Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on Efficacy and Safety ................................................................................................................................................. 4-1 4.1. Office of Scientific Investigations (OSI) ...................................................................................... 4-1 4.2. Product Quality .......................................................................................................................... 4-1 4.3. Clinical Microbiology .................................................................................................................. 4-1 4.4. Devices and Companion Diagnostic Issues ................................................................................ 4-1 5 Advisory Committee Meeting and Other External Consultations ..................................................... 5-1 6 Pediatrics ............................................................................................................................................ 6-1 7 Risk Evaluation and Mitigation Strategies (REMS) ............................................................................. 7-1 7.1. Safety Issue(s) that Warrant Consideration of a REMS ............................................................. 7-1 7.2. Conditions of Use to Address Safety Issue(s) ............................................................................. 7-1 7.3. Recommendations on REMS ...................................................................................................... 7-1 8 Postmarketing Requirements and Commitments ............................................................................. 8-1 1-2 Version date: February 1, 2016 for initial rollout (NME/original BLA reviews) Reference ID: 40178304028244 9 Nonclinical Pharmacology/Toxicology 9‐1 9.1. Executive Summary 9‐2 9.2. Referenced NDAs, BLAs, DMFs 9‐4 9.3. Pharmacology 9‐4 9.4. ADME/PK 9‐8 9.5. Toxicology 9‐11 9.5.1. General Toxicology 9‐11 9.5.2. Genetic Toxicology 9‐17 9.5.3. Carcinogenicity 9‐20 9.5.4. Reproductive and Developmental Toxicology 9‐20 10. Clinical Pharmacology 10.1‐1 10.1. Executive Summary 10.1‐2 10.1.1. Recommendations 10.1‐3 10.1.2. Post‐Marketing Requirement (PMR) and Commitment (PMC) 10.1‐5 10.2. Summary of Clinical Pharmacology Assessment 10.2‐5 10.2.1. Pharmacology and Clinical Pharmacokinetics 10.2‐5 10.2.2. General Dosing and Therapeutic Individualization 10.2‐5 10.3. Comprehensive Clinical Pharmacology Review 10.3‐7 10.3.1. General Pharmacology and Pharmacokinetic Characteristics 10.3‐7 10.3.2. Clinical Pharmacology Questions 10.3‐9 10.4. OCP Appendices 10.4‐13 10.4.1. Bioanalysis Report 10.4‐13 10.4.2. General Clinical Pharmacology 10.4‐16 10.4.3. Pharmacometrics Population PK Analysis 10.4‐33 10.4.4. Pharmacometrics Exposure‐Response Analysis 10.4‐42 Reference ID: 4028244 10.4.5. Genomics Factors 10.4‐56 11 Statistical and Clinical and Evaluation 11‐1 11.1. Sources of Clinical Data and Review Strategy 11‐6 11.1.1. Table of Clinical Studies 11‐6 11.2.3. Review Strategy 11‐9 11.3. Review of Relevant Individual Trials Used to Support Efficacy 11‐10 11.1.1. Study CO‐338‐017, “ARIEL2” 11‐10 11.1.2. Study Results for Study CO‐338‐017, ARIEL2 11‐25 11.2.3. Study CO‐338‐010, “Study 10” 11‐27 11.1.4. Study Results for Study 10 11‐43 11.2.5. Study CO‐338‐023, RUCAPANC 11‐45 11.3 Integrated Review of Effectiveness 11‐47 11.3.1. Assessment of Efficacy Across Trials 11‐47 11.3.2. Integrated Assessment of Effectiveness 11‐62 11.4. Review of Safety 11‐63 11.4.1 Safety Review Approach 11‐63 11.4.2. Review of the Safety Database 11‐64 11.4.3. Adequacy of Applicant’s Clinical Safety Assessments 11‐66 11.4.4. Safety Results 11‐68 11.4.5. Analysis of Submission‐Specific Safety Issues 11‐91 11.4.6. Safety Analyses by Demographic Subgroups 11‐97 11.4.7. Specific Safety Studies/Clinical Trials 11‐99 11.4.8. Additional Safety Explorations 11‐99 11.4.9. Safety in the Postmarket Setting 11‐99 11.4.10. Integrated Assessment of Safety 11‐99 Reference ID: 4028244 SUMMARY AND CONCLUSIONS 11‐101 11.5. Statistical Issues 11‐101 11.6. Conclusions and Recommendations 11‐101 12 Appendices 12‐1 12.1. Financial Disclosure 12‐2 Reference ID: 4028244 NDA/BLA Multi-disciplinary Review and Evaluation NDA 209115 Rubraca (rucaparib) Table of Tables Table 1: Agents for the Treatment of Women with Advanced Ovarian Cancer ........................................ 2-3 1-3 Version date: February 1, 2016 for initial rollout (NME/original BLA reviews) Reference ID: 40178304028244 NDA/BLA Multi-disciplinary Review and Evaluation NDA 209115 Rubraca (rucaparib) Reviewers of Multi-Disciplinary Review and Evaluation Regulatory Project Manager Kim Robertson Nonclinical Reviewer Haw-Jyh (Brian) Chiu Nonclinical Team Leader Todd Palmby Office of Clinical Pharmacology Reviewer(s) Sarah Schrieber / Jinzhong Liu Office of Clinical Pharmacology Team Leader(s) Pengfei Song Associate Director for Labeling William Pierce Clinical Reviewer for Efficacy Sanjeeve Balasubramaniam Clinical Reviewer for Safety Sara Horton Clinical Team Leader Julia Beaver Statistical Reviewer Laura Fernandes Statistical Team Leader Shenghui Tang Cross-Disciplinary Team Leader Julia Beaver Division Director (DHOT) John Leighton Division Director (OCP) Nam Atiqur Rahman Division Director (OB) Rajeshwari Sridhara Division Director (OHOP) Geoffrey Kim Office Director (or designated signatory authority) Richard Pazdur Additional Reviewers of Application OPQ Kristine Leahy Microbiology Xing Wang OPDP Nicholas Senior OSI Lauren Iacono-Connor OSE/DEPI Carolyn McCloskey / Steven Bird OSE/DMEPA Tingting Gao OSE/DRISK Mei-Yean Chen Other OPQ=Office of Pharmaceutical Quality OPDP=Office of Prescription Drug Promotion OSI=Office of Scientific Investigations OSE= Office of Surveillance and Epidemiology DEPI= Division of Epidemiology DMEPA=Division