Published data show benefit of niraparib with AAP in HRR-deficient mCSPC

Data from the phase 3 AMPLITUDE trial (NCT04497844) have been published in Nature Medicine, showing that adding niraparib (Zejula) to abiraterone acetate (Zytiga) and prednisone (AAP) significantly improved radiographic progression-free survival (rPFS) vs placebo and AAP in patients with metastatic castration-sensitive prostate cancer (mCSPC) harboring homologous recombination repair (HRR) gene alterations.¹

The data also suggest that the greatest rPFS benefit with the niraparib regimen is in those with BRCA alterations.

"Although current standard treatments are very effective for the majority of patients with advanced prostate cancer, a small but very significant proportion of patients have limited benefit,” explained lead author Gerhardt Attard, MD, PhD, FRCPProf, in a news release on the results.² “We now know that prostate cancers with alterations in HRR genes account for a significant group of patients whose disease recurs quickly and has an aggressive course. By combining with niraparib, we can delay the cancer returning and hopefully significantly prolong life expectancy.”

In total, the AMPLITUDE study enrolled 696 men across 32 countries. The median age of patients was 68 years. Overall, 56% of patients had BRCA1 or BRCA2 mutations, 78% had high-volume metastases, and 16% had received docetaxel. Patients in the study were randomly assigned 1:1 to receive abiraterone plus AAP (n = 348) or placebo plus AAP (n = 348). Baseline demographics and disease characteristics were well balanced between both arms. The primary end point was rPFS.

At a median follow-up of 30.8 months, data showed that the addition of niraparib led to a 37% reduction in the risk of radiographic progression compared with AAP alone in the intention-to-treat (ITT) population (HR, 0.63; 95% CI, 0.49 to 0.80; P = .0001). The median rPFS was not met in the niraparib plus AAP group vs 29.5 months in the placebo plus AAP group.

In the subgroup of patients with BRCA1 or BRCA2 mutations, the addition of abiraterone led to a 48% reduction in the risk of radiographic progression (HR, 0.52; 95% CI, 0.37 to 0.72; P < .0001). The median rPFS was not reached in the abiraterone plus AAP group and was 26 months in the AAP alone arm.

In an analysis of rPFS in patients without a detectable BRCA1 or BRCA2 alteration (and thus an alteration in either BRIP1, PALB2, RAD51B, RAD54L, CDK12, CHEK2, or FANCA), the HR was 0.81 (95% CI, 0.56 to 1.18).

The treatment effect of niraparib plus AAP was consistent across the majority of prespecified subgroups. However, the authors noted that “the small number of events within certain subgroups precludes definitive interpretation.”

The data for overall survival (OS), the trial’s key second end point, were immature at the time of data report. However, the authors noted a trend toward improved OS with the addition of niraparib in both the ITT population (HR, 0.79; 95% CI, 0.59 to 1.04; P = .10) and in the BRCA subgroup (HR, 0.75; 95% CI, 0.51 to 1.11; P = .15).

Data also showed significant improvements in time to symptomatic progression in both the ITT population (HR, 0.50; 95% CI, 0.36 to 0.69; P < .0001) and in the BRCA subgroup (HR, 0.44; 95% CI, 0.29 to 0.68; P = .0001). Time to subsequent therapy was also improved with the addition of niraparib in the ITT population (HR, 0.54; 95% CI, 0.41 to 0.70; nominal P < .0001).

Grade 3 or 4 adverse events (AEs) occurred in 75.2% of patients in the niraparib plus AAP arm vs 58.9% of patients in the placebo plus AAP arm. The most frequent grade 3 or 4 AEs were anemia (29.1% vs 4.6%) and hypertension (26.5% vs 18.4%).

Serious AEs were reported in 39.2% of patients in the treatment arm vs 27.6% of patients in the comparator arm. Treatment-emergent AEs leading to death occurred in 14 patients in the niraparib plus AAP group vs 7 patients in the placebo plus AAP group.

“These findings are striking because they support widespread genomic testing at diagnosis with use of a targeted treatment for patients who stand to derive the greatest benefit,” Attard concluded in the news release.² “For cancers with a mutation in one of the eligible HRR genes, where niraparib has been approved, a doctor should consider a discussion that balances the risks of [adverse] effects against the clear benefit to delaying disease growth and worsening symptoms.”

REFERENCES

1. Attard G, Agarwal N, Graff JN, et al. Niraparib and abiraterone acetate plus prednisone for HRR-deficient metastatic castration-sensitive prostate cancer: a randomized phase 3 trial. Nat Med. Published online October 7, 2025. doi:10.1038/s41591-025-03961-8

2. New drug combination offers hope for men with advanced prostate cancer. News release. University College London. October 7, 2025. Accessed October 7, 2025. https://www.eurekalert.org/news-releases/1100746