Dr. Choudhury on the Potential Benefit of PARP Inhibitor Use in mCRPC

Atish D. Choudhury, MD, PhD, chair, Gelb Center for Translational Research, senior physician, Dana-Farber Cancer Institute, assistant professor of medicine, Harvard Medical School, discusses key biomarkers that may assist in the prediction of PARP inhibitor benefit in metastatic castration-resistant prostate cancer (mCRPC).

Current research on the use of PARP inhibitors, such as olaparib (Lynparza) and talazoparib (Talzenna),within the homologous recombination–deficient (HRD) pathway aims to identify which patient populations are more likely to benefit from the PARP inhibitor therapies, Choudhury begins. Patients with the BRCA2 gene alteration have been shown to experience a greater benefit with PARP monotherapy, followed by those with BRCA1 alterations, he continues.

Recent evidence suggests that patients with ATM, CHEK2, or CDK12  mutations experience modest benefit from PARP monotherapy, Choudhury says. Other homologous recombination repair (HRR)–deficient gene alterations such as PALB2, RAD51, and FANCA demonstrate a more variable degree of benefit. More research is needed to determine the best use of PARP inhibitors in these populations, and develop novel agents that target other biomarkers in the HRD pathway, Choudhury states.

In addition to research on the use of PARP monotherapy, novel PARP combinations are also being investigated for mCRPC, Choudhury continues. The combination of olaparib and abiraterone acetate (Zytiga) was recently approved in the European Union as a first-line treatment for patients with mCRPC who have not previously undergone treatment with potent hormonal agents. This approval was based on findings from the phase 3 PROpel trial (NCT03732820) which showed that the combination significantly reduced the risk of disease progression or death compared with both placebo plus abiraterone or prednisolone.

Although the regimen has not received FDA approval, it has the potential of benefiting patients with a known BRCA2 mutation, HRR deficiency, and high-burden disease, Choudhury explains. However, existing data does not support the regimen's use in other clinical contexts, he notes. Accordingly, future research should aim to increase the body of evidence for these combinations, Choudhury concludes.

Editor’s Note: Dr Choudhury reports serving as a consultant or on a paid advisory board for Clovis, Dendreon, Bayer, Eli Lilly, AztraZeneca, Astellas, Blue Earth, Janssen, Tolmar; he has received honoraria from Bayler, Astellas Australia, Janssen Latin america, ANZUP, OncLive, MEDACorp, Oncology Learning Network, Aptitude Health, Targeted Oncology, Blackstone, Journal of Clinical Pathways, Cancer Network, Clinical Care Options, Great Debates and Updates, Pfizer, Springer Healthcare; he has received research funding from Bayer.