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Review
. 2024 May:126:102726.
doi: 10.1016/j.ctrv.2024.102726. Epub 2024 Mar 29.

First-line combination treatment with PARP and androgen receptor-signaling inhibitors in HRR-deficient mCRPC: Applying clinical study findings to clinical practice in the United States

Rana R McKay  1 , Alicia K Morgans  2 , Neal D Shore  3 , Curtis Dunshee  4 , Geeta Devgan  5 , Neeraj Agarwal  6
Affiliations
Free article
Review

First-line combination treatment with PARP and androgen receptor-signaling inhibitors in HRR-deficient mCRPC: Applying clinical study findings to clinical practice in the United States

Rana R McKay et al. Cancer Treat Rev. 2024 May.
Free article

Abstract

Introduction: Metastatic castration-resistant prostate cancer (mCRPC) remains incurable and develops from biochemically recurrent PC treated with androgen deprivation therapy (ADT) following definitive therapy for localized PC, or from metastatic castration-sensitive PC (mCSPC). In the mCSPC setting, treatment intensification of ADT plus androgen receptor (AR)-signaling inhibitors (ARSIs), with or without chemotherapy, improves outcomes vs ADT alone. Despite multiple phase 3 trials demonstrating a survival benefit of treatment intensification in PC, there remains high use of ADT monotherapy in real-world clinical practice. Prior studies indicate that co-inhibition of AR and poly(ADP-ribose) polymerase (PARP) may result in enhanced benefit in treating tumors regardless of alterations in DNA damage response genes involved either directly or indirectly in homologous recombination repair (HRR). Three recent phase 3 studies evaluated the combination of a PARP inhibitor (PARPi) with an ARSI as first-line treatment for mCRPC: TALAPRO-2, talazoparib plus enzalutamide; PROpel, olaparib plus abiraterone acetate and prednisone (AAP); and MAGNITUDE, niraparib plus AAP. Results from these studies have led to the recent approval in the United States of talazoparib plus enzalutamide for the treatment of mCRPC with any HRR alteration, and of both olaparib and niraparib indicated in combination with AAP for the treatment of mCRPC with BRCA alterations.

Summary: Here, we review the newly approved PARPi plus ARSI treatments within the context of the mCRPC treatment landscape, provide an overview of practical considerations for the combinations in clinical practice, highlight the importance of HRR testing, and discuss the benefits of treatment intensification for patients with mCRPC.

Keywords: Abiraterone acetate and prednisone; Enzalutamide; Niraparib; Olaparib; Talazoparib; mCRPC.

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Conflict of interest statement

Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: R.R.M. reports a consulting or advisory board role for AstraZeneca, AVEO Pharmaceuticals, Bayer, Blue Earth Diagnostics, Bristol Myers Squibb, Calithera, Caris, Dendreon, Eisai, Eli Lilly, Exelixis, Janssen, Merck, MOMA, Myovant, Novartis, Pfizer, Sanofi, Seagen, Sorrento Therapeutics, Telix, and Tempus; and research funding (to her institution) from AstraZeneca, Artera, Bayer, Bristol Myers Squibb, Exelixis, Oncternal, and Tempus. A.K.M. reports a consulting role for Antev, Astellas, AstraZeneca, Bayer, Exelixis, Janssen, Lantheus, Merck, Myovant, Novartis, Pfizer, Sanofi, and Telix; and research funding from Bayer, Lantheus, Myovant, Pfizer, and Sanofi. N.D.S. reports a consulting or advisory role for AbbVie, Alessa Therapeutics, AIkido, Amgen, Arquer, Asieris, Astellas Pharma, AstraZeneca, Bayer, Boston Scientific, Bristol Myers Squibb, CG Oncology, Clarity Pharmaceuticals, Clovis Oncology, Dendreon, Exact Imaging, Exact Sciences, FerGene, Ferring, FIZE Medical, Foundation Medicine, GenesisCare, Genentech, Guardant Health, ImmunityBio, Incyte, Invitae, Janssen, Lantheus, Lilly, Mdxhealth, Merck, Minomic, Myovant Sciences, Myriad Genetics, Nymox, Pacific Edge Biotechnology, Pfizer, Photocure, PlatformQ, Profound, Promaxo, Propella Therapeutics, Protara, Sanofi, Sesen Bio, Speciality Networks, Telix Pharmaceuticals, Tolmar, UroGen Pharma, Vaxiion, and Vessi; providing expert testimony for Ferring; and leadership or other fiduciary role in other board, society, committee, or advocacy group with Photocure. C.D. reports participation on advisory boards for Astellas Pharma, Bayer, Janssen, and Pfizer; and research funding from AstraZeneca, Bayer, Dendreon, Hengrui Pharmaceuticals, Janssen, Laekna Therapeutics, Myovant Sciences, and Pfizer. G.D. is an employee of Pfizer and may hold Pfizer stock/stock options. N.A. has received an honorarium for consultancy before May 2021 from Astellas Pharma, AstraZeneca, AVEO, Bayer, Bristol Myers Squibb, Calithera Biosciences, Eisai, EMD Serono, Exelixis, Foundation Medicine, Genentech, Gilead Sciences, Immunomedics, Janssen, Lilly, and MEI Pharma; and research funding (to his institution) from Arvinas, Astellas Pharma, AstraZeneca, Bayer, Bristol Myers Squibb, Calithera Biosciences, Celldex, Clovis Oncology, CRISPR Therapeutics, Eisai, EMD Serono, Exelixis, Genentech, Gilead Sciences, GlaxoSmithKline, Immunomedics, Janssen, Lava, Lilly, Merck, Nektar, Neoleukin, Novartis, ORIC Pharmaceuticals, Pfizer, Rexahn, Roche, Sanofi, Seagen, Takeda, and TRACON.

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