Adjustment for imbalances in baseline characteristics in the MAGNITUDE phase 3 study confirms the clinical benefit of niraparib in combination with abiraterone acetate plus prednisone in patients with metastatic prostate cancer.

BACKGROUND

MAGNITUDE (NCT03748641) demonstrated favourable outcomes with niraparib plus abiraterone acetate plus prednisone (+AAP) versus placebo+AAP in patients with BRCA1/2-altered metastatic castration-resistant prostate cancer (mCRPC). Imbalances in prognostic variables were reported between arms, which impacts estimation of both the clinical benefit and cost‑effectiveness of niraparib+AAP for healthcare systems. A pre-specified multivariable analysis (MVA) demonstrated improved overall survival (OS) with niraparib+AAP. Here, we used an inverse probability of treatment weighting (IPTW) model to adjust for covariate imbalances and assess time-to-event outcomes.

METHODS

IPTW analysis of time-to-event outcomes was conducted using data from patients with BRCA1/2-altered mCRPC (N = 225) in MAGNITUDE. Patients received niraparib+AAP or placebo+AAP. OS, radiographic progression-free survival, time to symptomatic progression, time to initiation of cytotoxic chemotherapy and time to prostate-specific antigen progression were assessed. Weighted Kaplan-Meier curves were generated for each endpoint, and adjusted hazard ratios (HR) were obtained from a weighted Cox model.

RESULTS

Improvements in survival outcomes were estimated for niraparib+AAP versus placebo+AAP: unadjusted median OS was 30.4 months versus 28.6 months, respectively (HR: 0.79; 95 % confidence interval [CI]: 0.55, 1.12; p = 0.183). Following IPTW, median OS increased to 34.1 months with niraparib+AAP versus a decrease to 27.4 with placebo (HR: 0.65; 95 % CI: 0.46, 0.93; p = 0.017). Similar improvements were observed for other time-to-event endpoints.

CONCLUSIONS

IPTW adjustment provided a more precise estimate of the clinical benefit of niraparib+AAP versus placebo+AAP in patients with BRCA1/2-altered mCRPC. Results were consistent with the pre-specified MVA, and further demonstrated the value of adjusting for baseline imbalances, particularly in smaller studies.

TRIAL REGISTRATION

NCT03748641 (MAGNITUDE).

Informations de copyright

Copyright © 2024. Published by Elsevier Ltd.

Déclaration de conflit d'intérêts

Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: GR: Received consulting or advisory role fees from Astellas, AstraZeneca, Janssen, Merck and Pfizer; research funding from Bayer; and travel, accommodations, or expense reimbursements from Janssen. GA: Received honoraria from Astellas and Janssen; consulting or advisory fees from Abbott Laboratories, Astellas, AstraZeneca, Bayer, ESSA, Ferring, Janssen, Medivation, Millennium, Novartis, Pfizer, Ventana Medical Systems and Veridex; speakers’ bureau fees from Astellas, AstraZeneca, Ferring, Ipsen, Janssen, Sanofi, Takeda and Ventana Medical Systems; research funding from Arno Therapeutics, Innocrin Pharma and Janssen; has patents or other intellectual property or received royalties for abiraterone acetate; received travel, accommodations, or expense reimbursements from Abbott Laboratories, Astellas, Bayer, ESSA, Ferring, Janssen, Medivation, Pfizer and Ventana Medical Systems; and is affiliated with the Institute of Cancer Research. MB: Received honoraria from Advanced Accelerator Applications, Amgen, Astellas, AstraZeneca, Bayer/Vital, Bristol Myers Squibb, Eisai, EUSA Pharma, Ipsen, Janssen, Merck, MSD, Novartis, Pfizer, Roche, and Sanofi/Aventis; consulting or advisory role for Astellas Pharma, AstraZeneca, Bayer, Bristol Myers Squibb, Eisai, Ipsen, Janssen, Merck, MSD, Novartis, Roche, and Sanofi; institution received research funding from Ipsen and Janssen; received travel, accommodation and expenses from Amgen, Bayer, Bristol Myers Squibb, and Janssen; employment at Janssen. DO: Received honoraria from Astellas, Bayer and Janssen; consulting or advisory role fees from AstraZeneca, Bayer, Clovis Oncology, Daiichi Sankyo, Janssen and Merck; research funding from Astellas, AstraZeneca, Bayer, Genentech/Roche, Janssen, Medivation, Merck, Pfizer and Tokai Pharmaceuticals; and travel, accommodations, or expense reimbursements from Astellas, AstraZeneca, Bayer, Ipsen, Janssen and Roche. KP: Employee of Janssen and shareholder of Johnson and Johnson. MT, LA, CC, SVS, MH: Employees of Janssen. SP: Received consultancy fees from Janssen for participation in advisory boards and general methodological advice. KC: Received honoraria from Astellas, AstraZeneca, Bayer, Janssen, Merck, and Roche; consulting or advisory fees from Amgen, Astellas, AstraZeneca, Bayer, Constellation Pharmaceuticals, Daiichi Sankyo, ESSA, Janssen, Merck, POINT Biopharma, Roche, and Sanofi; research funding from Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, ESSA, Janssen, Merck, Novartis, Pfizer, Roche, and Sanofi; and gave expert testimony for AstraZeneca and Novartis.