Adding niraparib to AAP extends rPFS in HRR-positive mCSPC

Data from the phase 3 AMPLITUDE trial (NCT04497844) showed that adding niraparib (Zejula) to abiraterone acetate (Zytiga) plus prednisone (AAP) led to a statistically significant improvement in radiographic progression-free survival (rPFS) vs placebo plus AAP in patients with metastatic castration sensitive prostate cancer (mCSPC) and homologous recombinant repair (HRR) gene mutations.¹

The data, which were presented at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, Illinois, suggest that the greatest rPFS benefit with the niraparib regimen is in those with BRCA alterations.

Overall, the addition of niraparib to AAP was shown to reduce the risk of radiographic progression or death by 37% among patients in the intent-to-treat population (HRR mutations) and by 48% in patients with BRCA mutations (BRCAm).

Among those with HRR mutations (ITT), the median rPFS was not met in the niraparib plus AAP arm, compared with 29.5 months in the placebo plus AAP arm (HR, 0.63; 95% CI, 0.49 to 0.80; P = .0001). In those with BRCA mutations, the median rPFS was not reached in the niraparib plus APP arm vs 26 months in the placebo plus APP arm (HR, 0.52; 95% CI, 0.37 to 0.72; P < .0001).

Gerhardt Attard, MD, FRCP, PhD

Gerhardt Attard, MD, FRCP, PhD, who presented results at ASCO, noted during the presentation, “AMPLITUDE met its primary end point of radiographic progression free survival. This makes it the first trial to show efficacy for the combination of inhibition of PARP and the androgen receptor pathway in metastatic castration-sensitive prostate cancer with alterations in genes involved in homologous recombination repair, with greatest benefit apparent in patients with BRCA.”

In total, the AMPLITUDE trial enrolled 696 patients who were randomly assigned to receive 200 mg niraparib plus 1000 mg abiraterone acetate plus 5 mg prednisone once daily (n = 348) or to matched placebo plus 1000 mg abiraterone acetate plus 5 mg prednisone once daily. Patients in both arms were allowed to receive androgen deprivation therapy for up to 6 months.

Participants were eligible for enrollment in the study if they had an alteration in at least 1 HRR eligible gene, which included: BRCA1, BRCA2, BRIP1, CDK12, CHEK2, FANCA, PALB2, RAD51B, and RAD54L. Patients also needed to have an ECOG performance score between 0 and 2.

The trial’s primary end point is rPFS. Key secondary end points include time to symptomatic progression, overall survival (OS), and safety.

Additional data from the trial showed that the benefit of niraparib to APP was generally consistent across all pre-specified subgroups.

Attard noted, “There are a couple of subgroups that have small numbers of events, notably patients presenting with metachronous disease and the subgroups split by geographical region.”

The addition of niraparib also reduced the risk of symptomatic progression by 50% in the ITT population (HR, 0.50; 95% CI, 0.36 to 0.69; P < .0001) and 56% in the BRCAm cohort (HR, 0.44; 95% CI, 0.29 to 0.68; P = .0001). At the time of data report, the median time to symptomatic progression was not reached in either arm in either the ITT population or in the BRCAm population.

Attard also reported, “At this first interim analysis for overall survival, we have about 50% of the number of deaths that will be required for final analysis, but estimates favor the addition of niraparib [to] AAP.”

Overall, the addition of niraparib to AAP was shown to reduce the risk of death by 21% in the HRRm population (HR, 0.79; 95% CI, 0.59 to 1.04; P = .10) and 25% in the BRCAm population (HR, 0.75; 95% CI, 0.51 to 1.11; P = .15).

“In addition to BRCA1 and BRCA2, there were 7 other HRR genes that allowed patients to be eligible for the trial,” Attard added. “Gene subgroups are small and were not pre-powered for formal analysis, but you'll appreciate probable heterogeneous effect across these single gene groups. I would expect that in the future, combinations with other trials, possibly using meta-analysis approaches, will give us greater certainty for the sensitivity of individual gene groups to PARP inhibition in this disease setting.”

The majority of patients who discontinued treatment due to progression went on to receive a subsequent therapy. There were comparable rates of subsequent therapy between the 2 arms with the exception of subsequent PARP inhibition, reported in 11% of patients in the niraparib arm vs 36% of patients in the placebo arm.

Regarding safety, grade 3 to 4 treatment-emergent adverse events (AEs) were reported in 75% of patients in the niraparib arm vs 59% in the placebo arm. The investigators also noted a less than 5% increase in the rate of discontinuation due to toxicity with niraparib vs placebo (15% vs 10%, respectively).

The most common grade 3 or higher AE was anemia, reported in 29% of patients in the niraparib arm vs 5% of patients in the placebo arm. Grade 3 or higher hypertension was also reported in 27% of patients in the niraparib arm vs 18% of patients in the placebo arm.

Other common AEs of any grade included constipation (35% vs 16%), nausea (31% vs 14%), fatigue (26% vs 18%), and arthralgia (21% vs 21%) in the niraparib vs placebo arms, respectively.

Based on these data, the authors concluded, “AMPLITUDE supports early genomic testing and niraparib plus AAP as a new treatment option for patients with mCSPC and HRR gene alterations.”

REFERENCE

1. Attard G, Agarwal N, Graff J, et al. Phase 3 AMPLITUDE trial: Niraparib (NIRA) and abiraterone acetate plus prednisone (AAP) for metastatic castration-sensitive prostate cancer (mCSPC) patients (pts) with alterations in homologous recombination repair (HRR) genes. J Clin Oncol. 2025;43 (suppl 17; abstr LBA5006). Doi: 10.1200/JCO.2025.43.17_suppl.LBA5006