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23 October 2014 EMA/CHMP/789139/2014 Committee for Medicinal Products for Human Use (CHMP) CHMP assessment report Lynparza International non-proprietary name: OLAPARIB Procedure No.: EMEA/H/C/003726/0000 Note Assessment report as adopted by the CHMP with all information of a commercial confidential nature deleted. 30 Churchill Place ● Canary Wharf ● London E14 5EU ● United Kingdom Telephone +44 (0)20 3660 6000 Facsimile +44 (0)20 3660 5520 Send a question via our website www.ema.europa.eu/contact An agency of the European Union © European Medicines Agency, 2014. Reproduction is authorised provided the source is acknowledged. Administrative information Name of the medicinal product: Lynparza Applicant: AstraZeneca AB SE-151 85 Södertälje 15185 Södertälje SWEDEN Active substance: OLAPARIB International Nonproprietary OLAPARIB Name/Common Name: Pharmaco-therapeutic group other antineoplastic agents (ATC Code): (L01) Therapeutic indication: Lynparza is indicated as monotherapy for the maintenance treatment of adult patients with platinum sensitive relapsed BRCA mutated (germline and/or somatic) high grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in response (complete response or partial response) to platinum-based chemotherapy. Pharmaceutical form: Capsule, hard Strength: 50 mg Route of administration: Oral use Packaging: Bottle (HDPE) Package size: 448 (4 x 112 capsules) capsules CHMP assessment report EMA/CHMP/789139/2014 Page 2/187 Table of contents Assessment report as adopted by the CHMP with all information of a commercial confidential nature deleted. ........................................................................................................... 1 1. Background information on the procedure .............................................. 7 1.1. Submission of the dossier ...................................................................................... 7 1.2. Manufacturers ...................................................................................................... 8 1.3. Steps taken for the assessment of the product ......................................................... 8 2. Scientific discussion ................................................................................ 9 2.1. Introduction......................................................................................................... 9 2.2. Quality aspects .................................................................................................. 13 2.2.1. Introduction .................................................................................................... 13 2.2.2. Active Substance ............................................................................................. 13 2.2.3. Finished Medicinal Product ................................................................................ 16 2.2.4. Discussion on chemical, pharmaceutical and biological aspects .............................. 20 2.2.1. Conclusions on the chemical, pharmaceutical and biological aspects ...................... 21 2.2.2. Recommendation(s) for future quality development ............................................. 21 2.3. Non-clinical aspects ............................................................................................ 21 2.3.1. Introduction .................................................................................................... 21 2.3.2. Pharmacology ................................................................................................. 22 2.3.3. Pharmacokinetics............................................................................................. 26 2.3.4. Toxicology ...................................................................................................... 33 2.3.5. Ecotoxicity/environmental risk assessment ......................................................... 41 2.3.6. Discussion on non-clinical aspects...................................................................... 43 2.3.7. Conclusion on the non-clinical aspects ................................................................ 48 2.4. Clinical aspects .................................................................................................. 48 2.4.1. Introduction .................................................................................................... 48 2.4.2. Pharmacokinetics............................................................................................. 52 2.4.3. Pharmacodynamics .......................................................................................... 64 2.4.4. Discussion on clinical pharmacology ................................................................... 68 2.4.5. Conclusions on clinical pharmacology ................................................................. 75 2.5. Clinical efficacy .................................................................................................. 76 2.5.1. Dose response studies...................................................................................... 76 2.5.2. Main studies ................................................................................................... 78 2.5.3. Discussion on clinical efficacy .......................................................................... 126 2.5.4. Conclusions on the clinical efficacy ................................................................... 131 2.6. Clinical safety .................................................................................................. 131 2.6.1. Discussion on clinical safety ............................................................................ 163 2.6.2. Conclusions on the clinical safety ..................................................................... 169 2.7. Pharmacovigilance ............................................................................................ 170 2.8. Risk Management Plan ...................................................................................... 170 2.9. Product information .......................................................................................... 183 2.9.1. User consultation ........................................................................................... 183 CHMP assessment report EMA/CHMP/789139/2014 Page 3/187 3. Benefit-Risk Balance............................................................................ 183 4. Recommendations ............................................................................... 186 CHMP assessment report EMA/CHMP/789139/2014 Page 4/187 List of abbreviations ACMG American College of Medical Genetics and Genomics ADME Absorption, distribution, metabolism and excretion ADR Adverse drug reaction AE Adverse event AML Acute myeloid leukaemia ANSM Agence nationale de sécurité du médicament et des produits de santé ALT Alanine transaminase AST Aspartate transaminase AUC Area under plasma concentration-time curve BCRP Breast cancer resistance protein bd Twice daily BIC Breast Cancer Information Core BICR Blinded independent central review BRCA Breast cancer susceptibility gene (in accordance with scientific convention, gene and mutation is italicised whereas protein is not italicised) BRCAm gBRCA and/or tBRCA mutated BRCAwt/VUS gBRCA and/or tBRCA wild type/variant of unknown significance BUN Blood urea nitrogen CA-125 Cancer antigen (CA)-125 (tumour biomarker) CAP College of American Pathologists CHMP Committee for Medicinal Products for Human Use CI Confidence interval CLIA Clinical Laboratory Improvement Amendments Cmax Maximum plasma concentration CR Complete response CRF Case report form CSR Clinical study report CT Computed tomography CTCAE Common Terminology Criteria (CTC) for Adverse Events CYP Cytochrome P450 DCO Data cut-off DNA Deoxyribonucleic acid DSB DNA double-strand breaks ECG Electrocardiogram ECOG PS Eastern Cooperative Oncology Group Performance Status EMA European Medicines Agency EMQN European Molecular Genetics Quality Network EU European Union FACT-O Functional Assessment of Cancer Therapy – Ovarian FAHMP Federal Agency for Medicines and Health Products FAS Full analysis set (the overall study population, unselected for BRCA mutation status, equivalent to intent to treat [ITT] population) FDA Food and Drugs Administration FFPE Formalin fixed paraffin embedded FTIM First time in man gBRCAm Germline BRCA mutated gBRCAwt/VUS Germline BRCA wild type/variant of unknown significance GCP Good Clinical Practice GCIG Gynecological Cancer Intergroup GFR Glomerular filtration rate hERG Human ether-a-go-go-related gene HR Hazard ratio HRD Homologous recombination deficient/deficiency HRQoL Health-related quality of life IC50 Half maximal inhibitory concentration ICH International Conference on Harmonisation ILD Interstitial lung disease ITT Intention to treat IVRS Interactive voice response system LMG Lauroyl macrogol-32 glycerides CHMP assessment report EMA/CHMP/789139/2014 Page 5/187 LS Least squares MAA Marketing Authorisation Application MCV Mean corpuscular volume MDR1 Multi-drug resistance protein 1 MDS Myelodysplastic syndrome MEB Medicines Evaluation Board MedDRA Medical Dictionary for Regulatory Activities MLPA Multiplex ligation-dependent probe amplification MPA Medical Products Agency MRI Magnetic resonance imaging MRP2 Multi-drug resistance protein 2 MTD Maximum tolerated dose NCCN National Comprehensive Cancer Network NGS Next generation sequencing NHEJ Non-homologous end joining OATP Organic anion-transporting protein OCT Organic cation-transporter
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