Summary

• MAGNITUDE (NCT03748641) is a phase 3, randomized, double-blind, placebo-controlled, global study, evaluating the efficacy and safety of AKEEGA with prednisone as first-line (L1) therapy in metastatic castration-resistant prostate cancer (mCRPC) for patients with certain homologous recombination repair (HRR) mutations, including BRCA1/2.^1-5 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).
  • Patients were prospectively allocated to cohort 1 or 2 based on prescreening for HRR positive (HRR+) or negative (HRR-) status, respectively, and subsequently randomized to receive niraparib/abiraterone acetate with prednisone (AAP) or matching placebo/AAP.
  • Based on the results of a prespecified early futility analysis to examine outcomes in the HRR- cohort (n=233), the independent data monitoring committee (IDMC) recommended stopping enrollment in this cohort to support patient safety and prevent overtreatment.²
  • At the time of the futility analysis, patients in the HRR- cohort were evaluated for the composite progression endpoint (rPFS, prostate-specific antigen [PSA] progression, or death, whichever occurred first) (HR, 1.09; 95% CI, 0.75-1.59). There were 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) that occurred. Additional grade 3/4 toxicity was observed in the niraparib/AAP group compared with the placebo/AAP group.

CLINICAL DATA

MAGNITUDE Study

Chi et al (2023)^1,5 and Efstathiou et al (2023)⁶ 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 gene mutations. Patients were randomized 1:1 to receive niraparib 200 mg by mouth (PO) once daily or matching placebo in combination with abiraterone acetate 1000 mg PO once daily with prednisone 5 mg twice daily.

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

Abbreviations: AA, abiraterone acetate; AML, acute myeloid leukemia; AR, androgen receptor; BPI-SF, Brief Pain Inventory-Short Form; CT, computed tomography; DAT, dual action tablet; ECOG PS, Eastern Cooperative Oncology Group performance status; GnRHa, gonadotropin-releasing hormone analog; HRR, homologous recombination repair; L1, first-line therapy; mCRPC, metastatic castration-resistant prostate cancer; mCSPC, metastatic castration-sensitive prostate cancer; MDS, myelodysplastic syndrome; MRI, magnetic resonance imaging; NIRA, niraparib; nmCRPC, non-metastatic castration-resistant prostate cancer; ORR, objective response rate; OS, overall survival; PARPi, poly ADP-ribose polymerase inhibitor; PBO, placebo; PFS2, progression-free survival on first subsequent therapy; PO, orally; PSA, prostate-specific antigen; R, randomization; rPFS, radiographic progression-free survival; TCC, time to cytotoxic chemotherapy; TSP, time to symptomatic progression; TTPP, time to PSA progression.
^aNovel second-generation AR-targeted therapy such as enzalutamide, apalutamide, or darolutamide; taxane-based chemotherapy; or >4 months of AAP before randomization.

HRR- Cohort

Patient Characteristics

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 either rPFS, PSA progression, or death) occurred.²
  • The composite progression endpoint (n=233) met futility criteria (HR, 1.09; 95% CI, 0.75-1.59), where futility was defined as ≥1.
  • There were 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) that occurred.
• Additional grade 3/4 toxicity was observed in the niraparib/AAP group compared to the placebo/AAP group.²
• Based on the efficacy and safety results in patients with HRR- mCRPC, the IDMC recommended stopping enrollment in this cohort to support patient safety and prevent overtreatment.²

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 25 July 2024. Summarized in this response are relevant data limited to the phase 3 MAGNITUDE study in patients with mCRPC.