| Abstract: |
<p>Background and objective: The phase 3 MAGNITUDE trial previously met its primary endpoint of an improvement in radiographic progression-free survival with niraparib + abiraterone acetate and prednisone (AAP) versus placebo + AAP in patients with metastatic castration-resistant prostate cancer (mCRPC) and alterations in genes involved in DNA homologous recombination repair (HRR+), particularly in BRCA1/2. Methods: Patients were prospectively screened for HRR alterations and randomized 1:1 to niraparib + AAP (n = 212) or placebo + AAP (n = 211). We report results from the prespecified, event-driven, final analysis of secondary efficacy endpoints. Key findings and limitations: Final analysis at median follow-up of 37.3 mo revealed no difference in overall survival (OS) between niraparib + AAP and placebo + AAP in the HRR+ population (hazard ratio [HR] 0.931, 95% confidence interval [CI] 0.720-1.203; p = 0.585) or the subgroup with BRCA1/2 alterations (HR 0.788, 95% CI 0.554-1.120; nominal p = 0.183). Prespecified multivariate analyses adjusted for baseline prognostic factors showed a trend toward longer OS with niraparib + AAP over placebo + AAP in the HRR+ population (HR 0.785, 95% CI 0.606-1.016; nominal p = 0.066) and the BRCA1/2 subgroup (HR 0.663, 95% CI 0.464-0.947; nominal p = 0.024). Niraparib + AAP led to a statistically significant, clinically meaningful improvement in time to symptomatic progression in both the HRR+ population (HR 0.547, 95% CI 0.396-0.754; p = 0.006) and the BRCA1/2 subgroup (HR 0.562, 95% CI 0.371-0.849; nominal p = 0.006), and a clinically meaningful improvement in time to cytotoxic chemotherapy in the HRR+ population (HR 0.688, 95% CI 0.499-0.950; p = 0.022) and the BRCA1/2 subgroup (HR 0.598, 95% CI 0.387-0.924; nominal p = 0.019) in comparison to placebo + AAP. The niraparib + AAP safety profile remains unchanged at longer follow-up; adverse events were primarily hematologic and manageable. Conclusions and clinical implications: The MAGNITUDE final analysis showed that patients with HRR+ mCRPC, including those with the approved indication of BRCA-altered mCRPC, generally continue to benefit from first-line treatment with niraparib + AAP in comparison to placebo + AAP. (c) 2025 The Authors. Published by Elsevier B.V. on behalf of European Association of Urology. This is an open access article under the CC BY license (http://creativecommons. org/licenses/by/4.0/).</p> |
