Niraparib plus abiraterone acetate with prednisone in patients with metastatic castration-resistant prostate cancer and homologous recombination repair gene alterations: second interim analysis of the randomized phase III MAGNITUDE trial

Background Patients with metastatic castration-resistant prostate cancer (mCRPC) and BRCA alterations have poor outcomes. MAGNITUDE found patients with homologous recombination repair gene alterations (HRR+), particularly BRCA1/2, benefit from first-line therapy with niraparib plus abiraterone acetate and prednisone (AAP). Here we report longer follow-up from the second prespecified interim analysis (IA2). Patients and methods Patients with mCRPC were prospectively identified as HRR+ with/without BRCA1/2 alterations and randomized 1:1 to niraparib (200 mg orally) plus AAP (1000 mg/10 mg orally) or placebo plus AAP. At IA2, secondary endpoints (time to symptomatic progression, time to initiation of cytotoxic chemotherapy, overall survival [OS]) were assessed. Results Overall, 212 HRR+ patients received niraparib plus AAP (BRCA1/2 subgroup, n=113). At IA2 with 24.8 months of median follow-up in the BRCA1/2 subgroup, niraparib plus AAP significantly prolonged radiographic progression-free survival (rPFS; blinded independent central review; median rPFS, 19.5 versus 10.9 months; hazard ratio [HR]=0.55 [95% confidence interval (CI) 0.39-0.78]; nominal P=0.0007) consistent with the first prespecified interim analysis. rPFS was also prolonged in the total HRR+ population (HR=0.76 [95% CI 0.60-0.97]; nominal P=0.0280; median follow-up, 26.8 months). Improvements in time to symptomatic progression and time to initiation of cytotoxic chemotherapy were observed with niraparib plus AAP. In the BRCA1/2 subgroup, the analysis of OS with niraparib plus AAP demonstrated an HR=0.88 (95% CI 0.58-1.34; nominal P = 0.5505); the prespecified inverse probability censoring weighting analysis of OS, accounting for imbalances in subsequent use of poly adenosine diphosphate-ribose polymerase inhibitors and other life-prolonging therapies demonstrated an HR=0.54 (95% CI 0.33-0.90; nominal P=0.0181). No new safety signals were observed. Conclusions MAGNITUDE, enrolling the largest BRCA1/2 cohort in first-line mCRPC to date, demonstrated improved rPFS and other clinically relevant outcomes with niraparib plus AAP in patients with BRCA1/2-altered mCRPC, emphasizing the importance of identifying this molecular subset of patients.