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Background: Enzalutamide significantly prolonged the survival of men with metastatic castration-resistant prostate cancer (PCa) after docetaxel in the randomised, phase 3, double-blind, placebo-controlled, multinational Patients with Progressive Castration-Resistant Prostate Cancer Previously Treated with Docetaxel-Based Chemotherapy (AFFIRM) trial (NCT00974311). Prostate-specific antigen (PSA) is commonly used as a marker of PCa disease burden, and the relationship of baseline PSA level to consequent treatment effect is of clinical interest., Objective: Exploratory analysis to evaluate any differences in patient characteristics and efficacy outcomes by baseline PSA level in the AFFIRM trial., Design, Setting, and Participants: Post hoc subanalysis of all randomised patients (n=1199) from the AFFIRM trial., Intervention: Participants were randomly assigned in a two-to-one ratio to receive oral enzalutamide 160 mg/d or placebo., Outcome Measurements and Statistical Analysis: The major clinical efficacy end points were overall survival (OS), radiographic progression-free survival (rPFS), and time to PSA progression (TTPP) versus placebo; baseline characteristics, treatment duration, and subsequent antineoplastic therapy were compared by baseline PSA quartile., Results and Limitations: Baseline PSA quartiles corresponded to the following PSA groups: <40 ng/ml (n=299), 40 to <111 ng/ml (n=300), 111 to <406 ng/ml (n=300), and ≥406 ng/ml (n=300). Enzalutamide consistently improved OS, rPFS, and TTPP compared with placebo across all subgroups, regardless of baseline PSA level. Hazard ratios for improvements in OS were 0.55 (95% confidence interval [CI], 0.36-0.85), 0.69 (95% CI, 0.47-1.02), 0.73 (95% CI, 0.53-1.01), and 0.53 (95% CI, 0.39-0.73) for PSA groups 1-4, respectively. The post hoc design of this analysis was not statistically powered to assess the relationship between baseline PSA and clinical efficacy outcomes., Conclusions: This post hoc analysis of the AFFIRM trial demonstrates consistent benefits in OS, rPFS, and TTPP with enzalutamide regardless of baseline disease severity, as assessed by PSA., Patient Summary: Exploratory post hoc analysis of the AFFIRM trial showed that enzalutamide improves overall survival, radiographic progression-free survival, and time to prostate-specific antigen progression compared with placebo regardless of baseline disease severity, as assessed by prostate-specific antigen., Trial Registration: ClinicalTrials.gov identifier NCT00974311., (Copyright © 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.)