The AMPLITUDE trial (NCT04497844) found that a combination of niraparib and abiraterone acetate (Akeega) with prednisone significantly improved key outcomes, potentially redefining the standard of care for this genetically defined group.

Niraparib is a selective PARP-1/2 inhibitor that targets cancer cells with defects in DNA repair pathways, particularly those involving HRR genes such as BRCA1, BRCA2, CDK12, and others. The drug had already shown efficacy in a later disease stage, in the MAGNITUDE trial, where its combination with abiraterone acetate improved radiographic progression-free survival (rPFS) in men with metastatic castration-resistant prostate cancer (mCRPC). Building on those results, AMPLITUDE set out to test the same approach earlier in the disease course.

The double-blind, placebo-controlled trial enrolled 696 men with mCSPC and specific germline or somatic HRR gene alterations, including BRIP1, CHEK2, FANCA, PALB2, RAD51B, and RAD54L, in addition to BRCA1 and BRCA2. Participants were randomized evenly to receive either niraparib (200 mg daily) with abiraterone acetate (1000 mg) and prednisone (5 mg), or placebo with the same hormonal therapy. Eligible patients could have undergone up to six months of androgen deprivation therapy (ADT), with or without prior docetaxel chemotherapy, and up to 45 days of prior abiraterone. The trial’s primary endpoint was investigator-assessed rPFS, while secondary measures included time to symptomatic progression and overall survival. The median follow-up was 30.8 months.

The results were striking. Patients receiving the niraparib combination experienced significantly longer progression-free survival, with the median not yet reached at the time of analysis, compared to 29.5 months in the control arm. This represented a 37% reduction in the risk of disease progression or death, with a hazard ratio (HR) of 0.63 and a highly significant p-value (p=0.0001). In the subgroup of patients with BRCA1 or BRCA2 mutations, the benefit was even more pronounced, with an HR of 0.52 (p<0.0001). The treatment also delayed the onset of cancer-related symptoms. Time to symptomatic progression was significantly extended in the niraparib group (HR 0.50; p<0.0001), and once again, the BRCA1/2 subgroup showed the greatest benefit (HR 0.44; p=0.0001).

Though overall survival results are not yet definitive, early data show a favorable trend. The hazard ratio for overall survival was 0.79 in the niraparib group, though this did not reach statistical significance (p=0.10). The trend was similar in the BRCA1/2 subgroup (HR 0.75; p=0.15). Additional follow-up is ongoing to determine whether these trends will translate into a statistically significant survival advantage.

Safety was a key focus of the trial. Grade 3 or 4 adverse events were more common in the niraparib group (75.2%) compared to those receiving abiraterone alone (58.9%), with the most frequent events being anemia (29.1% vs 4.6%) and hypertension (26.5% vs 18.4%). However, treatment discontinuations due to adverse events were relatively low in both groups—11.0% in the combination arm versus 6.9% in the control group—indicating a manageable safety profile with no unexpected risks.

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