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Australian Public Assessment Report for Apalutamide

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Australian Public Assessment Report for Apalutamide Australian Public Assessment Report for Apalutamide Proprietary Product Name: Erlyand/Janssen Apalutamide Sponsor: Janssen-Cilag Pty Ltd March 2019 Therapeutic Goods Administration About the Therapeutic Goods Administration (TGA) • The Therapeutic Goods Administration (TGA) is part of the Australian Government Department of Health and is responsible for regulating medicines and medical devices. • The TGA administers the Therapeutic Goods Act 1989 (the Act), applying a risk management approach designed to ensure therapeutic goods supplied in Australia meet acceptable standards of quality, safety and efficacy (performance) when necessary. • The work of the TGA is based on applying scientific and clinical expertise to decision- making, to ensure that the benefits to consumers outweigh any risks associated with the use of medicines and medical devices. • The TGA relies on the public, healthcare professionals and industry to report problems with medicines or medical devices. TGA investigates reports received by it to determine any necessary regulatory action. • To report a problem with a medicine or medical device, please see the information on the TGA website <https://www.tga.gov.au>. About AusPARs • An Australian Public Assessment Report (AusPAR) provides information about the evaluation of a prescription medicine and the considerations that led the TGA to approve or not approve a prescription medicine submission. • AusPARs are prepared and published by the TGA. • An AusPAR is prepared for submissions that relate to new chemical entities, generic medicines, major variations and extensions of indications. • An AusPAR is a static document; it provides information that relates to a submission at a particular point in time. • A new AusPAR will be developed to reflect changes to indications and/or major variations to a prescription medicine subject to evaluation by the TGA. Copyright © Commonwealth of Australia 2019 This work is copyright. You may reproduce the whole or part of this work in unaltered form for your own personal use or, if you are part of an organisation, for internal use within your organisation, but only if you or your organisation do not use the reproduction for any commercial purpose and retain this copyright notice and all disclaimer notices as part of that reproduction. Apart from rights to use as permitted by the Copyright Act 1968 or allowed by this copyright notice, all other rights are reserved and you are not allowed to reproduce the whole or any part of this work in any way (electronic or otherwise) without first being given specific written permission from the Commonwealth to do so. Requests and inquiries concerning reproduction and rights are to be sent to the TGA Copyright Officer, Therapeutic Goods Administration, PO Box 100, Woden ACT 2606 or emailed to <[email protected]>. AusPAR Erlyand Apalutamide Janssen-Cilag Pty Ltd PM-2018-00489-1-4 Page 2 of 83 Final 25 March 2019 Therapeutic Goods Administration Contents Common abbreviations _______________________________________________________ 5 I. Introduction to product submission _____________________________________ 9 Submission details ____________________________________________________________________ 9 Submission and evaluation background ___________________________________________ 10 Product background _________________________________________________________________ 10 Regulatory status ____________________________________________________________________ 12 Product Information_________________________________________________________________ 13 II. Registration time line ___________________________________________________ 13 III. Quality findings __________________________________________________________ 14 Drug substance (active ingredient) ________________________________________________ 14 Drug product _________________________________________________________________________ 14 Summary of human pharmacokinetics ____________________________________________ 15 Biopharmaceutics ___________________________________________________________________ 16 Quality summary and recommendation ___________________________________________ 20 IV. Nonclinical findings _____________________________________________________ 20 Introduction __________________________________________________________________________ 20 Pharmacology ________________________________________________________________________ 21 Pharmacokinetics ____________________________________________________________________ 24 Toxicology ____________________________________________________________________________ 27 Impurities ____________________________________________________________________________ 33 Nonclinical summary and conclusions _____________________________________________ 33 Nonclinical conclusions and recommendation ____________________________________ 35 V. Clinical findings ___________________________________________________________ 35 Introduction __________________________________________________________________________ 35 Dosage selection for the pivotal studies ___________________________________________ 37 Efficacy _______________________________________________________________________________ 37 Safety _________________________________________________________________________________ 38 Second round evaluation ____________________________________________________________ 45 Clinical benefit-risk assessment ____________________________________________________ 47 Clinical recommendation regarding authorisation _______________________________ 50 VI. Pharmacovigilance findings ___________________________________________ 50 Risk management plan ______________________________________________________________ 50 VII. Overall conclusion and risk/benefit assessment _________________ 54 Quality ________________________________________________________________________________ 54 Nonclinical ___________________________________________________________________________ 54 AusPAR Erlyand Apalutamide Janssen-Cilag Pty Ltd PM-2018-00489-1-4 Page 3 of 83 Final 25 March 2019 Therapeutic Goods Administration Clinical ________________________________________________________________________________ 54 Risk management plan ______________________________________________________________ 79 Risk-benefit analysis ________________________________________________________________ 79 Outcome ______________________________________________________________________________ 82 Attachment 1. Product Information ______________________________________ 82 AusPAR Erlyand Apalutamide Janssen-Cilag Pty Ltd PM-2018-00489-1-4 Page 4 of 83 Final 25 March 2019 Therapeutic Goods Administration Common abbreviations Abbreviation Meaning ACM Advisory Committee on Medicines ACSS Australia Canada Singapore Switzerland Consortium ACSS-NCE Australia Canada Singapore Switzerland Consortium’s New Chemical Entities Work Sharing pilot ADT Androgen deprivation therapy AE Adverse event AESI Adverse event of special interest ALP Alkaline phosphatase ALT Alanine aminotransferase API Active pharmaceutical ingredient AR Androgen receptor ARN-509 Apalutamide drug development name ARTG Australian Register of Therapeutic Goods ASA Australian Specific Annex AST Aspartate aminotransferase ASTRO American Society for Radiation Oncology Cmax Peak plasma concentration Cmin Minimum plasma concentration CRPC Castration-resistant prostate cancer CI Confidence interval CMI Consumer Medicines Information CNS Central nervous system CRF Case report form CT Computed tomography CTC Circulating tumour cells AusPAR Erlyand Apalutamide Janssen-Cilag Pty Ltd PM-2018-00489-1-4 Page 5 of 83 Final 25 March 2019 Therapeutic Goods Administration Abbreviation Meaning CTCAE Common Terminology Criteria for Adverse Events CYP (450) Cytochrome P450 system DHT Dihydroxytestosterone DLP Data lock point DLT Dose-limiting toxicity ECG Electrocardiogram ECOG PS Eastern Cooperative Oncology Group Performance Status EMA European Medicines Agency ER Exposure ratio FDA Food and Drug Administration FDHT- -[18 F] Fluoro- -dihydrotestosterone GABA PET 16β Gammaα aminobutyric acid GI Gastrointestinal GGT Gamma-glutamyl transferase GLP Good Laboratory Practice GMR Geometric mean ratio GnRH Gonadotropin releasing hormone GnRHa Gonadotropin releasing hormone analog Hb Haemoglobin Hct Haematocrit IC50 50% inhibitory concentration ICF Informed consent form ICH International Conference on Harmonization IDMC Independent data and safety monitoring committee IP Investigational product JNJ-56021927 Apalutamide drug development name AusPAR Erlyand Apalutamide Janssen-Cilag Pty Ltd PM-2018-00489-1-4 Page 6 of 83 Final 25 March 2019 Therapeutic Goods Administration Abbreviation Meaning OS Overall survival mCRPC Metastatic castration-resistant prostate cancer MedDRA Medical Dictionary for Regulatory Activities MFS Metastasis-free survival MRI Magnetic resonance imaging MTD Maximum tolerated dose NCCN National Comprehensive Cancer Network (USA) NCI National Cancer Institute (USA) NM-CRPC Non-metastatic castration-resistant prostate cancer PSADT Prostate specific antigen doubling time PCWG2 Prostate Cancer Working Group 2 PK Pharmacokinetic(s) PFS Progression-free survival PI Product Information PO Oral (per os) PSA Prostate-specific antigen PSUR Periodic safety update report RBC Red blood cell RDI Relative dose intensity SAE Serious adverse event SOC System Organ Class SRE Skeletal-related event TEAE Treatment emergent adverse event TTM Time to metastasis Tmax Time to peak plasma concentration
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