The evolving landscape of PARP inhibitors in castration-resistant prostate cancer: a spotlight on treatment combinations

ABSTRACT

Introduction

PARP inhibition in prostate cancer has become a standard-of-care option for men with metastatic castration-resistant prostate cancer (mCRPC) with deficiency in homologous recombination repair (HRRd). The benefit varies based upon the characteristics of the PARP inhibitor used and the underlying HRR defect. Optimal patient selection remains a clinical challenge, and investigations are underway to identify effective combination therapies to expand the population that benefits.

Areas covered

We review the clinical development of the FDA-approved PARP inhibitors olaparib and rucaparib. Additionally, we explore the status of other PARP inhibitors that remain experimental in prostate cancer, based upon review of published abstracts, articles, and clinicaltrials.gov. Most new studies, including phase 3 trials for talazoparib and rucaparib, involve combinations with novel androgen receptor signaling inhibitors. We review the landscape of emerging PARP inhibitor-based combination therapies.

Expert opinion

For men with BRCA1 or BRCA2 mutations, olaparib has a clear role for early use in the disease course of mCRPC. For men with other HRR mutations, that benefit remains less well defined, particularly with the availability of other treatment choices. Ultimately, combination strategies are likely to be the best avenue for men without BRCA1 or BRCA2 mutations to be treated with PARP inhibition.

KEYWORDS:

• Prostate cancer
• homologous recombination repair deficiency
• PARP inhibition
• hormone therapy

Article highlights

• The PARP inhibitors olaparib and rucaparib are currently in clinical use for specific patients with advanced prostate cancer and underlying HRR mutations.

• The benefit of PARP inhibitors is not uniform across all HRR mutations.

• Earlier use of PARP inhibitors, especially in combination with novel androgen receptor signaling inhibitors, will likely become standard in the near future.

• Combination therapies with immunotherapy or chemotherapy may prove synergistic and expand the number of patients eligible for treatment with PARP inhibitors.

• Ultimately, a personalized approach will be required given the number of available and emerging therapies, and the optimal way to use PARP inhibitors is still not defined.

Declaration of interest

BA Teply has served as a paid consultant/advisor to Seagen, Janssen, AstraZeneca, Lilly, and Sanofi; and has served on a scientific review panel for Pfizer/Myovant; and has received research funding (to his institution) from QED Therapeutics, Bristol-Myers Squibb, Inovio Pharmaceuticals, and Bellicum Pharmaceuticals. ES Antonarakis has served as a paid consultant/advisor to Sanofi, Dendreon, Janssen Biotech, ESSA, Merck, AstraZeneca, Clovis Oncology, Lilly, Bayer, Amgen, Astellas Pharma, Blue Earth Diagnostics, Bristol Myers Squibb/Celgene, Constellation Pharmaceuticals, GlaxoSmithKline, Curium Pharma, Exact Sciences, Foundation Medicine, Invitae and Tempus; has received research funding (to his institution) from Janssen Biotech, Johnson & Johnson, Sanofi, Dendreon, Aragon Pharmaceuticals, Exelixis, Millennium, Genentech, Novartis, Astellas Pharma, Tokai Pharmaceuticals, Merck, AstraZeneca, Clovis Oncology, Constellation Pharmaceuticals and

Celgene; and is the co-inventor of a patented biomarker technology licensed to Qiagen. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.