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, placebocontrolled, global study evaluating 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 progressionfree survival (rPFS). Key secondary endpoints include time to cytotoxic chemotherapy (TCC), time to symptomatic progression (TSP), and overall survival (OS).^1-4
  • 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 primary and key secondary endpoint results are described in Table: Prespecified Primary and Key Secondary Endpoints.
  • At the first interim analysis³:
    • 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 (HR 0.53; 95% CI, 0.36-0.79; P=0.001).
  • At the second interim analysis⁵:
    • In patients with BRCA1/2 mutations, after a median follow-up of 24.8 months, a total of 43 vs 49 death events occurred in the niraparib/AAP vs placebo/AAP group (HR, 0.88; 95% CI, 0.581.34; nominal P=0.5505). These endpoints were not adjusted for multiple comparisons. Therefore, the Pvalues displayed are nominal, and statistical significance has not been established.
  • At the final analysis⁶:
    • In patients with BRCA1/2 mutations, after a median follow-up of 35.9 months, median OS favored the niraparib/AAP vs placebo/AAP group: 30.4 vs 28.6 months (HR 0.788; 95% CI, 0.554-1.120; nominal P=0.1828). These endpoints were not adjusted for multiple comparisons. Therefore, the P-values displayed are nominal, and statistical significance has not been established.
    • OS benefit in the niraparib/AAP group was also demonstrated in a preplanned multivariate analysis using prespecified prognostic factors (HR 0.663; 95% CI, 0.464-0.947; nominal P=0.0237). These endpoints were not adjusted for multiple comparisons. Therefore, the P-values displayed are nominal, and statistical significance has not been established.
• A summary of treatment-emergent adverse events (TEAEs) from the second interim analysis is described in Table: Summary of Most Common (≥10% in Either Group) TEAEs.
  • 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 and 157 (74.1%) vs 108 (51.2%) patients in the final analysis.
  • In the niraparib/AAP vs placebo/AAP group, AEs leading to discontinuation of niraparib or placebo were reported in 15.1% vs 5.7% of patients in the second interim analysis, and TEAEs leading to discontinuation were reported in 18.4% vs 8.1% of patients in the final analysis.⁵
  • Safety profiles at the second interim⁴ and final⁶ analyses were consistent with those of the first interim analysis, with no new safety signals observed.
• 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.⁷
• Results from sensitivity analyses conducted to evaluate the impact of AAP run-in treatment on the efficacy of niraparib/AAP have been reported.⁸
• Results from patient-reported outcome (PRO) analyses of health-related quality of life (HRQoL), pain, and tolerability (side-effect bother), which evaluated the Functional Assessment of Cancer Therapy-Prostate (FACT-P), Brief Pain Inventory-Short Form (BPI-SF), and European Quality of Life Five-Dimension Five-Level (EQ5D-3L) score changes from baseline, have been reported.^9,10
• 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.¹¹

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 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

• Ongoing, phase 3, randomized, double-blind, placebo-controlled, global study.³
• In cohorts 1 and 2, patients were randomized 1:1 to receive niraparib 200 mg orally (PO) once daily or matching placebo in combination with abiraterone acetate 1000 mg PO once daily plus prednisone 5 mg twice daily.³
• 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).^3,12
  • 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 PO once daily with prednisone 5 mg twice daily.³
• Patients were stratified by prior taxane-based chemotherapy for metastatic castration-sensitive prostate cancer (mCSPC), prior androgen receptor (AR) inhibitor therapy for nonmetastatic castration-resistant prostate cancer (nmCRPC) or mCSPC, prior AAP for L1 mCRPC, and BRCA1/2 vs other HRR gene alterations (HRR+ cohort).²
• The study design is presented in Figure: MAGNITUDE Study Design.

Results

Patient Characteristics

• Baseline characteristics were broadly comparable between treatment groups; however, rates of visceral metastases, bone metastases, and ECOG PS 1 were imbalanced, to the disadvantage of the niraparib/AAP group.³
• Select baseline patient characteristics in the HRR+ cohort are shown in Table: Select Baseline Patient Characteristics: BRCA1/2 Population.

HRR+ Cohort

Efficacy

• A summary of results for the patients in the HRR+ cohort is provided in Table: Prespecified Primary and Key Secondary Endpoints.
• At the first interim analysis, a statistically significant improvement in BICR-assessed median rPFS was observed in the niraparib/AAP vs placebo/AAP group for patients with BRCA1/2 mutations (median follow-up: 16.7 months) and HRR+ patients (median follow-up: 18.6 months), as shown in Table: Prespecified Primary and Key Secondary Endpoints.³
  • rPFS in prespecified subgroups defined by baseline characteristics showed no heterogeneity of effect across subgroups.
• At the second interim analysis, after 8.1 months of additional follow-up from the first interim analysis, the following endpoints were evaluated.⁵ These endpoints were not adjusted for multiple comparisons. Therefore, the P-values displayed are nominal, and statistical significance has not been established.
  • In patients with BRCA1/2 mutations, a consistent treatment effect in BICR-assessed median rPFS was observed in the niraparib/AAP vs placebo/AAP group: 19.5 months vs 10.9 months (HR, 0.55; 95% CI, 0.390.78; nominal P=0.0007).
  • In all HRR+ patients, an improvement in BICR-assessed median rPFS was observed in the niraparib/AAP vs placebo/AAP group: 16.7 months vs 13.7 months (HR, 0.76; 95% CI, 0.60-0.97; nominal P=0.0280).
  • In patients with BRCA1/2 mutations, an improvement in TCC (HR, 0.56; 95% CI, 0.350.90; nominal P=0.0152) and TSP (HR, 0.54; 95% CI, 0.35-0.85; nominal P=0.0071) was observed in the niraparib/AAP vs placebo/AAP group.
  • In all HRR+ patients, a statistically significant prolongation in both TCC (HR, 0.67; 95% CI, 0.47-0.94; P=0.0206) and TSP (HR, 0.60; 95% CI, 0.42-0.84; P=0.0029) was observed in patients treated with niraparib/AAP vs placebo/AAP.
  • At a median follow-up of 24.8 months in the BRCA1/2 population, there was a trend in stratified analysis toward improved OS with niraparib/AAP. A total of 43 vs 49 death events occurred in the niraparib/AAP vs placebo/AAP group (HR, 0.88; 95% CI, 0.58-1.34; nominal P=0.5505).⁴
    • After adjusting for important prognostic factors in a multivariate analysis and accounting for differences in subsequent therapies in an inverse probability censoring weighted (IPCW) analysis, OS improvement was observed with niraparib/AAP vs placebo/AAP in the BRCA1/2 population (HR, 0.68; 95% CI, 0.45-1.05; nominal P=0.0793 vs HR, 0.54; 95% CI, 0.33-0.90; nominal P=0.0181).
  • At a median follow-up of 26.8 months in the HRR+ population, the OS data were immature with 72.8% of the required death events for the final analysis observed. In the OS stratified analysis, HR was 1.01 (95% CI, 0.75-1.36; P=0.9480).
    • After adjusting for baseline characteristics in a multivariate analysis and accounting for differences in subsequent therapies in an IPCW analysis, OS improvement was observed with niraparib/AAP vs placebo/AAP in the HRR+ population (HR, 0.82; 95% CI, 0.60-1.10; nominal P=0.1821 vs HR, 0.70; 95% CI, 0.49-0.99; nominal P=0.0414).
• At the final analysis, after a median follow-up of 35.9 months, median OS favored the niraparib/AAP vs placebo/AAP group in patients with BRCA1/2 mutations: 30.4 vs 28.6 months (HR 0.788; 95% CI, 0.554-1.120; nominal P=0.1828).⁶ These endpoints were not adjusted for multiple comparisons. Therefore, the P-values displayed are nominal, and statistical significance has not been established.
  • In the niraparib/AAP vs placebo/AAP group, median treatment duration was 20.5 vs 14.4 months.
  • In the niraparib/AAP vs placebo/AAP group, 53.1% vs 76.8% of patients discontinued treatment due to disease progression. Use of subsequent treatment was high and included the use of PARP inhibitors and platinum-based chemotherapy.

Safety

• Safety data from the second interim analysis are summarized in Table: Safety Summary: Second Interim Analysis.⁵
  • The most common AEs leading to dose interruption or reduction in the niraparib/AAP group were anemia, thrombocytopenia, and neutropenia.

• The most common TEAEs are included in Table: Summary of Most Common (≥10% in Either Group) TEAEs.⁵
  • The most common AEs for niraparib/AAP vs placebo/AAP, regardless of causality, were anemia (50.0% vs 22.7%), hypertension (33.0% vs 22.3%), and constipation (33.0% vs 15.6%).

• At the final analysis,⁶ the safety profile in the BRCA1/2 population was consistent with that of the HRR+ cohort and remained consistent with prior analyses. Safety data from the final analysis are summarized in Table: Safety Summary: Final Analysis.⁶

• Pulmonary embolism occurred in 4.7% vs 1.4% of patients in the niraparib/AAP vs placebo/AAP group, with no cases of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) in the niraparib/AAP group.
• Safety profiles across both interim analyses⁵ and the final analysis⁶ were consistent, with no new safety signals.

HRR- Cohort

Efficacy

• A prespecified futility analysis was conducted in the HRR- cohort 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.¹²
  • The composite progression endpoint (n=233) met futility criteria (HR, 1.09; 95% CI, 0.75-1.59), where futility was defined as ≥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.

Safety

• Additional grade 3/4 toxicity was observed in the niraparib/AAP vs placebo/AAP group.¹²
• 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.¹²

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 20 September 2024.