15 November 2018 EMA/879617/2018 Committee for Medicinal Products for Human Use (CHMP) CHMP assessment report Erleada International non-proprietary name: apalutamide Procedure No. EMEA/H/C/004452/0000 Note Assessment report as adopted by the CHMP with all information of a commercially confidential nature deleted. 30 Churchill Place ● Canary Wharf ● London E14 5EU ● United Kingdom Telephone +44 (0)20 3660 6000 Facsimile +44 (0)20 3660 5555 Send a question via our website www.ema.europa.eu/contact An agency of the European Union © European Medicines Agency, 2019. Reproduction is authorised provided the source is acknowledged. Administrative information Name of the medicinal product: Erleada Applicant: Janssen-Cilag International N.V. Turnhoutseweg 30 B-2340 Beerse BELGIUM Active substance: apalutamide International Non-proprietary Name: apalutamide Pharmaco-therapeutic group Endocrine therapy, anti-androgens (ATC Code): ATC code: L02BB05 Therapeutic indication(s): Erleada is indicated in adult men for the treatment of non-metastatic castration-resistant prostate cancer (NM-CRPC) who are at high risk of developing metastatic disease (see section 5.1). Pharmaceutical form(s): Film-coated tablet Strength(s): 60 mg Route(s) of administration: Oral use Packaging: blister (PVC/PCTFE/alu) and bottle (HDPE) Package size(s): Blister: 112 tablets and 120 tablets Bottle: 120 tablets CHMP assessment report EMA/879617/2018 Page 2/139 Table of contents 1. Background information on the procedure .............................................. 8 1.1. Submission of the dossier ..................................................................................... 8 1.2. Steps taken for the assessment of the product ........................................................ 9 2. Scientific discussion .............................................................................. 10 2.1. Problem statement ............................................................................................. 10 2.1.1. Disease or condition ........................................................................................ 10 2.1.2. Epidemiology .................................................................................................. 11 2.1.3. Clinical presentation, diagnosis and stage/prognosis ............................................ 11 2.1.4. Management ................................................................................................... 11 2.2. Quality aspects .................................................................................................. 12 2.2.1. Introduction.................................................................................................... 12 2.2.2. Active Substance ............................................................................................. 12 2.2.3. Finished Medicinal Product ................................................................................ 16 2.2.4. Discussion on chemical, pharmaceutical and biological aspects.............................. 20 2.2.5. Conclusions on the chemical, pharmaceutical and biological aspects ...................... 21 2.2.6. Recommendations for future quality development ............................................... 21 2.3. Non-clinical aspects ............................................................................................ 21 2.3.1. Introduction.................................................................................................... 21 2.3.2. Pharmacology ................................................................................................. 21 2.3.3. Pharmacokinetics ............................................................................................ 24 2.3.4. Toxicology ...................................................................................................... 26 2.3.5. Ecotoxicity/environmental risk assessment ......................................................... 34 2.3.6. Discussion on non-clinical aspects ..................................................................... 36 2.3.7. Conclusion on the non-clinical aspects ............................................................... 39 2.4. Clinical aspects .................................................................................................. 39 2.4.1. Introduction.................................................................................................... 39 2.4.2. Pharmacokinetics ............................................................................................ 41 2.4.3. Pharmacodynamics .......................................................................................... 59 2.4.4. Discussion on clinical pharmacology ................................................................... 62 2.4.5. Conclusions on clinical pharmacology ................................................................. 63 2.5. Clinical efficacy .................................................................................................. 63 2.5.1. Dose response study........................................................................................ 63 2.5.2. Main study(ies) ............................................................................................... 63 2.5.3. Discussion on clinical efficacy .......................................................................... 100 2.5.4. Conclusions on the clinical efficacy .................................................................. 105 2.6. Clinical safety .................................................................................................. 106 2.6.1. Discussion on clinical safety ............................................................................ 124 2.6.2. Conclusions on the clinical safety .................................................................... 127 2.7. Risk Management Plan ...................................................................................... 128 2.8. Pharmacovigilance ........................................................................................... 132 2.9. New Active Substance ...................................................................................... 132 CHMP assessment report EMA/879617/2018 Page 3/139 2.10. Product information ........................................................................................ 132 2.10.1. User consultation ......................................................................................... 132 2.10.2. Labelling exemptions ................................................................................... 132 2.10.3. Additional monitoring ................................................................................... 133 3. Benefit-Risk Balance ........................................................................... 134 3.1. Therapeutic Context ......................................................................................... 134 3.1.1. Disease or condition ...................................................................................... 134 3.1.2. Available therapies and unmet medical need ..................................................... 134 3.1.3. Main clinical studies ....................................................................................... 134 3.2. Favourable effects ............................................................................................ 134 3.3. Uncertainties and limitations about favourable effects ........................................... 135 3.4. Unfavourable effects ......................................................................................... 135 3.5. Uncertainties and limitations about unfavourable effects ....................................... 136 3.6. Effects Table .................................................................................................... 136 3.7. Benefit-risk assessment and discussion ............................................................... 137 3.7.1. Importance of favourable and unfavourable effects ............................................ 137 3.7.2. Balance of benefits and risks .......................................................................... 138 3.7.3. Additional considerations on the benefit-risk balance ......................................... 138 3.8. Conclusions ..................................................................................................... 138 4. Recommendations ............................................................................... 138 CHMP assessment report EMA/879617/2018 Page 4/139 List of abbreviations ADR adverse drug reaction ADT androgen deprivation therapy AR androgen receptor ARV7 androgen receptor splice variant 7 AUC area under the plasma concentration-time curve BCS biopharmaceutical classification system BICR blinded independent central review BCRP breast cancer resistance protein BSA body surface area CHMP Committee for Medicinal Products for Human Use CI confidence interval CL/F apparent oral clearance Cmax maximum observed plasma concentration Cmin minimum observed plasma concentration CQA critical quality attributes CPP critical process parameters CRPC castration-resistant prostate cancer CTCAE Common Terminology Criteria for Adverse Events CYP Cytochrome P450 CPP Critical Process Parameter CQA Critical Quality Attribute DAD diode array detector DSC differential scanning calorimetry DVS dynamic vapour sorption ECOG PS Eastern Cooperative Oncology Group Performance Status EMA European Medicines Agency FACT-P Functional