Résumé : Background: Declines in prostate-specific antigen (PSA) levels at 12 wk are used to evaluate treatment response in metastatic castration-resistant prostate cancer (mCRPC). PSA fall by ≥30% at 4 wk (PSA4w30) has been reported to be associated with better outcome in a single-centre cohort study. Objective: To evaluate clinical relevance of early PSA decline in mCRPC patients treated with next-generation hormonal treatments (NGHTs) such as abiraterone and enzalutamide. Design, setting, and participants: This was a retrospective multicentre analysis. Eligible patients received NGHT for mCRPC between 6 January 2006 and 31 December 2017 in 13 cancer centres worldwide, and had PSA levels assessed at baseline and at 4 and/or 12 wk after treatment. PSA response was defined as a ≥30% decline (progression as a ≥25% increase) from baseline. Outcome measurements and statistical analysis: Association with overall survival (OS) was analysed using landmark multivariable Cox regression adjusting for previous chemotherapy, including cancer centre as a shared frailty term. Results and limitations: We identified 1358 mCRPC patients treated with first-line NGHT (1133 had PSA available at 4 wk, and 948 at both 4 and 12 wk). Overall, 583 (52%) had a PSA4w30; it was associated with longer OS (median: 23; 95% confidence interval [CI]: 21–25) compared with no change (median: 17; 95% CI: 15–18) and progression (median: 13; 95% CI: 10–15). A PSA12w30 was associated with lower mortality (median OS 22 vs 14; hazard ratio = 0.57; 95% CI = 0.48–0.67; p < 0.001). PSA4w30 strongly correlated with PSA12w30 (ρ = 0.91; 95% CI = 0.90–0.92; p < 0.001). In total, 432/494 (87%) with a PSA4w30 achieved a PSA12w30. Overall, 11/152 (7%) patients progressing at 4 wk had a PSA12w30 (1% of the overall population). Conclusions: PSA changes in the first 4 wk of NGHT therapies are strongly associated with clinical outcome from mCRPC and can help guide early treatment switch decisions. Patient summary: Prostate-specific antigen changes at 4 wk after abiraterone/enzalutamide treatment are important to determine patients’ outcome and should be taken into consideration in clinical practice.