SUMMARY

• In MAGNITUDE, the phase 3 study evaluating the efficacy and safety of AKEEGA with prednisone as first-line (L1) therapy in metastatic castration-resistant prostate cancer (mCRPC) for patients with certain homologous recombination repair (HRR) mutations, including BRCA1/2, progression or change in the prostate-specific antigen (PSA) level was not used as a lone indicator for disease progression or treatment discontinuation. For patients who had an increasing PSA in the absence of radiographic or clinical progression, study treatment was continued.^1-3
  • Patients who received abiraterone acetate plus prednisone (AAP) for mCRPC prior to study entry underwent PSA testing to document a lack of PSA progression before random assignment.³
  • Patients were prospectively allocated to cohorts based on prescreening for HRR biomarker positive (HRR+) or biomarker negative (HRR-) status and subsequently randomized to receive niraparib or matching placebo (PBO) in combination with AAP.³
  • Time to PSA progression and PSA response rate were prespecified exploratory endpoints.^4,5 These endpoints were not adjusted for multiple comparisons. Therefore, the P-value is nominal and statistical significance has not been established.
    • At the first interim analysis, after a median follow-up of 16.7 months:³
      • HRR+ patients: median time to PSA progression in the niraparib/AAP group was 18.5 months vs 9.3 months in the PBO/AAP group (hazard ratio [HR], 0.57; 95% confidence interval [CI], 0.43-0.76; nominal P<0.001).
      • BRCA1/2 subgroup: median time to PSA progression in the niraparib/AAP group was not evaluable (NE) vs 9.2 months in the PBO/AAP group (HR, 0.46; 95% CI, 0.30-0.69; nominal P<0.001).
    • At the second interim analysis, after a median follow-up of 24.8 months, in the BRCA1/2 subgroup:^5,6
      • Median time to PSA progression in the niraparib/AAP group was 18.4 months vs 9.2 months in the PBO/AAP group (HR, 0.48; 95% CI, 0.33-0.70; nominal P<0.0001).
      • Confirmed PSA response was observed in 89 (78.8%) vs 73 (65.2%) patients in the nira/AAP group vs PBO/AAP group.
    • PSA-related results are provided in Table: PSA Results in the MAGNITUDE Study.
• PSA results have been reported from a post hoc analysis of the MAGNITUDE study that adjusted for imbalances in baseline characteristics using inverse probability of treatment weighting (IPTW) analysis (Table: Unadjusted and Adjusted Time to PSA Progression).^7,8
• The AMPLITUDE study is an ongoing, phase 3, randomized, double-blind, placebo-controlled, multicenter, global study evaluating the efficacy and safety of niraparib and abiraterone acetate (AA) in a dual-action tablet (DAT) formulation with prednisone plus androgen deprivation therapy (ADT) compared to matching oral placebo/abiraterone acetate with prednisone plus ADT in patients with deleterious germline or somatic homologous recombination repair (HRR) gene-altered metastatic castration-sensitive prostate cancer (mCSPC; N=696).⁹
  • Patients were randomized 1:1 to receive either AKEEGA (a dual-action tablet containing niraparib [200 mg] and abiraterone acetate [1000 mg]) plus prednisone (5 mg) once daily (AKEEGA plus prednisone group; n=348) or PBO/AAP (PBO/AAP group; n=348).
  • Patients receiving AKEEGA plus prednisone had improved time for PSA progression compared with patients receiving PBO/AAP (HR, 0.50; 95% CI, 0.39-0.65; nominal P<0.0001).
  • PSA-related results are listed in Table: PSA Results in the AMPLITUDE Study.

CLINICAL DATA

MAGNITUDE Study

Chi et al (2023, 2025)^3,5,10,11 and Efstathiou et al (2023)¹² reported the efficacy and safety of AKEEGA with prednisone compared with PBO/AAP in mCRPC for patients with (n=423) and without (n=233) certain HRR mutations, including BRCA1/2 (n=225).

Study Design/Methods

• Phase 3, randomized, double-blind, PBO-controlled, global study
• Patients were randomized 1:1 to receive niraparib 200 mg by mouth (PO) once daily or matching PBO in combination with abiraterone acetate 1000 mg PO once daily plus prednisone 5 mg twice daily. A third, open-label cohort was added to evaluate niraparib 200 mg and abiraterone acetate 1000 mg (dual action tablet formulation) PO once daily with prednisone 5 mg twice daily.

Results

Patient Characteristics

• Baseline characteristics were broadly comparable between treatment arms; however, rates of visceral metastases, bone metastases, and Eastern Cooperative Oncology Group performance status (ECOG PS) of 1 were imbalanced to the disadvantage of the niraparib/AAP group.³
• Baseline PSA levels are shown in Table: Baseline PSA Levels in the MAGNITUDE Study.

Efficacy

• PSA-related results are listed in Table: PSA Results in the MAGNITUDE Study.
• Multivariate analyses (MVA) for rPFS and OS were preplanned. Results for adjusting of baseline variables, including PSA, is summarized in Table; Multivariate Analyses.

Post Hoc Analysis

Roubaud et al (2024)^7,8 reported the efficacy of AKEEGA with AAP in patients with BRCA1/2-altered mCRPC (n=225) in a MAGNITUDE post hoc analysis, adjusting for imbalances in baseline characteristics using IPTW analysis. Time-to-event outcome analyses were evaluated and MVA was conducted based on prespecified prognostic variables of OS in mCRPC. PSA outcomes using data from the final analysis are described in Table: Unadjusted and Adjusted Time to PSA Progression.

AMPLITUDE Study

Attard et al (2025) reported the efficacy and safety results of AKEEGA plus prednisone vs PBO/AAP plus ADT in patients with deleterious germline or somatic HRR gene-altered mCSPC (N=696).⁹

Study Design/Methods

• Phase 3, randomized, double-blind, PBO-controlled, multicenter, global study.
• Patients were randomized 1:1 to receive either AKEEGA (a dual-action tablet containing niraparib [200 mg] and abiraterone acetate [1000 mg]) plus prednisone (5 mg) once daily (AKEEGA plus prednisone group; n=348) or PBO/AAP (PBO/AAP group; n=348).
• Key efficacy endpoint testing was conducted using a hierarchical graphical approach, first in the BRCA subgroup (BRCA1 or BRCA2 alterations), then HRR effector subgroup (ie, immediate effectors of HRR at DNA double-strand breaks [BRCA subgroup + BRIP1, PALB2, RAD51B, RAD54L]), and finally extending to intention-to-treat (ITT) patients (HRR effectors subgroup + CDK12, CHEK2, and FANCA).

Results

Patient Characteristics

• Patient characteristics were well balanced between the 2 groups.
• Baseline PSA levels are shown in Table: Baseline PSA Levels in the AMPLITUDE Study – ITT Population.

Efficacy

• PSA-related results are listed in Table: PSA Results in the AMPLITUDE Study.
• The objective response rate was 72% (76/106) in the AKEEGA plus prednisone group and 74% (81/110) in PBO/AAP group.
• Patients who achieved a complete or partial response experienced a longer duration of response in the AKEEGA plus prednisone group than in the abiraterone alone group (HR, 0.55; 95% CI, 0.35-0.86; nominal P=0.008).
• Patients receiving AKEEGA plus prednisone had improved time for PSA progression compared with patients receiving PBO/AAP (HR, 0.50; 95% CI, 0.39-0.65; nominal P<0.0001).

Literature Search

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File (and/or other resources, including internal/external databases) was conducted on 02 September 2025. Summarized in this response are relevant data limited to the phase 3 MAGNITUDE study in patients with mCRPC and AMPLITUDE study in patients with mCSPC.