Summary

• Alternative Formats of Information
  • A summary of the information provided in this response is provided as a video that can be accessed by clicking the following link:
    • Video: AKEEGA - MAGNITUDE Gene-by-Gene 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 (L1) 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
• Results from a prespecified MAGNITUDE gene-by-gene analysis evaluating the efficacy of niraparib/AAP in 186 patients with single-gene HRR alteration, other than BRCA1/2, have been reported.⁸
  • Single-gene alterations included ATM, BRIP1, CDK12, CHEK2, FANCA, HDAC2, or PALB2 and excluded co-occurring alterations.
  • Prespecified primary, secondary, and other efficacy endpoint results for individual alterations and combined functional groups are described in Table: Gene-by-Gene Analysis of Prespecified Primary, Secondary, and Other Endpoints and Table: Functional Group Analysis of Prespecified Primary, Secondary, and Other Endpoints.
• 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

CLINICAL DATA

MAGNITUDE Study

Chi et al (2023, 2025)^3,5-7 and Efstathiou et al (2023)⁴ 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 mutations, including BRCA1/2 (n=225).

The study design is presented in Figure: MAGNITUDE Study Design.

MAGNITUDE Gene-by-Gene Analysis

Sandhu et al (2022)⁸ reported results from a prespecified gene-by-gene analysis evaluating the efficacy of niraparib/AAP in patients with mCRPC and a single-gene HRR alteration, other than BRCA1/2 (N=186).

Study Design/Methods

• The analysis included 91 patients randomized to niraparib/AAP and 95 patients randomized to placebo/AAP with a single alteration in the ATM, BRIP1, CDK12, CHEK2, FANCA, HDAC2, or PALB2 gene, and excluded co-occurring alterations due to small sample size per tumor genotype and inability to draw meaningful conclusions.
• CDK12 alterations were added to the HRR+ cohort eligibility midway through study enrollment; therefore, patients with CDK12 alterations were included in this analysis regardless of which cohort they were enrolled.
• Given the rarity of some single-gene alterations, groups based on functional similarity (HRR-Fanconi group [BRIP1, FANCA, PALB2] and HRR-associated group [CHEK2, HDAC2]) were also analyzed.
• The study design is presented in Figure: MAGNITUDE Gene-by-Gene Analysis 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
• Single gene alterations at baseline in the HRR+ cohort are shown in Table: Single Gene Alterations at Baseline (HRR+ Cohort).

Efficacy

• A summary of results for patients with PALB2, CHEK2, and HDAC2 gene alterations showed benefit for all primary, secondary, and other endpoints (Table: Gene-by-Gene Analysis of Prespecified Primary, Secondary, and Other Endpoints).
• Patients with HRR-Fanconi pathway (BRIP1, FANCA, or PALB2) or HRR-associated (CHEK2 or HDAC2) gene alterations also showed improvement in all endpoints when combined into functional groups (Table: Functional Group Analysis of Prespecified Primary, Secondary, and Other Endpoints).
• This analysis of individual alterations was not powered for formal statistical inference.

Safety

• At the second interim analysis, 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).⁵
  • 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.
• Safety profiles across both interim analyses and the final analysis⁶ were consistent, with no new safety signals. The most common AEs for niraparib/AAP vs placebo/AAP, regardless of causality, were anemia (50.0% vs 22.7%, respectively), hypertension (33.0% vs 22.3%, respectively), and constipation (33.0% vs 15.6%).⁵

• 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 

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 12 August 2025.