CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 210951Orig1s000 MULTI-DISCIPLINE REVIEW Summary Review Office Director Cross Discipline Team Leader Review Clinical Review Non-Clinical Review Statistical Review Clinical Pharmacology Review CDTL review is complete and has been added to the NDA/BLA Multidisciplinary Review and Evaluation. My recommendation for this application is regular approval. Reference ID: 4220973 --------------------------------------------------------------------------------------------------------- This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------- /s/ ---------------------------------------------------- CHANA WEINSTOCK 02/14/2018 Reference ID: 4220973 NDA/BLA Multi-Disciplinary Review and Evaluation NDA 210951 Erleada (apalutamide) NDA/BLA Multi-disciplinary Review and Evaluation Application Type NDA Application Number(s) 210951 Priority or Standard Priority Submit Date(s) October 09, 2017 Received Date(s) October 10, 2017 PDUFA Goal Date April 10, 2018 Division/Office DOP1/OHOP Review Completion Date February 13, 2018 Established Name Apalutamide (Proposed) Trade Name Erleada Pharmacologic Class Androgen receptor inhibitor Code name JNJ-56021927, ARN-509 Applicant Aragon Pharmaceuticals, Inc., represented by Janssen Research & Development, LLC. Formulation(s) 60 mg tablets Dosing Regimen 240 mg Applicant Proposed ERLEADA is indicated for the treatment of patients with non- Indication(s)/Population(s) metastatic, castration-resistant prostate cancer (NM-CRPC). Recommendation on Regular approval Regulatory Action Recommended ERLEADA is indicated for the treatment of patients with non- Indication(s)/Population(s) metastatic, castration-resistant prostate cancer (NM-CRPC). (if applicable) 1 Version date: February 1, 2016 for initial rollout (NME/original BLA reviews) Reference ID: 4221387 NDA/BLA Multi-Disciplinary Review and Evaluation NDA 210951 Erleada (apalutamide) Table of Contents Reviewers of Multi-Disciplinary Review and Evaluation .............................................................. 10 Additional Reviewers of Application ............................................................................................. 10 Glossary ......................................................................................................................................... 11 1 Executive Summary ............................................................................................................... 13 Product Introduction ...................................................................................................... 13 Conclusions on the Substantial Evidence of Effectiveness ............................................ 13 Benefit-Risk Assessment ................................................................................................ 17 Patient Experience Data ................................................................................................. 19 2 Therapeutic Context .............................................................................................................. 22 Analysis of Condition ...................................................................................................... 22 Analysis of Current Treatment Option ........................................................................... 23 3 Regulatory Background ......................................................................................................... 24 U.S. Regulatory Actions and Marketing History ............................................................. 24 Summary of Presubmission/Submission Regulatory Activity ........................................ 24 4 Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on Efficacy and Safety ................................................................................................................. 28 Office of Scientific Investigations (OSI) .......................................................................... 28 Product Quality .............................................................................................................. 28 Clinical Microbiology ...................................................................................................... 28 Devices and Companion Diagnostic Issues .................................................................... 28 5 Nonclinical Pharmacology/Toxicology................................................................................... 29 Executive Summary ........................................................................................................ 29 Referenced NDAs, BLAs, DMFs ....................................................................................... 31 Pharmacology ................................................................................................................. 31 ADME/PK ........................................................................................................................ 36 Toxicology ....................................................................................................................... 40 General Toxicology .................................................................................................. 40 Genetic Toxicology .................................................................................................. 51 Carcinogenicity ........................................................................................................ 52 2 Version date: February 1, 2016 for initial rollout (NME/original BLA reviews) Reference ID: 4221387 NDA/BLA Multi-Disciplinary Review and Evaluation NDA 210951 Erleada (apalutamide) Reproductive and Developmental Toxicology ........................................................ 52 Other Toxicology Studies ........................................................................................ 54 6 Clinical Pharmacology ............................................................................................................ 56 Executive Summary ........................................................................................................ 56 Summary of Clinical Pharmacology Assessment ............................................................ 57 Pharmacology and Clinical Pharmacokinetics ........................................................ 57 General Dosing and Therapeutic Individualization ................................................. 58 Comprehensive Clinical Pharmacology Review ............................................................. 61 General Pharmacology and Pharmacokinetic Characteristics ................................ 61 Clinical Pharmacology Questions ............................................................................ 63 7 Sources of Clinical Data and Review Strategy ....................................................................... 75 Table of Clinical Studies .................................................................................................. 75 Review Strategy .............................................................................................................. 78 8 Statistical and Clinical and Evaluation ................................................................................... 79 Review of Relevant Individual Trials Used to Support Efficacy ...................................... 79 SPARTAN (ARN-509-003) ........................................................................................ 79 Study Results ........................................................................................................... 88 Assessment of Efficacy Across Trials ..................................................................... 114 Integrated Assessment of Effectiveness ............................................................... 115 Review of Safety ........................................................................................................... 116 Safety Review Approach ....................................................................................... 116 Review of the Safety Database ............................................................................. 121 Adequacy of Applicant’s Clinical Safety Assessments .......................................... 123 Safety Results ........................................................................................................ 125 Analysis of Submission-Specific Safety Issues ....................................................... 133 Clinical Outcome Assessment (COA) Analyses Informing Safety/Tolerability ...... 138 Safety Analyses by Demographic Subgroups ........................................................ 142 Specific Safety Studies/Clinical Trials .................................................................... 143 Additional Safety Explorations .............................................................................. 143 Safety in the Postmarket Setting ................................................................... 143 Integrated Assessment of Safety ................................................................... 144 3 Version date: February 1, 2016 for initial rollout (NME/original BLA reviews) Reference ID: 4221387 NDA/BLA Multi-Disciplinary Review and Evaluation NDA 210951 Erleada (apalutamide) SUMMARY AND