CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 212099Orig1s000 MULTI-DISCIPLINE REVIEW Summary Review Office Director Cross Discipline Team Leader Review Clinical Review Non-Clinical Review Statistical Review Clinical Pharmacology Review NDA 212099 Multi-disciplinary Review and Evaluation Darolutamide/NUBEQA NDA/BLA Multi-Disciplinary Review and Evaluation Application Type NDA Application Number(s) 212099 Priority or Standard Priority Submit Date(s) February 26, 2019 Received Date(s) February 26. 2019 PDUFA Goal Date August 26, 2019 Division/Office Division of Oncology Products 1/Office of Hematology & Oncology Products Review Completion Date Established/Proper Name Darolutamide (Proposed) Trade Name Nubeqa Pharmacologic Class Androgen receptor inhibitor Code name 427492003 | Hormone refractory prostate cancer (disorder) Applicant Bayer Doseage form 300 mg tablets Applicant proposed Dosing NUBEQA 600 mg, (two 300 mg tablets) administered orally Regimen twice daily. Swallow tablets whole. Take NUBEQA with food. Patients should also receive a gonadotropin-releasing hormone (GnRH) analog concurrently or should have had bilateral orchiectomy. Applicant Proposed NUBEQA is an androgen receptor inhibitor indicated for the Indication(s)/Population(s) treatment of patients with non-metastatic castration-resistant prostate cancer. Applicant Proposed Non-metastatic castration resistant prostate cancer (nmCRPC) SNOMED CT Indication Disease Term for each Proposed Indication Recommendation on Regular approval Regulatory Action Recommended NUBEQA is an androgen receptor inhibitor indicated for the Indication(s)/Population(s) treatment of patients with non-metastatic castration-resistant (if applicable) prostate cancer. Recommended SNOMED CT Indication Disease Term for each Indication (if applicable) Recommended Dosing NUBEQA 600 mg, (two 300 mg tablets) administered orally Regimen twice daily. 1 Version date: April 2, 2018 Reference ID: 4469844 NDA 212099 Multi-disciplinary Review and Evaluation Darolutamide/NUBEQA Table of Contents Table of Tables ........................................................................................................................ 5 Table of Figures ....................................................................................................................... 8 Reviewers of Multi-Disciplinary Review and Evaluation............................................................10 Glossary .................................................................................................................................12 1 Executive Summary .........................................................................................................14 1.1. Product Introduction ................................................................................................14 1.2. Conclusions on the Substantial Evidence of Effectiveness ..........................................14 1.3. Benefit-Risk Assessment ...........................................................................................17 1.4. Patient Experience Data ............................................................................................20 2 Therapeutic Context ........................................................................................................21 2.1. Analysis of Condition ................................................................................................21 2.2. Analysis of Current Treatment Options ......................................................................21 3 Regulatory Background....................................................................................................23 3.1. U.S. Regulatory Actions and Marketing History ..........................................................23 3.2. Summary of Presubmission/Submission Regulatory Activity.......................................23 3.2.1. Regulatory history of MFS as a primary efficacy endpoint in nmCRPC ..................23 3.2.2. Key regulatory history of darolutamide under IND 114769..................................24 4 Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on Efficacy and Safety...........................................................................................................25 4.1. Office of Scientific Investigations (OSI) ......................................................................25 4.2. Product Quality.........................................................................................................25 4.3. Clinical Microbiology.................................................................................................25 4.4. Devices and Companion Diagnostic Issues .................................................................25 5 Nonclinical Pharmacology/Toxicology ..............................................................................26 5.1. Executive Summary ..................................................................................................26 5.2. Referenced NDAs, BLAs, DMFs ..................................................................................29 5.3. Pharmacology...........................................................................................................29 5.4. ADME/PK..................................................................................................................34 5.5. Toxicology ................................................................................................................40 5.5.1. General Toxicology ............................................................................................40 5.5.2. Genetic Toxicology.............................................................................................49 5.5.3. Carcinogenicity ..................................................................................................52 5.5.4. Reproductive and Developmental Toxicology .....................................................52 5.5.5. Other Toxicology Studies....................................................................................52 2 Version date: April 2, 2018 Reference ID: 4469844 NDA 212099 Multi-disciplinary Review and Evaluation Darolutamide/NUBEQA 6 Clinical Pharmacology ......................................................................................................53 6.1. Executive Summary ..................................................................................................53 6.2. Summary of Clinical Pharmacology Assessment .........................................................55 6.2.1. Pharmacology and Clinical Pharmacokinetics......................................................55 6.2.1.1 Mechanism of Action ......................................................................................55 6.2.1.2 Clinical Pharmacokinetics ..............................................................................55 6.2.2. General Dosing and Therapeutic Individualization ..............................................56 6.2.2.1. General Dosing ..............................................................................................56 6.2.2.2. Therapeutic Individualization........................................................................56 6.3 Comprehensive Clinical Pharmacology Review............................................................57 6.3.1 General Pharmacology andPharmacokinetic Characteristics ............................57 6.3.2 Clinical Pharmacology Questions ......................................................................61 7 Sources of Clinical Data and Review Strategy....................................................................78 7.1. Table of Clinical Studies ............................................................................................78 7.2. Review Strategy ........................................................................................................79 8 Statistical and Clinical and Evaluation...............................................................................80 8.1. Review of Relevant Individual Trials Used to Support Efficacy ....................................80 8.1.1. ARAMIS .............................................................................................................80 8.1.2. Study Results .....................................................................................................91 8.1.3 Assessment of Efficacy Across Trials ................................................................. 121 8.1.4 Integrated Assessment of Effectiveness............................................................ 121 8.2 Review of Safety ..................................................................................................... 122 8.2.1 Safety Review Approach .................................................................................. 122 8.2.2 Review of the Safety Database ......................................................................... 126 8.2.3 Adequacy of Applicant’s Clinical Safety Assessments ........................................ 128 8.2.4 Safety Results .................................................................................................. 130 8.2.5 Analysis of Submission-Specific Safety Issues .................................................... 139 8.2.5.1 Cardiac disorder ....................................................................................... 139 8.2.5.2 Seizure....................................................................................................