PARP inhibitors for homologous recombination-deficient prostate cancer

ABSTRACT

Introduction: Prostate adenocarcinoma represents a leading cause of cancer-related mortality. Increased emphasis on understanding the molecular basis of prostate cancer has identified a substantial burden of homologous recombination (HR) pathway mutations, which are enriched in castrate-resistant disease. This discovery has yielded novel therapeutic opportunities.

Areas covered: We will discuss the treatment of castrate-resistant prostate cancer (CRPC), with a focus on the use of poly (ADP-ribose) polymerase (PARP) inhibitors in this space. Evidence for use in HR-deficient patients will be outlined with discussion of the mechanism of action for this drug class, pathways of resistance, and approaches for expanding PARP inhibitor use to non–HR-deficient prostate cancer subgroups.

Expert opinion: PARP inhibition represents an exciting tool for management of HR-inactivated CRPC. With rapid adoption of next-generation sequencing technologies and other molecular techniques, the number of patients in this category is likely to increase. Ongoing and future investigations will be critical for improved understanding of the promise and appropriate treatment sequencing of PARP inhibition and optimal options for HR-proficient and -deficient prostate cancer populations. Questions remain about the clinical significance of monoallelic vs. biallelic HR mutations, the relevance of germline vs. somatic-only mutations, and the importance of mutations in non-canonical HR genes.

KEYWORDS:

• PARP inhibitors
• DNA repair
• homologous recombination deficiency
• castrate resistant prostate carcinoma
• olaparib
• rucaparib
• niraparib

Article Highlights

• Mutations in the homologous recombination (HR) DNA repair pathway are common in prostate cancer, affecting 20-25% of castrate resistant prostate cancers (CRPC) and 8-12% of localized prostate cancers.

• HR-deficient prostate cancers my exhibit sensitivty to poly (ADP-ribose) polymerase (PARP) inhibitors, and multiple trials testing these agents (olaparib, rucaparib, niraparib) are currently underway in the metastatic CRPC setting.

• Use of PARP inhibitors in HR-deficient hormone sensitive prostate cancer (biochemically recurrent or metastatic disease) is an intriguing concept that requires clinical investigation.

• Combination approaches utilizing PARP inhibitors together with other agents may expand the clinical utility of these agents beyond the HR-deficient population by inducing synthetic lethality in different ways

This box summarizes key points contained in the article.

Declaration of interest

E S Antonarakis is a paid consultant/advisor to Janssen, Astellas, Sanofi, Dendreon, Medivation, ESSA, AstraZeneca, Clovis and Merck; he has received research funding to his institution from Janssen, Johnson & Johnson, Sanofi, Dendreon, Genentech, Novartis, Tokai, Bristol Myers-Squibb, AstraZeneca, Clovis and Merck; and he is the co-inventor of a biomarker technology that has been licensed to Tokai and 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. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Additional information

Funding

This work was partially supported by National Institutes of Health Grant P30 CA006973 (E.S.A.), the Patrick C. Walsh fund (E.S.A) and the Prostate Cancer Foundation (E.S.A). The content is solely the responsibility of the authors and does not represent the official views of the National Cancer Institute or the National Institutes of Health.