AMPLITUDE: Niraparib plus AAP improves survival in mCSPC patients with gene mutations

The combination of niraparib (NIRA) and abiraterone acetate plus prednisone (AAP) results in significant improvements in radiographic progression-free survival (rPFS) and time to symptomatic progression (TSP) in metastatic castration-sensitive prostate cancer (mCSPC) patients with alterations in homologous recombination repair (HRR) genes, as shown by the results of the phase III AMPLITUDE trial.

In addition, the safety profile of NIRA plus AAP is consistent with that seen in the MAGNITUDE trial, with a less than 5-percent increase in treatment discontinuation due to toxicity relative to placebo. [J Clin Oncol 2023;41:3339-3351]

“The AMPLITUDE trial met its primary endpoint of rPFS, with likely greatest benefit in patients with BRCA alterations,” said lead author Dr Gerhardt Attard from Cancer Institute, University College London, London, UK. “Improvements in rPFS are supported by a statistically significant benefit in time to symptomatic progression and a trend toward improved overall survival (OS).” [ASCO 2025, abstract LBA5006]

A total of 696 patients (median age 68 years) were randomly allocated to NIRA plus APP (n=348) or AAP alone (n=348). Of these, 55.6 percent had BRCA1/2 alterations, 78 percent were high-volume metastatic (M1), 87 percent were de novo M1, and 16 percent had prior docetaxel therapy.

Over a median follow-up of 30.8 months, Attard and his team observed significantly longer rPFS in the NIRA plus AAP arm than the AAP along arm (median, not reached [NR] vs 29.5 months, 95 percent confidence interval [CI], 25.8–NR; hazard ratio [HR], 0.63, 95 percent CI, 0.49–0.80; p=0.0001), as well as in the prespecified BRCA1/2 subgroup (HR, 0.52, 95 percent CI, 0.37–0.72; p<0.0001).

TSP also improved significantly in the NIRA plus AAP group (HR, 0.50, 95 percent CI, 0.36–0.69; p<0.0001; BRCA1/2: HR, 0.44, 95 percent CI, 0.29–0.68; p=0.0001).

At the first interim analysis, a trend in OS favoured patients treated with NIRA plus AAP (HR, 0.79, 95 percent CI, 0.59–1.04; p=0.10; BRCA1/2: HR, 0.75, 95 percent CI, 0.51–1.11; p=0.15).

Safety profile

The proportion of patients experiencing grade 3/4 adverse events (AEs) was higher in the NIRA plus AAP arm (75.2 percent vs 58.9 percent). The most common AEs were anaemia (29.1 percent vs 4.6 percent) and hypertension (26.5 percent vs 18.4 percent).

Although AEs were frequent, treatment discontinuation remained low in both arms (NIRA plus AAP: 11.0 percent; AAP alone: 6.9 percent).

“There were no new safety signals,” Attard said. “AMPLITUDE supports NIRA plus AAP as a potential new standard of care for patients with HRR gene–altered mCSPC.”

In AMPLITUDE, patients were eligible if they had received ≤6 months of androgen deprivation therapy ± ≤6 cycles of docetaxel ± ≤45 days of AAP with metastatic disease extended beyond lymph nodes. Attard and colleagues used the Kaplan-Meier product limit method and a stratified Cox model for time-to-event variables and HR. They estimated the treatment effect using a stratified log-rank test.

Approximately 261 rPFS events were required for an HR ≤0.64 to demonstrate efficacy.

“The AMPLITUDE study evaluated how well a combination of three medicines (niraparib, abiraterone, and prednisone) worked in a specific type of prostate cancer that has spread beyond the prostate, needs testosterone to grow, and has genetic changes that prevent cancer cells from fixing damaged DNA,” according to Attard.

Specifically, niraparib prevents cancer cells from fixing mistakes in the DNA, causing the death of cancer cells, while abiraterone reduces male hormones and slows down tumour growth. Prednisone also prevents tumour growth while reducing the side effects of abiraterone.