Background: In Asia, including Japan, combined androgen blockade (CAB) therapy with bicalutamide is widely administered for metastatic prostate cancer. Alternative anti-androgen therapy (AAT) with flutamide after CAB therapy with bicalutamide was common before the androgen receptor-targeted therapy era. The objective of the OCUU-CRPC study was to compare the efficacy and safety between second-line hormonal therapy of enzalutamide and flutamide as alternative AAT after CAB therapy that included bicalutamide in patients with CRPC. Methods: A total of 104 patients with CRPC with or without distant metastases after disease progression who received CAB therapy with bicalutamide were randomly assigned at a 1:1 ratio according to distant metastases to the enzalutamide (160 mg/day) and flutamide (375 mg/day) groups. The primary endpoint for the drug efficacy was the response rate of prostate-specific antigen (PSA; i.e., declined by ≥50%) at 3 months. Results: Between January 2015 and February 2018, 103 patients were randomly assigned, 52 to enzalutamide and 51 to flutamide. 25 (48%) and 38 (75%) patients, respectively, discontinued their assigned treatment before study end, mainly due to progressive disease. Median follow-up time was 13.4 months (IQR 9.6–23.8) in the enzalutamide group and 17.0 months (9.7–24.4) in the flutamide group. Enzalutamide resulted in significant improvements in the response rate of PSA at 3 months (84.6% vs 31.4%; p< 0.001). Enzalutamide significantly improved in all secondary endpoints: the PSA progression rate at 3 months (HR, 0.17; 95% CI, 0.05 to 0.47; p< 0.01) and at 6 months (HR, 0.22; 95% CI, 0.09 to 0.50; p< 0.01); and PSA response rate at 6 months (75.0% vs 29.4%; p< 0.01); and time to PSA progression (median: not reached vs 6.6 months; HR, 0.29; 95% CI, 0.15 to 0.54; p< 0.01). The observed adverse event profile was consistent with that from phase III enzalutamide trials. Conclusions: Enzalutamide significantly reduced risk of progression compared with flutamide in patients with CRPC after CAB therapy with bicalutamide. This trial is registered with ClinicalTrials.gov, number. Clinical trial information: NCT02346578