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.

LBA5006 Background: NIRA is a highly selective and potent inhibitor of poly (ADP-ribose) polymerase (PARP)-1/2. In the MAGNITUDE trial, NIRA + AAP significantly improved radiographic progression-free survival (rPFS) in HRR gene–altered metastatic castration-resistant prostate cancer. The double-blind, placebo (PBO)-controlled AMPLITUDE trial (NCT04497844) evaluated the efficacy and safety of NIRA + AAP in HRR gene–altered mCSPC. Methods: Pts with germline or somatic HRR gene alterations ( BRCA1 , BRCA2 , BRIP1 , CDK12 , CHEK2 , FANCA , PALB2 , RAD51B , RAD54L ) were randomized 1:1 to a dual-action tablet (NIRA 200 mg + abiraterone acetate 1000 mg) plus prednisone 5 mg, or PBO + AAP (hereafter AAP). Eligible pts had received ≤6 mo of androgen deprivation therapy (ADT) ± ≤6 cycles of docetaxel (DOC) ± ≤45 d of AAP with metastatic disease extended beyond lymph nodes. The primary end point is investigator-assessed rPFS (time from randomization to radiographic progression or death). Secondary end points include time to symptomatic progression (TSP), overall survival (OS), and safety. The Kaplan-Meier product limit method and a stratified Cox model were used for time-to-event variables and the hazard ratio (HR) and stratified log-rank test for estimating treatment effect. This is the first and final analysis for rPFS and the first interim analysis (of 3) for OS (data cutoff, 7 Jan 2025). Approximately 261 rPFS events were required (2-sided α, 0.025; power, 91%) for an HR ≤0.64 to demonstrate efficacy. Results: 696 pts were randomized to NIRA + AAP (n=348) or AAP (n=348). Median age was 68 y (IQR, 61-74); 55.6% had BRCA1/2 alterations, 78% were high-volume metastatic (M1), 87% were de novo M1, and 16% had prior DOC. Median follow-up is 30.8 mo. The primary end point was met, with rPFS significantly longer with NIRA + AAP (median, not reached [NR]) vs AAP (29.5 mo [95% CI, 25.8-NR]; HR, 0.63 [95% CI, 0.49-0.80], p=0.0001), including in the prespecified BRCA1/2 subgroup (HR, 0.52 [95% CI, 0.37-0.72], p<0.0001). TSP was significantly improved with NIRA + AAP vs AAP (HR, 0.50 [95% CI, 0.36-0.69], p<0.0001; BRCA1/2 : HR, 0.44 [95% CI, 0.29-0.68], p=0.0001). A trend in OS was seen at this first interim analysis (193/389 events) favoring NIRA + AAP (HR, 0.79 [95% CI, 0.59-1.04], p=0.10; BRCA1/2 : HR, 0.75 [95% CI, 0.51-1.11], p=0.15). Grade 3/4 adverse events (AEs) occurred in 75.2% with NIRA + AAP and 58.9% with AAP, most commonly anemia (29.1% vs 4.6%) and hypertension (26.5% vs 18.4%). Treatment discontinuations due to AEs were low: NIRA + AAP: 11.0%; AAP: 6.9%. Conclusions: NIRA + AAP significantly improved rPFS and TSP vs AAP in pts receiving ADT +/- prior DOC and had a favorable effect on OS. There were no new safety signals. AMPLITUDE supports NIRA + AAP as a potential new standard of care for pts with HRR gene–altered mCSPC. Clinical trial information: NCT04497844 .