Niraparib Treatment Displays Promising Clinical Activity in mCRPC Regardless of BRCA Status

Matthew Smith, MD, PhD

In the GALAHAD (NCT02854436) study, researchers observed anti-tumor activity with the PARP inhibitor, niraparib (Zejula), in patients with metastatic castration-resistance prostate cancer (mCRPC) and DNA repair gene defects (DRDs) who progressed on previous treatment with an androgen signaling inhibitor and a taxane.1

The objective response rate (ORR) for patients with germline pathogenic or somatic biallelic pathogenic alterations in BRCA1 or BRCA2 (BRCA group) was 34.2% (95% CI 23.7%–46.0%), evaluable in 76 patients. The ORR for patients having biallelic alterations in other prespecified DRDs (non-BRCA group) was 10.6% (95% CI, 3.5%-23.1%) evaluable in 47 patients.2

This multicenter, open-label, single-arm, phase 2 study enrolled 289 patients between September 28, 2016, and June 26, 2020. Sixty-three percent (n=182) received 3 or more systemic therapies for prostate cancer prior to the enrollment. Seventy-seven percent (n=223) of the 289 patients were included in the overall efficacy analysis population with 142 in the BRCA group and 81 patients in the non-BRCA group.

Patients received oral niraparib 300 mg once daily until treatment discontinuation, death, or study termination. All patients who received 1 or more doses of the study drug were included in the safety analysis population. The primary end point was ORR, and the secondary end points were overall survival (OS), radiographic progression-free survival (rPFS), time to radiographic progression, time to prostate-specific antigen (PSA) progression, and safety.

Eligible patients must have been at least 18 years old with histologically confirmed mCRPC and DRDs with progression on a previous next-generation androgen signaling inhibitor, a taxane per Response Evaluation Criteria in Solid Tumors 1.1 or Prostate Cancer Working Group 3 criteria, and an ECOG performance status of 0 to 2.

The median follow-up at final analysis was 10.0 months (range, 6.6–13.3). Secondary end points measured the following in 142 patients in the BRCA cohort and in 81 patients in the non-BRCA cohort. The BRCA cohort’s OS was 13.01 months (95% CI, 11.04-14.29) compared to 9.63 months (95% CI, 8.05-13.44) in the non-BRCA cohort. The rPFS favored the BRCA cohort with 8.08 months (95% CI, 5.55-8.38) versus 3.71 months (95% CI, 1.97-5.49) in the non-BRCA cohort. Time to radiographic progression was 8.08 months (95% CI, 5.75-8.97) in the BRCA cohort and 3.78 months (95% CI, 2.00-5.55) in the non-BRCA cohort. The BRCA cohort’s time to PSA progression was 5.13 months (95% CI, 4.60-5.59) versus 3.65 months (95% CI, 2.83-3.71) in the non-BRCA cohort.

The safety analysis revealed the most common any-grade treatment-emergent adverse events (TRAEs) to be nausea (58%), anemia (54%), and vomiting (38%). The most common grade 3 or higher TRAEs were anemia (33%), thrombocytopenia (16%), and neutropenia (10%). Forty-six percent (n=134) of the 289 patients experienced at least 1 serious TRAE. The most common serious TRAEs were thrombocytopenia in 17 patients (6%) and anemia in 13 patients (4%). Two AEs led to death—1 in each cohort. Investigators deemed both deaths to be possibly related to niraparib treatment with the BRCA cohort death caused by urosepsis and the non-BRCA cohort death caused by sepsis.

Researchers agreed that niraparib is safe and showed antitumor activity in heavily pretreated patients with mCRPC and DRDs, favoring patients who have BRCA mutations. Moreover, the findings from GALAHAD highlight the importance of molecular testing to inform treatment and disease management decision for prostate cancer.

_References

_{1. Smith MR, Scher HI, Sandhu S, et al. Niraparib in patients with metastatic castration-resistant prostate cancer and DNA repair gene defects (GALAHAD): a multicentre, open-label, phase 2 trial. Lancet Oncol. 2022;23(3):362-373. doi:10.1016/S1470-2045(21)00757-9}

_{2. An efficacy and safety study of niraparib in men with metastatic castration-resistant prostate cancer and dna-repair anomalies (Galahad). ClinicalTrials.gov. Updated March 8, 2022. Accessed March 8, 2022. https://bit.ly/34zgwm0}