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, evaluating the efficacy and safety of AKEEGA with prednisone compared to 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). Key secondary endpoints include time to cytotoxic chemotherapy (TCC), time to symptomatic progression (TSP), and overall survival (OS).^1-6
• 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.⁷
  • 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. Grade ≥3 adverse events (AEs) were reported in 153 (72.2%) and 104 (49.3%) patients in the niraparib/AAP and in the placebo/AAP group, respectively. Discontinuation of niraparib or placebo due to TEAEs occurred in 15.1% of patients in the niraparib/AAP group and 5.7% of patients in the placebo/AAP group.⁵ Safety profiles at the final analysis⁶ and second interim analysis⁴ were consistent with that of the first interim analysis, with no new safety signals observed.

CLINICAL DATA

MAGNITUDE Study

Chi et al (2023)^3,5,6 and Efstathiou et al (2023)⁴ reported the efficacy and safety of AKEEGA with prednisone compared to 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)⁷ 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,⁵ 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.
  • Grade ≥3 AEs were reported in 153 (72.2%) and 104 (49.3%) patients in the niraparib/AAP and placebo/AAP groups, respectively.
  • Treatment-related AEs were reported in 165 (77.8%) and 121 (57.3%) patients in the niraparib/AAP and placebo/AAP groups, respectively.
    • There was 1 treatment-related death in each group (niraparib/AAP: pneumonia; placebo/AAP: acute myocardial infarction).
  • Serious AEs occurred in 93 (43.9%) patients in the niraparib/AAP group and 61 (28.9%) patients in the placebo/AAP group.
  • Dose reduction of niraparib or placebo due to an AE occurred in 20.3% of patients in the niraparib/AAP group vs 3.8% of patients in the placebo/AAP group.
    • The most common AEs leading to dose interruption or reduction in the niraparib/AAP group were anemia, thrombocytopenia, and neutropenia.
  • Discontinuation of niraparib or placebo due to an AE occurred in 15.1% of patients in the niraparib/AAP group and 5.7% of patients in the placebo/AAP group.
  • Death due to an AE occurred in 19 (9.0%) patients in the niraparib/AAP group and 9 (4.3%) patients in placebo/AAP group.
    • Coronavirus disease-2019 (COVID-19) was the leading cause of death in the niraparib/AAP group (4.7%) and in the placebo/AAP group (0.9%).
• 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

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 21 August 2024.