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Background: Patients with metastatic castration-resistant prostate cancer (mCRPC) and BRCA alterations have poor outcomes. MAGNITUDE found patients with homologous recombination repair gene alterations (HRR+), particularly BRCA1/2, benefit from first-line therapy with niraparib plus abiraterone acetate and prednisone (AAP). Here we report longer follow-up from the second prespecified interim analysis (IA2)., Patients and Methods: Patients with mCRPC were prospectively identified as HRR+ with/without BRCA1/2 alterations and randomized 1 : 1 to niraparib (200 mg orally) plus AAP (1000 mg/10 mg orally) or placebo plus AAP. At IA2, secondary endpoints [time to symptomatic progression, time to initiation of cytotoxic chemotherapy, overall survival (OS)] were assessed., Results: Overall, 212 HRR+ patients received niraparib plus AAP (BRCA1/2 subgroup, n = 113). At IA2 with 24.8 months of median follow-up in the BRCA1/2 subgroup, niraparib plus AAP significantly prolonged radiographic progression-free survival {rPFS; blinded independent central review; median rPFS 19.5 versus 10.9 months; hazard ratio (HR) = 0.55 [95% confidence interval (CI) 0.39-0.78]; nominal P = 0.0007} consistent with the first prespecified interim analysis. rPFS was also prolonged in the total HRR+ population [HR = 0.76 (95% CI 0.60-0.97); nominal P = 0.0280; median follow-up 26.8 months]. Improvements in time to symptomatic progression and time to initiation of cytotoxic chemotherapy were observed with niraparib plus AAP. In the BRCA1/2 subgroup, the analysis of OS with niraparib plus AAP demonstrated an HR of 0.88 (95% CI 0.58-1.34; nominal P = 0.5505); the prespecified inverse probability censoring weighting analysis of OS, accounting for imbalances in subsequent use of poly adenosine diphosphate-ribose polymerase inhibitors and other life-prolonging therapies, demonstrated an HR of 0.54 (95% CI 0.33-0.90; nominal P = 0.0181). No new safety signals were observed., Conclusions: MAGNITUDE, enrolling the largest BRCA1/2 cohort in first-line mCRPC to date, demonstrated improved rPFS and other clinically relevant outcomes with niraparib plus AAP in patients with BRCA1/2-altered mCRPC, emphasizing the importance of identifying this molecular subset of patients., Competing Interests: Disclosure KNC received consulting fees from Amgen, Astellas, AstraZeneca, Bayer, Janssen, Merck, Pfizer, POINT Biopharma, and Roche; and grants (to institution) from Amgen, AstraZeneca, Bayer, ESSA, Janssen, Merck, POINT Biopharma, and Roche. SS received honoraria from AstraZeneca, Bristol Myers Squibb, Janssen, Merck, and Novartis (DSM Committee Chair); and grants from AstraZeneca, Genentech, Merck, Novartis, and Pfizer. MRS received consulting or advisory fees from Amgen, Astellas, Bayer, Janssen, Eli Lilly, Novartis, and Pfizer; research funding from Bayer, ESSA, Janssen, Eli Lilly, and ORIC Pharmaceuticals; and travel, accommodations, and expense reimbursements from Amgen, Bayer, Janssen, and Eli Lilly. GA received honoraria from Astellas and Janssen; consulting or advisory fees from Abbott Laboratories, Astellas, AstraZeneca, Bayer, ESSA, Ferring, Janssen, Medivation, Millennium Pharmaceuticals, 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. MS received honoraria and consulting or advisory role fees from AstraZeneca, Astellas, Amgen, Ipsen, Johnson & Johnson, Merck, and Pfizer; grants (to institution) from Johnson & Johnson and Merck; and travel, accommodations, and expense reimbursements from Cipla, Ipsen, and Pfizer. 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, and Pfizer; and travel, accommodations, or expense reimbursements from Astellas, AstraZeneca, Bayer, Ipsen, Janssen, and Roche. EC received honoraria from Astellas, AstraZeneca, Bayer, Janssen, Merck, Pfizer, and Telix Pharmaceuticals; consulting or advisory fees from Astellas, AstraZeneca, Bayer, Daiichi Sankyo, Janssen, Merck, and Pfizer; grants (to institution) from AstraZeneca, Bayer, and Janssen; and travel, accommodations, or expense reimbursements from AstraZeneca, Bayer, Janssen, and Pfizer. GR received consulting or advisory role fees from Astellas, AstraZeneca (to institution), Bayer, Gilead (to institution), Janssen, Ipsen, and Pfizer; research funding from Bayer (to institution); honoraria for lectures/speakers’ bureau fees from AstraZeneca (to institution), Bayer, and Janssen; and travel, accommodations, or expense reimbursements from AstraZeneca, Bayer, and Janssen. AJPdSG received honoraria for lectures/speakers’ bureau fees from Adium Pharma, Astellas, AstraZeneca, Bayer, and Janssen; and travel, accommodations, and expense reimbursements from Astellas and Janssen. EJS has stock or other ownership of Fortis and Teon Therapeutics; received honoraria from Janssen and Johnson & Johnson; and received consulting or advisory role fees from Fortis and Janssen. DER received grants (to institution) from AstraZeneca, Bayer, Bristol Myers Squibb/Celgene, Promontory Therapeutics, and Taiho Pharma; consulting or advisory fees from AstraZeneca, Bayer, Bristol Myers Squibb/Celgene, Genentech, Myovant, and Promontory Therapeutics; and medical writing assistance from Genentech and Janssen. HG received consulting or advisory fees from Astellas, AstraZeneca, Ipsen, Janssen, Merck, Merck-Serono, and Pfizer; honoraria for lectures/speakers’ bureau fees from Ipsen and Merck; and received travel, accommodations, and expense reimbursements from AstraZeneca. EE received consulting or advisory fees, speakers’ bureau fees, and research funding from Astellas, AstraZeneca, Merck, Myovant Sciences, Novartis, Pfizer, and Sanofi. GEM, SD, DW, BD, KU, AdC, PF, and WK are employed by Janssen Research & Development, LLC. WJ has declared no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The first interim analysis of the phase III, randomized, double-blind, placebo-controlled, multinational TITAN study demonstrated improved overall survival (OS) and radiographic progression-free survival (rPFS) with apalutamide added to ongoing androgen deprivation therapy (ADT) in patients with metastatic castration-sensitive prostate cancer. The final analysis confirmed improvement in OS and other long-term outcomes. We evaluated prostate-specific antigen (PSA) kinetics and the association between PSA decline and outcomes in patients with metastatic castration-sensitive prostate cancer from TITAN., Patients and Methods: Patients received apalutamide (240 mg/day) or placebo plus ADT (1 : 1). This post hoc exploratory analysis evaluated PSA kinetics and decline in relation to rPFS (22.7 months' follow-up) and OS, time to PSA progression, and time to castration resistance (44.0 months' follow-up) in patients with or without confirmed PSA decline using a landmark analysis, the Kaplan-Meier method, and Cox proportional hazards model., Results: One thousand and fifty-two patients (apalutamide, 525; placebo, 527) were enrolled. Best confirmed PSA declines (≥50% or ≥90% from baseline or to ≤0.2 ng/ml) were achieved at any time during the study in 90%, 73%, and 68% of apalutamide-treated versus 55%, 29%, and 32% of placebo-treated patients, respectively. By 3 months of apalutamide treatment, best deep PSA decline of ≥90% or to ≤0.2 ng/ml occurred in 59% and 51% of apalutamide- and in 13% and 18% of placebo-treated patients, respectively. Achievement of deep PSA decline at landmark 3 months of apalutamide treatment was associated with longer OS [hazard ratio (HR) 0.35; 95% confidence interval (CI) 0.25-0.48), rPFS (HR 0.44; 95% CI 0.30-0.65), time to PSA progression (HR 0.31; 95% CI 0.22-0.44), and time to castration resistance (HR 0.38; 95% CI 0.27-0.52) compared with no decline (P < 0.0001 for all). Similar results were observed at landmark 6 and 12 months of apalutamide treatment., Conclusions: Apalutamide plus ADT demonstrated a robust (rapid, deep, and durable) PSA decline that was associated with improved clinical outcomes, including long-term survival., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)