Clinical trialPhase 3Prostate cancer

Niraparib and abiraterone acetate plus prednisone for HRR-deficient metastatic castration-sensitive prostate cancer: a randomized phase 3 trial

Nat Med · 2025696 patients (348 in each group)

Attard G, Agarwal N, Graff JN, Sandhu S, Efstathiou E, Özgüroğlu M, et al. Nat Med. 2025. 31:4109-4118

Study type: Clinical trial
Study name: AMPLITUDE
Phase: Phase 3
Design: Phase 3 randomised, double-blind trial with 1:1 randomisation (niraparib + AAP versus placebo + AAP)
Sample size: 696 patients (348 in each group)
Source: Nat Med · 2025
Trial registration: NCT04497844

In plain words

In this study, men with prostate cancer that had spread but still responded to hormone treatment, and whose tumour cells had a fault in DNA-repair genes (such as BRCA), were given either the drug niraparib or a placebo together with standard treatment (abiraterone and prednisone). Adding niraparib significantly lengthened the time before the disease grew on scans. On the other hand, side effects such as anaemia (sometimes needing a blood transfusion) and high blood pressure were more common. Data on survival are not yet complete; decisions about this treatment should be made with your own doctor.

Key results

Median not reached in the niraparib + AAP group vs 26 months in the AAP group; HR = 0.52

Radiographic progression-free survival (rPFS) in the BRCA subgroup

95% CI 0.37–0.72; P < 0.0001

HR = 0.63

Radiographic progression-free survival (rPFS) in the ITT population

95% CI 0.49–0.80; P = 0.0001

HR = 0.79

Overall survival (OS) in the overall population

95% CI 0.59–1.04; data immature (193 of 389 events)

HR = 0.75

Overall survival (OS) in the BRCA subgroup

95% CI 0.51–1.11

Drugs in this study:Abiraterone (Zytiga)

Dose and schedule cards

Niraparib/abiraterone combination tablet (AMPLITUDE and FDA label)

BRCA2 mutation in mCSPC, or BRCA mutation in mCRPC (FDA label indications); with ADTOn the page “Prostate cancer” · With DNA repair gene mutations (HRR/BRCA): PARP inhibitors in mCSPC and mCRPC

BRCA2 mutation in mCSPC, or BRCA mutation in mCRPC (FDA label indications); with ADT

Drug	Dose	Route	Schedule
mCSPC with a BRCA2 mutation
Niraparib/abiraterone acetate	200/1000 mg once daily	Oral, on an empty stomach (at least 1 hour before or 2 hours after a meal)	Daily
Prednisone	5 mg once daily	Oral	Daily
mCRPC with a BRCA mutation
Niraparib/abiraterone acetate	200/1000 mg once daily	Oral, on an empty stomach	Daily
Prednisone	10 mg once daily	Oral	Daily

Cycle length: Continuous (28-day cycles)
Duration: Until progression or unacceptable toxicity

Per the FDA label; AMPLITUDE trial (niraparib 200 + abiraterone 1000 mg + prednisone 5 mg daily in mCSPC with HRR alterations). Blood counts weekly during the first month, every 2 weeks for the next 2 months, monthly until the end of the first year and every other month thereafter. For haemoglobin below 8, platelets below 100,000 or neutrophils below 1000, withhold and, after recovery, resume at the reduced dose of 100/1000 mg (for a first drop in platelets to 75,000 or more, the same dose may also be resumed); for hepatotoxicity, resume at 100/500 mg. Monitor blood pressure, potassium and fluid retention. Grade 3–4 anaemia (29%) and hypertension (27%) were the most common adverse events in AMPLITUDE.

On the page “Prostate cancer” · With DNA repair gene mutations (HRR/BRCA): PARP inhibitors in mCSPC and mCRPC

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Niraparib + abiraterone acetate and prednisone (AAP)

Fixed-dose combination tablet of niraparib 200 mg + abiraterone acetate 1000 mg with prednisone 5 mg, orally once daily continuously in 28-day cycles, with continued ADT (348 patients).

2Placebo + abiraterone acetate and prednisone (AAP)

Placebo for the combination tablet + abiraterone acetate 1000 mg + prednisone 5 mg, orally once daily, with ADT (348 patients).

Source of the regimen details: Full text of the paper (PMC12705445) and ClinicalTrials.gov NCT04497844

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

696 patients with metastatic castration-sensitive prostate cancer (metastases on CT/MRI or bone scan; nodal-only disease was not eligible) with a deleterious alteration in one of the HRR genes (BRCA1, BRCA2, BRIP1, PALB2, RAD51B, RAD54L, CDK12, CHEK2, FANCA). Allowed: up to 6 months of prior ADT (started at least 14 days before randomisation), up to 45 days of abiraterone-prednisone, and prior docetaxel; prior PARP inhibitor treatment was an exclusion criterion. Median age 68 years; 56% BRCA1/BRCA2 alterations; 78% high volume; 16% prior docetaxel.

Endpoints

Primary endpoint: radiographic progression-free survival (rPFS), assessed first in the BRCA subgroup and then in the intention-to-treat (ITT) population. Key secondary endpoint: overall survival (OS).

Safety and side effects

Grade 3 or 4 adverse events: 75% in the niraparib + AAP group versus 59% in the AAP group; the most common were anaemia (29%; 25% of patients needed a blood transfusion) and hypertension (27%). Treatment interruption in 66.9% versus 42.4%. 14 adverse events leading to death in the niraparib group and 7 in the placebo group.

Clinical significance and place in guidelines

This trial shows that adding a PARP inhibitor to next-generation hormone therapy in the castration-sensitive setting can improve radiographic progression-free survival in patients with HRR gene alterations, especially BRCA1/BRCA2. Given the immature overall survival data and the increase in adverse events (especially anaemia), the final place of this combination requires further follow-up. The status of regulatory approvals and clinical guideline recommendations should be checked separately and is not mentioned in the abstract.

Limitations

Overall survival data are immature (193 of 389 events) and the confidence interval of the overall survival hazard ratio includes 1. Median rPFS in the niraparib group had not yet been reached at the time of the analysis. Grade 3 or 4 adverse events and deaths due to adverse events were more frequent in the niraparib group. Further details on the design and analyses should be checked in the full text of the paper.

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.