PARP Inhibitor Combo Shows Promising Efficacy in HRR-Altered mCSPC

In the phase 3 AMPLITUDE trial (NCT04497844), adding niraparib to abiraterone acetate (AAP; Akeega) plus prednisone was associated with longer radiographic progression-free survival (rPFS) in metastatic castration-sensitive prostate cancer (mCSPC) in patients harboring homologous recombination repair (HRR) gene alterations, compared with placebo plus abiraterone (Zytiga).¹

According to initial and final primary end point results, recently published in Nature Medicine, the study met its primary end point with an improved rPFS in the investigational arm (median not reached) vs 26 months in the placebo arm (HR, 0.52; 95% CI, 0.37–0.72; P <.0001) after a median follow-up of 30.8 months among patients with a BRCA1/2 mutation.

Furthermore, in the first presentation of interim analysis data of secondary end points, patients with a BRCA1/2 mutation also experienced improvements in time to symptomatic progression (HR, 0.44; 95% CI, 0.29–0.68; P =.0001). While median data for the key secondary end point of overall survival (OS) were immature as of the data cutoff, there is an estimated 25% reduction in the risk of death for BRCA1/2-harboring patients.

These data represent an important development in treatment of mCSPC with HRR alterations, which occur in roughly a quarter of patients.¹ While the combination was approved by the FDA for treatment of BRCA-positive metastatic castration-resistant prostate cancer in 2023 based on efficacy demonstrated by the phase 3 MAGNITUDE study (NCT03748641),² its efficacy is challenged in the face of deleterious germline or somatic HRR alterations, as such alterations are associated with treatment resistance and worse outcomes.¹ These latest results from the AMPLITUDE study hold promise in expanding the combination’s application to a castration-sensitive indication of prostate cancer.

“This is, to our knowledge, the first demonstration of efficacy of a PARP inhibitor in mCSCP,” noted the investigators, Attard et al, in the manuscript.¹ “The reduction in [rPFS] is clinically significant, most notably in cancers with a BRCA1/2 mutation, and this combination could represent a new treatment option for such patients.”

Phase 3 findings were previously presented at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting.

The phase 3 AMPLITUDE trial is a randomized, double-blind, placebo-controlled study evaluating the combination of niraparib and AAP plus prednisone against a placebo plus abiraterone in 696 patients with HRR-altered mCSPC in the first line.³ Patients were randomized 1:1 to receive either the treatment combination or the placebo treatment (n = 348 per group). The median age of the patient population was 68 years. Of these patients, more than half (56%) had BRCA1 or BRCA2 alterations.

What Is the Safety Profile?

Overall, the combination demonstrated a manageable safety profile. A slightly higher incidence of grade 3 or 4 adverse events (AEs) was observed in the investigational arm (75%; n = 261/347) compared with the placebo arm (59%; n = 205/348), with the most frequent AEs being anemia (29%) and hypertension (27%).

Treatment discontinuations due to AEs were relatively comparable between arms but were slightly higher in the experimental arm (14.7% vs 10.3%). Treatment-emergent AEs resulted in death in twice the number of patients in the investigation arm compared with the placebo arm (n = 14 and n = 7, respectively).

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. Nature Medicine. Published online October 7, 2025. doi:https://doi.org/10.1038/s41591-025-03961-8

2. FDA approves niraparib and abiraterone acetate plus prednisone for BRC. FDA. August 11, 2023. Accessed October 13, 2025. https://tinyurl.com/2mersatt

3. A Study of Niraparib in Combination With Abiraterone Acetate and Prednisone Versus Abiraterone Acetate and Prednisone for the Treatment of Participants With Deleterious Germline or Somatic Homologous Recombination Repair (HRR) Gene-Mutated Metastatic Castration-Sensitive Prostate Cancer (mCSPC) (AMPLITUDE). ClinicalTrials.gov. Updated October 10, 2025. Accessed October 13, 2025. https://clinicaltrials.gov/study/NCT04497844