Niraparib Combo Boosts rPFS in Metastatic HRR-Altered CSPC

"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," according to study author Gerhardt Attard MD, PhD, FRCP.

Combining niraparib (Zejula) with abiraterone acetate (Zytiga) and prednisone (AAP) significantly prolonged radiographic progression-free survival (rPFS) vs placebo plus AAP among patients with metastatic castration-sensitive prostate cancer (CSPC) harboring BRCA1/2 mutations or other homologous recombination repair (HRR) alterations, according to findings from the phase 3 AMPLITUDE trial (NCT04497844) published in Nature Medicine.1

Among patients in the BRCA subgroup (n = 387), the median rPFS was not evaluable (NE; 95% CI, 41.2-NE) in the niraparib arm vs 26.0 months (95% CI, 22.1-41.2) in the placebo arm (HR, 0.52; 95% CI, 0.37-0.72; P <.0001). Furthermore, across the HRR effector subgroup (n = 456), the median rPFS was NE (95% CI, 41.2-NE) and 27.6 months (95% CI, 25.6-NE) in each respective arm (HR, 0.57; 95% CI, 0.42-0.77; P = .0003). In the intention-to-treat (ITT) population (n = 696), data showed a median rPFS of NE (95% CI, 41.2-NE) vs 29.5 months (95% CI, 25.8-NE) in each arm (HR, 0.63; 95% CI, 0.49-0.80; P = .0001).

Time to symptomatic progression appeared to improve with the addition of niraparib to AAP in the BRCA subgroup (HR, 0.44; 95% CI, 0.29-0.68; P = .0001) and the ITT population (HR, 0.50; 95% CI, 0.36-0.69; P <.0001). At the time of the first interim analysis for overall survival (OS), data showed that the niraparib combination numerically reduced the risk of death in the BRCA subgroup (HR, 0.75; 95% CI, 0.51-1.11; P = .15) and the ITT population (HR, 0.79; 95% CI, 0.59-1.04; P = .10). Investigators also noted an improvement in time to subsequent therapy with the niraparib regimen in the ITT population (HR, 0.54; 95% CI, 0.41-0.70; P <.0001) as well as the BRCA subgroup (HR, 0.47; 95% CI, 0.33-0.66; P <.0001) and the HRR effector subgroup (HR, 0.50; 95% CI, 0.36-0.69; P <.0001).

“Although current standard treatments are [quite] effective for the majority of patients with advanced prostate cancer, a small but significant proportion of patients have limited benefit. 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,” lead study author Gerhardt Attard MD, PhD, FRCP, John Black Charitable Foundation Professor of Oncology at University College London Cancer Institute, stated in a press release on these findings.2 “By combining with niraparib we can delay the cancer returning and hopefully significantly prolong life expectancy….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.”

In the double-blind phase 3 AMPLITUDE trial, patients were randomly assigned 1:1 to receive niraparib at 200 mg or matched placebo in combination with abiraterone acetate at 1000 mg and prednisone at 5 mg orally once daily. Investigators stratified patients based on HRR gene status, prior docetaxel use, and metastasis volume.

The trial’s primary end point was rPFS per investigator evaluation. Secondary end points included time to symptomatic progression, OS, time to subsequent therapy, and safety.

Patients 18 years and older with an ECOG performance status of 0 to 2 and at least 1 deleterious HRR alteration following central testing of tumor tissue were eligible for enrollment on the trial. Eligible HRR genes included BRCA1, BRCA2, BRIP1, PALB2, and RAD51B.

With a total of 696 patients,191, 230, and 348 received niraparib plus AAP in the BRCA subgroup, HRR effector subgroup, and ITT population, respectively. In each respective population, 196, 226, and 348 received placebo plus AAP.

Across the ITT population, the median age was 68 years (range, 40-88) in the niraparib arm and 67 years (range, 40-92) in the placebo arm. Most patients in each respective arm were White (70.7% vs 73.9%) and from Europe (48.3% vs 50.9%). Additionally, most patients had an ECOG performance status of 0 (69.5% vs 62.6%), a Gleason score of more than 7 at diagnosis (79.3% vs 75.3%), and metastatic disease (86.5% vs 86.8%).

The median second PFS was not reached in the niraparib arm and 44.0 months in the placebo arm (HR, 0.66; 95% CI, 0.51-0.86; P = .002). In each respective arm, the objective response rate was 72% vs 74%; the duration of response was longer in the niraparib arm (HR, 0.55; 95% CI, 0.35-0.86; P = .008). Time to prostate-specific antigen (PSA) progression also improved with the addition of niraparib to AAP (HR, 0.50; 95% CI, 0.39-0.65; P <.0001).

Adverse effects (AEs) of any grade occurred in 99.7% of the niraparib arm and 98.0% of the placebo arm, with 75.2% and 58.9% from each arm experiencing grade 3/4 toxicities. Serious AEs affected 39.2% and 27.6% of patients, respectively, and 14.7% vs 10.3% had AEs leading to treatment discontinuation. Moreover, 4.0% and 2.0% from each arm died due to AEs.

In the niraparib and placebo arms, respectively, the most common toxicities of any grade included anemia (51.6% vs 23.9%), hypertension (43.8% vs 32.5%), constipation (35.2% vs 16.4%), nausea (30.8% vs 14.4%), and fatigue (26.2% vs 18.4%). Grade 3 or higher AEs included anemia (29.1% vs 4.6%), hypertension (26.5% vs 18.4%), and hypokalemia (11.5% vs 10.9%).

“For cancers with a mutation in 1 of the eligible HRR genes, where niraparib has been approved, a doctor should consider a discussion that balances the risks of [AEs] against the clear benefit to delaying disease growth and worsening symptoms,” Attard stated in the press release.2

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. UCL News. October 7, 2025. Accessed October 8, 2025. https://tinyurl.com/5bprx94a