Dr. Zhang on the Use of PARP Inhibitor–based Combinations in mCRPC

Tian Zhang, MD, MHS, associate professor, the Department of Internal Medicine, Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, discusses the use of PARP inhibitor–based combinations in patients with metastatic castration-resistant prostate cancer (mCRPC).

At the 2023 Prost8 Cancer Conference, Zhang and colleagues conferred on the combination of PARP inhibitors with novel hormonal agents, specifically regarding when and how to use those particular combinations, Zhang begins. PARP inhibitor monotherapy has an accepted role for the treatment of patients with homologous recombination repair (HRR) deficiency, Zhang says.

For example, in May 2020, the FDA approved both olaparib (Lynparza) for the treatment of adult patients with deleterious or suspected deleterious germline or somatic HRR gene-mutated mCRPC who have progressed following prior treatment with enzalutamide (Xtandi) or abiraterone acetate (Zytiga), and rucaparib (Rubraca) for the treatment of adult patients with a BRCA mutation (germline and/or somatic)—associated mCRPC who have been treated with androgen receptor–directed therapy and a taxane-based chemotherapy.

Data from the phase 3 TRITON3 trial (NCT02975934), which evaluated rucaparib vs physician’s choice of therapy of abiraterone, enzalutamide (Xtandi), or docetaxel, in patients with mCRPC and HRR deficiency, added further evidence to support treating patients with PARP inhibitors vs chemotherapy or an androgen receptor (AR)–targeted agent alone, Zhang explains.

However, controversy remains in the space about whether PARP inhibitors should be used in combination with an AR-targeted agent, Zhang says. The debate centers around whether a PARP inhibitor plus an AR-targeted therapy should be used up-front for all patients with CRPC, regardless of HRR status, or if the combination should be used in a more select patient population, Zhang explains. Additionally, the question remains whether the combination of a PARP inhibitor with an AR-targeted therapy is better than sequencing each treatment as a monotherapy, Zhang continues.

Factors to consider when addressing questions about PARP inhibitor–based combinations include toxicity issues, cost issues, and whether a patient is appropriate for the underlying AR-targeted agent, Zhang concludes.