Summary

• Alternative Formats of Information
  • A brief overview of the MAGNITUDE study with key safety and efficacy information is available as video that can be accessed by clicking the following link:
    • Video: AKEEGA - MAGNITUDE Study Overview (Second Interim Analysis)
• MAGNITUDE (NCT03748641) is a phase 3, randomized, double-blind, placebo-controlled, global study that evaluated the efficacy and safety of AKEEGA with prednisone compared with placebo/abiraterone acetate with prednisone (AAP) as first-line therapy in metastatic castration-resistant prostate cancer (mCRPC) for patients with certain homologous recombination repair (HRR) mutations, including BRCA1/2. The primary endpoint is radiographic progression-free survival (rPFS).^1-7
  • Patients were prospectively allocated to cohort 1 or 2 based on prescreening for HRR+ or HRR- status and subsequently randomized to receive niraparib or matching placebo in combination with AAP.
• Prespecified endpoint results are described in Table: Prespecified Primary and Key Secondary Endpoints.
  • At the first interim analysis (IA1)³:
    • In patients with BRCA1/2 mutations, after a median follow-up of 16.7 months, a statistically significant improvement in median rPFS as assessed by blinded independent central review (BICR) was observed in the niraparib/AAP vs placebo/AAP group: 16.6 vs 10.9 months (hazard ratio [HR], 0.53; 95% confidence interval [CI], 0.36-0.79; P=0.001).
  • At the final analysis⁷:
    • After a median follow-up of 37.3 months, no difference in overall survival (OS) between niraparib/AAP and placebo/AAP was observed in the HRR+ population (HR, 0.931; 95% CI, 0.720-1.203; P=0.585); however, in the BRCA1/2 subgroup, the median OS favored the niraparib/AAP group compared with the placebo/AAP group: 30.36 months vs 28.55 months (HR, 0.788; 95% CI, 0.554-1.120).
  • A summary of treatment-emergent adverse events (TEAEs) is described in Table: Summary of Most Common (≥10% in Either Group) TEAEs at IA2 (HRR+ Population). In the niraparib/AAP vs placebo/AAP group, grade ≥3 adverse events (AEs) were reported in 153 (72.2%) vs 104 (49.3%) patients in the second interim analysis (IA2) and 157 (74.1%) vs 108 (51.2%) patients in the final analysis. In the niraparib/AAP vs placebo/AAP group, TEAEs leading to discontinuation were reported in 18.4% vs 8.1% of patients in the final analysis.^6,7 Safety profiles at the final analysis and IA2 were consistent with those observed at the IA1, with no new safety signals reported.⁶
• Results have been reported from a post hoc analysis that adjusted for imbalances in baseline characteristics using inverse probability of treatment weighting (IPTW) analysis (Table: Unadjusted and Adjusted Outcomes).^8,9
• Results from a prespecified gene-by-gene analysis evaluating the efficacy of niraparib/AAP in 186 patients with mCRPC and a single-gene HRR alteration, other than BRCA1/2, have been reported.¹⁰ 
• Results from sensitivity analyses conducted to evaluate the impact of AAP run-in treatment on the efficacy of niraparib/AAP have been reported.¹¹
• Results from an analysis of health-related quality of life (HRQoL), pain, and tolerability which evaluated Functional Assessment of Cancer Therapy-Prostate (FACT-P) and Brief Pain Inventory-Short Form (BPI-SF) score changes from baseline, have been reported.^12,13
• Results from an analysis that stratified efficacy by outcomes of the 2 different enrollment assays (tissue and plasma) used to classify patients as HRR+ have been reported.¹⁴

CLINICAL DATA

MAGNITUDE Study

Chi et al (2023, 2025)^3,4,6,7 and Efstathiou et al (2023)⁵ reported the efficacy and safety of AKEEGA with prednisone compared with placebo/AAP in mCRPC for patients with (n=423) and without (n=233) certain HRR gene mutations, including BRCA1/2 (n=225).

Study Design/Methods

• Phase 3, randomized, double-blind, placebo-controlled, global study
• Patients were prospectively allocated to cohort 1 or 2 based on prescreening for HRR+ or HRR- status. The HRR+ panel included ATM, BRCA1, BRCA2, BRIP1, CDK12, CHEK2, FANCA, HDAC2, and PALB2 (qualified by plasma, tissue, and/or saliva/whole blood assays).^3,15
  • Patients in the HRR+ cohort were positive by ≥1 assay prior to randomization.
  • Patients in the HRR- cohort were tested by both tissue and plasma assays prior to randomization.
• A third, open-label cohort (cohort 3) was added to evaluate niraparib 200 mg and abiraterone acetate 1000 mg (dual action tablet formulation) orally (PO) once daily with prednisone 5 mg twice daily.
• Preplanned sensitivity analyses for OS included a proportional-hazards Cox regression multivariate analysis (MVA) adjusted for externally validated, clinically relevant baseline prognostic factors, inverse probability of censoring weighting (IPCW) adjusted for imbalances in the use of subsequent therapies, and censoring for death due to coronavirus disease 2019 (COVID-19).
• The study design is presented in Figure: MAGNITUDE Study Design.

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
• Select baseline patient characteristics are shown in Table: Select Baseline Patient Characteristics: BRCA1/2 and HRR+.

HRR+ Cohort

Efficacy

• A summary of results is provided in Table: Prespecified Primary and Key Secondary Endpoints.

IA2

• In the BRCA1/2 subgroup⁴:
  • The prespecified IPCW analysis of OS was used to account for imbalances in subsequent use of PARP inhibitors and other life-prolonging therapies: niraparib/AAP vs placebo/AAP (HR, 0.54; 95% CI, 0.33-0.90; nominal P=0.0181).
  • The prespecified OS MVA was used to account for important prognostic factors: niraparib/AAP vs placebo/AAP (HR, 0.68; 95% CI, 0.45-1.05; nominal P=0.0793).
  • These endpoints were not adjusted for multiple comparisons. Therefore, the P-values displayed are nominal, and statistical significance has not been established.
• In the HRR+ population⁴:
  • OS MVA was used to adjust for baseline characteristics: niraparib/AAP vs placebo/AAP (HR, 0.82; 95% CI, 0.60-1.10; nominal P=0.1821).
  • IPCW analysis was used to adjust for subsequent PARP inhibitors and other life-prolonging therapies: niraparib/AAP vs placebo/AAP (HR, 0.70; 95% CI, 0.49-0.99; nominal P=0.0414).
  • These endpoints were not adjusted for multiple comparisons. Therefore, the P-values displayed are nominal, and statistical significance has not been established.

Final Analysis 

• In the niraparib/AAP group and placebo/AAP group, 48 (22.6%) and 40 (19.0%) patients were still receiving treatment, respectively. There were 53.1% of patients in the niraparib/AAP vs 76.8% of patients in the placebo/AAP group that discontinued treatment due to disease progression.⁷
  • Results from the IPCW analysis revealed a longer OS with niraparib/AAP vs placebo/AAP in the HRR+ population (HR, 0.714; 95% CI, 0.525-0.970; nominal P=0.031) and in the BRCA1/2 subgroup (HR, 0.645; 95% CI, 0.415-1.002; nominal P=0.051). These endpoints were not adjusted for multiple comparisons. Therefore, the P-values displayed are nominal, and statistical significance has not been established.
  • At IA2, a prespecified sensitivity analysis in which COVID-19-related deaths were censored assessed the potential impact of the pandemic on OS. No COVID-19-related deaths occurred between IA2 and the final analysis. In the updated analysis with censoring of COVID-19-related deaths, the HR for OS was 0.871 (95% CI, 0.667-1.138; nominal P=0.310) in the HRR+ population and 0.704 (95% CI, 0.488-1.015; nominal P=0.059) in the BRCA1/2 subgroup. These endpoints were not adjusted for multiple comparisons. Therefore, the P-values displayed are nominal, and statistical significance has not been established.
• Subsequent treatment in patients with disease progression is summarized in Tables: Subsequent Treatment (BRCA+ Subgroup) and Subsequent Treatment (HRR+ Population).

Safety

• At IA2, a total of 211 patients in the niraparib/AAP group and 203 patients in the placebo/AAP group reported AEs, described in Table: Summary of Most Common (≥10% in Either Group) TEAEs at IA2 (HRR+ Population).⁴
• The most common AEs for niraparib/AAP vs placebo/AAP, regardless of causality, were anemia, hypertension, and constipation. The most common AEs leading to dose interruption or reduction in the niraparib/AAP group were anemia, thrombocytopenia, and neutropenia.⁴

• At the final analysis,⁷ the safety profile in the BRCA+ subgroup was consistent with that of the HRR+ population and remained consistent with prior analyses. Safety data from the final analysis are summarized in Tables: Safety Summary: Final Analysis (HRR+ Population) and TEAEs of Special Interest: Final Analysis (HRR+ Population).

• Safety profiles across IA1, IA2, and the final analysis were consistent, with no new safety signals.⁶ 

HRR- Cohort

Efficacy and Safety

• A prespecified futility analysis was conducted in the HRR- population after enrolling 233 of the planned 600 patients and approximately 125 composite progression events (first of rPFS, prostate-specific antigen [PSA] progression, or death) occurred.^15,17 
  • The composite progression endpoint (n=233) met futility criteria (HR, 1.09; 95% CI, 0.75-1.59; P=0.66), where futility was defined as HR ≥1.
  • A total of 83 PSA events (HR, 1.03; 95% CI, 0.67-1.59) and 65 rPFS events (HR, 1.03; 95% CI, 0.63-1.67) occurred.
• Additional grade 3/4 toxicity was observed in the niraparib/AAP group compared with the placebo/AAP group.¹⁵
• Based on the efficacy and safety results in patients with HRR- mCRPC, the independent data monitoring committee recommended stopping enrollment in this cohort to support patient safety and prevent overtreatment.¹⁵

Post Hoc Analysis

Roubaud et al (2024)^8,9 reported the efficacy of AKEEGA with AAP in patients with BRCA1/2-altered mCRPC (n=225) in MAGNITUDE after adjustment for imbalances in baseline characteristics. In a post hoc analysis that adjusted for imbalances in baseline characteristics using IPTW analysis, time-to-event outcome analyses were evaluated in patients with BRCA1/2-altered mCRPC. MVA was conducted based on prespecified prognostic variables of OS in mCRPC. Outcomes are described in Table: Unadjusted and Adjusted Outcomes.

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 30 May 2025.