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Abstract Objective The objective of this retrospective study was to evaluate whether the effect of second-line therapy of flutamide after bicalutamide can predict the response to abiraterone. Results Thirty-four patients received abiraterone and 32 received enzalutamide after treatment with second-line flutamide for castration-resistant prostate cancer. Prostate-specific antigen-progression-free survival during treatment with abiraterone or enzalutamide was the endpoint. The response to flutamide therapy was defined as any decrease in prostate-specific antigen compared to baseline prostate-specific antigen. Among the abiraterone-treated patients, those for whom flutamide after bicalutamide was effective showed significantly lower prostate-specific antigen changes than those for whom it was ineffective (P = 0.0175). Prostate-specific antigen-progression-free survival was significantly higher in the abiraterone patients when flutamide was effective than in the patients when it was ineffective (P = 0.027). However, in enzalutamide-treated patients, the prostate-specific antigen changes were not significantly different between those for whom flutamide after bicalutamide was effective and those for whom it was ineffective (P = 0.75). In the enzalutamide patients, prostate-specific antigen-progression-free survival was not significantly different between those for whom flutamide was effective and those for whom it was ineffective (P = 0.92). Therefore, the response to second-line flutamide predicts the efficacy of abiraterone. This information should be helpful when choosing between abiraterone and enzalutamide for patients with castration-resistant prostate cancer.