BRCA2 Subgroup Benefits From PARP Inhibitors in mCRPC

Patients who have metastatic castration- resistant prostate cancer (mCRPC) and exhibit the BRCA2 mutation often face a challenging prognosis. However, insights shared by David R. Wise, MD, PhD, at the 41st Annual Chemotherapy Foundation Symposium Innovative Cancer Therapy for Tomorrow®, held on November 8 to 10, 2023, shed light on positive outcomes for this specific subgroup. Highlighting the TRITON3 trial (NCT02975934) findings, Wise explained that the PARP inhibitor rucaparib (Rubraca) showed a significant improvement in progression-free survival (PFS) compared with docetaxel. Specifically, findings revealed a PFS of 11.2 months with rucaparib vs 8.3 months with docetaxel (HR, 0.53; 95% CI, 0.37-0.77).¹

“The [TRITON3] trial successfully met its primary end point of overall best physician’s choice. Within the [BRCA] subset, improvement with rucaparib over docetaxel is evident. The significant improvement seen within this subset informs my clinical approach due to the substantial use of docetaxel. In the absence of comparative data between other PARP inhibitors and docetaxel, I leans toward selecting a PARP inhibitor for patients with BRCA2 mutations,” Wise said. Wise is assistant professor of medicine and urology at New York University (NYU) Grossman School of Medicine in New York, medical oncologist and director of the Genitourinary Medical Oncology Program, and codirector of the Department of Medicine Clinical Investigator Track NYU Langone Health in New York.

In the phase 3 TRITON trial, patients were randomly assigned 2:1 between arms. The trial evaluated 4855 patients, with 270 patients receiving 600 mg of oral rucaparib twice a day, and 135 patients receiving physician’s choice of control, which was docetaxel (55% of patients) or second-generation androgen receptor pathway inhibitors abiraterone acetate (Zytiga) (21%) or enzalutamide (Xtandi) (24%). Within these 2 groups, approximately 201 patients in the rucaparib arm and 101 patients receiving physician’s choice of the control had a BRCA mutation.²

The median PFS was 11.2 months in the subgroup with BRCA mutations receiving rucaparib compared with the control group, which was 6.4 months (HR, 0.50; 95% CI, 0.36-0.69; P =.001). The subgroup with ataxia telangiectasia mutations showed less improvement, with a PFS of 8.1 months in the group receiving rucaparib and 6.8 months in the control group (HR, 0.95; 95% CI, 0.59 - 1.52).^1,2

Wise highlighted findings from another trial (NCT03732820) that showed benefit for patients with the BRCA2 mutation, evaluating first-line olaparib (Lynparza) plus abiraterone for patients with mCRPC. In this double-blind phase 3 trial, patients were randomly assigned 1:1, receiving either once-daily 1000 mg of abiraterone plus prednisone or prednisolone with twicedaily 300 mg of olaparib or placebo. Investigators reported a significantly longer PFS in the experimental arm vs the control arm of 24.8 vs 16.6 months (HR, 0.66; 95% CI, 0.54-0.81; P =.001).³

Further research with PARP inhibitors such as resistance and perioperative PARP inhibitors as well as combining the PARP inhibitor olaparib with lutetium-177 prostate-specific member antigen (PSMA) therapy is needed.

“I strongly advocate for the initiation of a phase 3 trial focusing on perioperative, PARP inhibitor treatment. I am enthusiastic about collaborating with colleagues on this initiative. There are also promising combination trials involving lutetium-177 PSMA, and in the realm of hormone sensitivity, we anticipate forthcoming data on PARP,” Wise concluded.

References

1. Wise D. New targets and new combinations in mCRPC management. Presented at: 41st Annual CFS Chemotherapy Foundation Symposium Innovative Cancer Therapy for Tomorrow; November 8-10, 2023; New York, NY.

2. Fizazi K, Piulats JM, Reaume MN, et al; TRITON3 Investigators. Rucaparib or physician’s choice in metastatic prostate cancer. N Engl J Med. 2023;388(8):719-732. doi:10.1056/nejmoa2214676

3. Clarke NW, Armstrong AJ, Thiery-Vuillemin A, et al; PROpel Investigators. Abiraterone and olaparib for metastatic castration-resistant prostate cancer. NEJM Evid. Published June 3, 2022. doi:10.1056/EVIDoa2200043