Background: Enzalutamide and abiraterone plus prednisolone demonstrated improvement of survival for castration-resistant prostate cancer (CRPC). However, it remains quite unclear which agent is better in terms of efficacy and safety for Asian patients. Methods: An investigator-initiated, multicenter, randomized controlled trial was conducted in Japan. CRPC patients before chemotherapy were randomly assigned to the enzalutamide or the abiraterone plus prednisolone arm (1:1). The primary endpoint is time to prostate-specific antigen (PSA) progression and secondary endpoints include PSA response rate (≥50% decline from baseline), overall survival, radiographic progression-free survival, and safety assessment. Results: Between February 20, 2015 and July 30, 2019, 203 patients were enrolled. After randomization, 92 in the enzalutamide and 92 in the abiraterone plus prednisolone arm were treated and analyzed. Time to PSA progression was not significantly different between arms (median 21.2 and 11.9 months in the enzalutamide and the abiraterone plus prednisolone arm, respectively; hazard ration 0.81, 95% CI 0.51-1.27, p = 0.1732). There was a significant difference in PSA response rate between arms (72% and 57% in the enzalutamide and the abiraterone plus prednisolone arm, respectively, p = 0.0425). There were no significant differences in overall and radiographic progression-free survival between arms (median 32.9 and 35.5months in the enzalutamide and the abiraterone plus prednisolone arm, respectively; hazard ration 1.17, 95% CI 0.72-1.88, p = 0.5290 and median 17.6 and 14.0 months in the enzalutamide and the abiraterone plus prednisolone arm, respectively; hazard ration 0.92, 95% CI 0.63-1.34, p = 0.6532). Grade ≥3 of adverse events were observed in 11% and 21% in the enzalutamide and the abiraterone plus prednisolone arm, respectively (p = 0.1044). Conclusions: Enzalutamide did not show any survival benefits compared with abiraterone plus prednisolone but showed better PSA response rate with no significant differences of severe adverse event rate for Japanese CRPC patients. Our data suggest that antecedent use of enzalutamide to abiraterone plus prednisolone have potentially clinical benefits in Asian CRPC populations. Clinical trial information: UMIN000015529.