Niraparib Plus Abiraterone in HRR-Deficient mCSPC

Key Takeaways

• Longer radiographic progression-free survival was observed with niraparib plus abiraterone across the prespecified BRCA, HRR effector, and intention-to-treat populations.
• Overall survival remained immature and numerically favored niraparib, while several secondary endpoints also trended in the same direction.
• Higher toxicity accompanied the niraparib regimen, with more grade 3 or 4 events, more dose modifications, and a notable anemia and transfusion burden.

The effect was strongest in patients with BRCA alterations, with findings also favoring niraparib across the intention-to-treat population. AMPLITUDE evaluated the combination in a biomarker-selected first-line setting defined by deleterious HRR alterations. Radiographic progression-free survival improved, while toxicity was higher with the niraparib combination.

In the phase 3 AMPLITUDE trial, 696 patients were randomly assigned 1:1 to niraparib 200 mg plus abiraterone acetate 1000 mg plus prednisone 5 mg daily or placebo plus abiraterone plus prednisone. Eligible men were aged 18 years or older, had an ECOG performance status of 0 to 2, and had a deleterious HRR alteration detected centrally in tumor tissue, plasma, or germline DNA. Sponsor-approved local tests and PREVALENCE study results were also accepted, and eligible genes were BRCA1, BRCA2, BRIP1, PALB2, RAD51B, RAD54L, CDK12, CHEK2, and FANCA. Median age was 68 years, 56% had BRCA1 or BRCA2 alterations, 78% had high-volume metastases, and 16% had received prior docetaxel. The prespecified testing sequence moved from the BRCA subgroup to the HRR effector subgroup and then to the intention-to-treat population, and the primary endpoint was investigator-assessed radiographic progression-free survival.

At a median follow-up of 30.8 months, radiographic progression-free survival was longer in the BRCA subgroup, with a hazard ratio of 0.52, a 95% confidence interval of 0.37 to 0.72, and P<0.0001. Median radiographic progression-free survival was not reached with niraparib in BRCA versus 26.0 months with control. The HRR effector subgroup also favored niraparib, with a hazard ratio of 0.57, a 95% confidence interval of 0.42 to 0.77, and P=0.0003. In the intention-to-treat population, the hazard ratio was 0.63, with a 95% confidence interval of 0.49 to 0.80 and P=0.0001, and median radiographic progression-free survival was not reached with niraparib. Median radiographic progression-free survival was also not reached with niraparib in the HRR effector analysis. The primary endpoint was met across the prespecified testing sequence.

The first interim overall survival analysis occurred after 193 deaths and remained immature. Point estimates favored niraparib but were not statistically significant, with a hazard ratio of 0.75 in BRCA and 0.79 in the intention-to-treat population. Time to symptomatic progression favored the combination in the BRCA subgroup and the intention-to-treat population. Second progression-free survival, time to PSA progression, and duration of response also favored niraparib plus abiraterone in exploratory analyses. Patient-reported quality of life initially declined with niraparib plus abiraterone before later converging with the control group. The survival analysis remained immature.

Safety was less favorable with niraparib. Grade 3 or 4 adverse events occurred in 75.2% versus 58.9%, and serious adverse events occurred in 39.2% versus 27.6%. Discontinuations due to adverse events were 14.7% versus 10.3%, dose reductions were 21.9% versus 6.9%, and dose interruptions were 66.9% versus 42.4%. Treatment-emergent adverse events leading to death occurred in 14 versus 7 patients. The most common grade 3 or 4 events with niraparib were anemia at 29.1% versus 4.6% and hypertension at 26.5% versus 18.4%, with 25.1% versus 3.7% requiring transfusion for anemia. One case of myelodysplastic syndrome was reported in the niraparib group.

The authors concluded that the regimen significantly improved radiographic progression-free survival in HRR-altered mCSPC, with adverse events described as medically manageable with dose modification and supportive care.