Dr Takvorian on the Evolution of PARP Inhibitors in Prostate Cancer

Samuel U. Takvorian, MD, MS, assistant professor, medicine (hematology-oncology), the Hospital of the University of Pennsylvania, discusses the evolution of regulatory decisions regarding the use of PARP inhibitors for patients with prostate cancer.

The list of PARP inhibitors approved for the treatment of patients with prostate cancer has expanded over the past 4 to 5 years, Takvorian says. In 2020, olaparib (Lynparza) and rucaparib (Rubraca) became the first PARP inhibitors to be approved for patients with metastatic prostate cancer.

In May 2020, the FDA approved olaparib monotherapy for adult patients with deleterious or suspected deleterious somatic or germline homologous recombination repair (HRR) gene–mutated metastatic castration-resistant prostate cancer (mCRPC) who have progressed after prior treatment with the androgen receptor (AR) signaling inhibitors abiraterone acetate (Zytiga) or enzalutamide (Xtandi). This regulatory decision was supported by findings from the phase 3 PROfound trial (NCT02987543), in which olaparib elicited a 66% reduction in the risk of disease progression or death vs enzalutamide or abiraterone acetate (HR, 0.34; P < .0001) in patients with mCRPC harboring BRCA1/2 or ATM mutations.

In the same month, the FDA approved rucaparib monotherapy for adult patients with BRCA-mutant, recurrent mCRPC who had received prior AR–targeted therapy and prior taxane-based therapy. This regulatory decision was based on data from the phase 2 TRITON2 trial (NCT02952534), in which rucaparib led to a confirmed investigator-assessed overall response rate of 44% (95% CI, 31%-57%) in this patient population.

2023 saw the FDA approvals of 3 PARP inhibitor–based combination therapies for patients with prostate cancer. In May 2023, olaparib in combination with abiraterone acetate and prednisone or prednisolone gained FDA approval for patients with mCRPC harboring deleterious or suspected deleterious BRCA mutations. This regulatory decision was supported by findings from the phase 3 PROpel trial (NCT03732820), in which the median radiographic progression-free survival (rPFS) in patients with BRCA mutations (n = 85) who received the olaparib regimen was not yet reached compared with 8 months (95% CI, 6-15) in patients who received placebo plus abiraterone (HR, 0.24; 95% CI, 0.12-0.45).

In June 2023, talazoparib (Talzenna) plus enzalutamide was approved by the FDA for patients with HRR gene–mutated mCRPC, based on findings from the phase 3 TALAPRO-2 trial (NCT03395197), in which the talazoparib combination resulted in a significant rPFS benefit vs enzalutamide alone (HR, 0.45; 95% CI, 0.33-0.61; P < .0001).

Lastly, in August 2023, the FDA granted approval to niraparib (Zejula) plus abiraterone acetate and prednisone for adult patients with mCRPC harboring deleterious or suspected deleterious BRCA mutations. This approval was based on data from the phase 3 MAGNITUDE trial (NCT03748641), in which the niraparib combination significantly improved rPFS vs abiraterone acetate plus prednisone in patients with BRCA-mutated disease (HR, 0.53; P = .001).