Olaparib and rucaparib for the treatment of DNA repair-deficient metastatic castration-resistant prostate cancer

ABSTRACT

Introduction

Metastatic prostate cancer is a heterogeneous disease characterized by clinical and genomic heterogeneity. Many prostate cancers harbor mutations causing DNA repair deficiency, specifically homologous recombination deficiency, sensitizing to drugs that inhibit poly ADP-ribose polymerase (PARP). PARP is an enzyme that is involved in single-stranded DNA repair and is the target of newly approved treatments for metastatic prostate cancer.

Areas Covered

Here, the authors’ review the clinical trials leading to the recent approvals of two PARP inhibitors (PARPi), olaparib and rucaparib, specifically TOPARP-A, TOPARP-B, PROfound and TRITON-2. They also compare the different FDA approvals for both of these medications and outline the safety of this class of drugs in prostate cancer.

Expert opinion

Because PARPi are particularly effective in men with somatic or germline alterations in BRCA1 and BRCA2, we recommend that all men be tested for DNA alterations with next-generation sequencing in tumor cells obtained from either tissue or blood. We also recommend that olaparib or rucaparib be considered relatively early in the treatment sequence in metastatic castration-resistant prostate cancer patients with BRCA1 or BRCA2 mutations. Other DNA alterations might also sensitize to PARPi though the response rates are lower, so other standard therapies should be prioritized first.

KEYWORDS:

• Olaparib
• rucaparib
• metastatic castration-resistant prostate cancer
• parp inhibitor

Article highlights

• Alterations to DNA damage and repair genes, such as homologous recombination repair (HRR), is common in metastatic prostate cancer.

• PARP inhibitors are effective in treating patients with HRR alterations.

• Efficacy is variable depending on the HRR gene that is mutated.

• PARP inhibitors are generally well-tolerated, with common adverse events including fatigue, nausea, and cytopenias with anemia being the most frequent.

• Olaparib and rucaparib are both FDA approved for metastatic castration-resistant prostate cancer with HRR mutations and BRCA1/2 mutations, respectively.

This box summarizes key points contained in the article.

Declaration of interest

BL Maughan is a paid consultant/advisor to Janssen, Astellas, Bristol-Myers Squibb, Clovis, Tempus, Merck, Exelixis, Bayer Oncology and Peloton Therapeutics. He has also received research funding to his institution from Exelixis, Bavarian-Nordic, Clovis and Bristol-Myers Squibb. ES Antonarakis is a paid consultant/advisor to Janssen, Astellas, Sanofi, Dendreon, Pfizer, Amgen, AstraZeneca, Bristol-Myers Squibb, 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. He is also the co-inventor of an AR-V7 biomarker technology that has been 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 work was partially supported by National Institutes of Health Cancer Center Support Grant P30CA006973