SUMMARY  

• AKEEGA is a combination of niraparib, a poly adenosine diphosphate (ADP)-ribose polymerase (PARP) inhibitor, and abiraterone acetate, an inhibitor of the enzyme 17-α-hydroxylase/C17,20-lyase (CYP17).¹
  • Niraparib is an orally available, highly selective PARP inhibitor with potent activity against the PARP-1 and PARP-2 (deoxyribonucleic acid) DNA repair polymerases.
  • Abiraterone acetate, the active ingredient of ZYTIGA, is a prodrug that is converted in vivo to abiraterone, an androgen biosynthesis inhibitor, that selectively inhibits CYP17. CYP17 is expressed in testicular, adrenal, and prostatic tumor tissues and is required for androgen biosynthesis.²
• 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).^1,3-8
  • 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)⁴:
      • 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 analysis⁸:
      • 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) at final analysis is described in Table: Safety Summary: Final Analysis (HRR+ Population). In the niraparib/AAP vs placebo/AAP group, grade 3-4 adverse events (AEs) were reported in 157 (74.1%) vs 108 (51.2%) patients and TEAEs leading to discontinuation were reported in 18.4% vs 8.1% of patients, respectively.^7,8 Safety profiles at the final analysis and second interim analysis (IA2) were consistent with those observed at IA1, with no new safety signals reported.⁷
  • Additional analyses of the MAGNITUDE study have been conducted.^9-15
• AMPLITUDE is an ongoing, phase 3, randomized, double-blind, placebo-controlled, multicenter, global study evaluating the efficacy and safety of AKEEGA plus prednisone plus androgen deprivation therapy (ADT) compared to matching oral placebo/abiraterone acetate in a dual action tablet formulation 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).^16-19 
  • The primary endpoint of rPFS in the AKEEGA with prednisone group vs placebo/abiraterone acetate plus prednisone (AAP) group was met:¹⁹ 
    • BRCAm subgroup: NE vs 26.0 months; HR, 0.52; 95% CI, 0.37-0.72; P<0.0001
    • HRRm population: NE vs 29.5 months; HR, 0.63; 95% CI, 0.49-0.80; P=0.0001
  • A summary of TEAEs is described in Table: Adverse Events. In the AKEEGA plus prednisone vs placebo/AAP group, treatment-related TEAEs and TEAEs leading to discontinuation were reported in 89% vs 74% and 15% vs 10% of patients, respectively. The most common AEs of interest were anemia (52% vs 24%) and hypertension (45% vs 33%), respectively.¹⁹ 
• ProBio (Prostate-Biomarker, NCT03903835) is an ongoing, phase 3, outcome-adaptive, multiarm, multiple-assignment, randomized, open-label, international biomarker-driven platform study in patients with de novo metastatic hormone-sensitive prostate cancer (mHSPC) or L1 mCRPC. Patients will be randomized to receive either standard of care (SOC) or an experimental treatment including abiraterone acetate or AKEEGA, based on predefined biomarker signatures. The study has a planned enrollment of 750 patients. The efficacy and safety results have not been published.^20,21

CLINICAL DATA

MAGNITUDE Study

Chi et al (2023, 2025)^4,6-8 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).^4,22
  • 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.⁴
• 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 subgroup⁶:
  • 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+ population⁶:
  • 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.⁸ 
  • 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.

Safety

• At the final analysis,⁸ 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 Table: Safety Summary: Final Analysis (HRR+ Population).

TEAEs of special interest are presented in Table: TEAEs of Special Interest: Final Analysis (HRR+ Population).

• Safety profiles across IA1, IA2, and the final analysis were consistent, with no new safety signals.⁷ 

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.^22,24
  • 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 ≥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.²²
• 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.²²

AMPLITUDE Study 

Attard et al (2025)¹⁹ reported efficacy and safety results of AKEEGA with prednisone plus ADT vs placebo/AAP plus ADT in patients with deleterious germline or somatic HRR gene-altered mCSPC (N=696).

Study Design/Methods

• Phase 3, randomized, double-blind, placebo-controlled, multicenter, global study
• The study design is presented in Figure: AMPLITUDE Study Design.
• The HRR effectors group (BRCA1/2 + BRIP1, PALB2, RAD51B, RAD54L) are prespecified for formal statistical analysis after BRCAm and prior to HRRm.
  • BRCA1/2 alterations include co-occurring BRCA1 or BRCA2 alterations.

Results

Patient Characteristics

• Patient characteristics were well balanced between the 2 groups (Table: Select Baseline Patient and Disease Characteristics – HRRm (ITT) Population).

Efficacy

• A summary of study results is provided in Table: Primary and Secondary Endpoint Results. The median follow-up was 30.8 months (data cutoff: January 7, 2025).
• Subgroup analyses by alteration type are summarized in Table: Subgroup Analysis by BRCA and non-BRCA Alterations.
• The treatment effect of AKEEGA plus prednisone vs placebo/AAP on median rPFS in the HRRm population was generally consistent across several prespecified subgroups, including patients with high-volume disease at baseline (41.2 months [events/N, 100/269] vs 26.3 months [130/271]; HR, 0.65; 95% CI, 0.50-0.85) and M1 disease at diagnosis (NE [100/301] vs 27.4 months [142/302]; HR, 0.60; 95% CI, 0.47-0.78).

Safety

• A summary of AEs reported in both treatment arms is shown in Table: Adverse Events. Other common AEs of any grade included constipation (35% vs 16%), nausea (31% vs 14%), fatigue (26% vs 18%), and arthralgia (21% each), in the AKEEGA vs PBO/AAP groups, respectively.

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 23 May 2025. Summarized in this response are relevant data pertaining to this topic in patients with prostate cancer.