Use of the PARP inhibitor niraparib in combination with the androgen biosynthesis inhibitor abiraterone acetate and the corticosteroid prednisone reduced the risk of disease progression, both radiographic and symptomatic, in patients with metastatic castration-sensitive prostate cancer harboring alterations in homologous recombination repair (HRR) genes, according to findings from the phase III AMPLITUDE trial. Particular benefit was observed among patients who had a BRCA1 or BRCA2 alteration, said lead study author Gerhardt Attard, MD, PhD, FRCP, the John Black Charitable Foundation Endowed Chair in Urological Cancer Research, Cancer Institute, University College London, United Kingdom, in a press briefing during the 2025 ASCO Annual Meeting.¹

“This is the first study to show efficacy for PARP inhibition and androgen receptor pathway inhibition in metastatic castration-sensitive prostate cancer,” Dr. Attard said. “In my opinion, this trial supports niraparib and abiraterone plus prednisone as a treatment option for patients [in] this poor-prognostic disease group.”

Bradley A. McGregor, MD, Director of Clinical Research for the Lank Center of Genitourinary Oncology at Dana-Farber Cancer Institute in Boston, and an ASCO expert in genitourinary cancers, shared these comments during the press briefing: “It really highlights that you don’t know if you don’t test. It’s going to be incredibly important that patients [who] are diagnosed with castration-sensitive prostate cancer undergo somatic and germline testing to see if [they] have these mutations, so they can be offered the right therapy at the right time.”

Background and Study Methods

Dr. Attard noted that patients with metastatic prostate cancer can have alterations in HRR genes, including BRCA1/2. He also pointed out that when PARP inhibitors are used as later-line monotherapy for these patients, resistance typically develops in less than 12 months.²

PARP inhibition in combination with abiraterone acetate and prednisone has already shown a benefit for patients who have metastatic castration-resistant prostate cancer with HRR alterations in the phase III MAGNITUDE trial.³ This study led to approval by the U.S. Food and Drug Administration of niraparib and abiraterone acetate plus prednisone for patients with deleterious or suspected deleterious BRCA-mutated metastatic castration-resistant prostate cancer. Based on the MAGNITUDE trial, the chosen HRR genes for inclusion were BRCA1, BRCA2, BRIP1, CDK12, CHEK2, FANCA, PALB2, RAD51B, and RAD54L.

This is the first study to show efficacy for PARP inhibition and androgen receptor pathway inhibition in metastatic castration-sensitive prostate cancer.

— GERHARDT ATTARD, MD, PhD, FRCP

Tweet this quote

In the AMPLITUDE trial, a total of 696 patients were randomly assigned in a 1:1 ratio to receive either niraparib with abiraterone acetate and prednisone or abiraterone acetate and prednisone with placebo.

Key Findings

Among patients with BRCA1/2 mutations specifically, the median radiographic progression–free survival was not reached in the arm given niraparib, abiraterone acetate, and prednisone vs 26.0 months in the placebo arm (hazard ratio [HR] = 0.52; 95% confidence interval [CI] = 0.37–0.72; P < .0001). For patients with all HRR mutations, the radiographic progression–free survival was also not reached in the arm given niraparib, abiraterone acetate, and prednisone compared with 29.5 months in the placebo arm (HR = 0.63; 95% CI = 0.49–0.80; P = .0001).

“This is a really exciting result: The AMPLITUDE trial met its primary endpoint, both in all patients with HRR mutations and in patients with a BRCA1 or BRCA2 mutation, with a significant reduction in the risk of radiographic disease progression or death by 48% in the BRCA-mutated group and 37% in the HRR-mutated group,” Dr. Attard said.

Bradley A. McGregor, MD

In patients with BRCA1/2 mutations, the risk of worsening symptoms—which included the need for radiation, a procedure or intervention, or further cancer treatment—was reduced by 56% with the addition of niraparib (HR = 0.44; 95% CI = 0.29–0.68; P = .0001). For all patients, the risk of worsening symptoms was reduced by 50% with the addition of niraparib to abiraterone acetate and prednisone (HR = 0.50; 95% CI = 0.36–0.69; P < .0001).

A first interim analysis for overall survival demonstrated a reduction in the risk of death of 25% with the addition of niraparib to abiraterone acetate and prednisone for patients with BRCA1/2 mutations (HR = 0.75; 95% CI = 0.51–1.11; P = .15) and by 21% in the HRR-mutated group (HR = 0.79; 95% CI = 0.59–1.04; P = .10). Overall survival data are still immature, but Dr. Attard suggested these early data show a trend favoring the combination therapy of niraparib, abiraterone acetate, and prednisone.

Safety and Tolerability

No new safety signals were reported with the triplet regimen in the study. A total of 75.2% of patients treated with niraparib plus abiraterone acetate and prednisone experienced a grade 3 or 4 adverse event compared with 58.9% of those treated with placebo plus abiraterone acetate and prednisone. Fatal treatment-emergent adverse events were observed in 14 patients in the arm given niraparib, abiraterone acetate, and prednisone and in 7 patients in the placebo arm.

Of note, anemia was reported in 29.1% of patients who received niraparib, abiraterone acetate, and prednisone, with the majority requiring a transfusion, compared with 4.6% in the placebo arm. Hypertension was reported in 26.5% of patients in the arm given niraparib, abiraterone acetate, and prednisone vs 18.4% of the placebo arm. All common adverse events were managed with supportive measures.

Dose interruptions were required in 66.9% of patients in the arm given niraparib, abiraterone acetate, and prednisone compared with 42.4% of patients in the placebo arm; dose reductions were required for 21.9% and 6.9% of patients, respectively. A total of 14.7% of patients in the arm given niraparib, abiraterone acetate, and prednisone discontinued treatment (including one patient because of myelodysplastic syndrome), as did 10.3% of patients in the placebo arm.

DISCLOSURE: Funding for this study was provided by Janssen Research & Development, LLC. Dr. Attard has received honoraria from Astellas Pharma, and Janssen; has served as a consultant or advisor to Abbott Laboratories, Amgen, Astellas Pharma, AstraZeneca, Bayer, Blue Earth Therapeutics, ESSA, Ferring, Janssen-Cilag, Medivation, Merck, Merck Serono, Millennium, Novartis, Pfizer, Ventana Medical Systems, Veracyte, and Veridex; has served on the speakers bureau of Astellas Pharma, AstraZeneca, Ferrin, Ipsen, Janssen, Sandoz, Sanofi, Takeda, and Ventana Medical Systems; has received institutional research funding from Astellas Pharma, Blue Earth Therapeutics, Janssen, Novartis, and Veracyte; has reported he is on the Institute of Cancer Research rewards to inventors list of abiraterone acetate, is listed as an inventor on a docetaxel predictive biomarker (Veracyte), and is listed as an inventor on a patent related to blood biomarkers (UCL, Cancer Research Horizons); and has received reimbursement for travel expenses from Abbott Laboratories, Amgen, Arvinas, Astellas Pharma, AstraZeneca, Bayer, Bristol Myers Squib, ESSA, Ferring, Janssen, Medivation, Merck Serono, Novartis, Orion Clinical, Pfizer, Propella Therapeutics, Sanofi, and Ventana Medical Systems. Dr. McGregor has served as a consultant or advisor to Arcus Biosciences, Astellas Pharma, BMS, Eisai, Exelixis, Gilead Sciences, Loxo/Lilly, Pfizer, and Seattle Genetics/Astellas; and has received research funding from BMS, Calithera Biosciences, Exelixis, Pfizer/EMD Serono, and Seattle Genetics/Astellas. For full disclosures of the other study authors, visit coi.asco.org.

REFERENCES

1. Attard G, Agarwal N, Graff J, et al: Phase 3 AMPLITUDE trial: Niraparib and abiraterone acetate plus prednisone for metastatic castration-sensitive prostate cancer patients with alterations in homologous recombination repair genes. 2025 ASCO Annual Meeting. Abstract LBA5006. Presented June 3, 2025.

2. Fizazi K, Piulats JM, Reaume MN, et al: Rucaparib or physician’s choice in metastatic prostate cancer. N Engl J Med 388:719-732, 2023.

3. Chi KN, Rathkopf D, Smith MR, et al: Niraparib and abiraterone acetate for metastatic castration-resistant prostate cancer. J Clin Oncol 41:3339-3351, 2023.