5042 Background: In Asia, bicalutamide-combined androgen blockade (CAB) is widely used to treat metastatic or locally advanced prostate cancer. Enzalutamide (ENZA) shows benefits in men with metastatic and nonmetastatic castration-resistant prostate cancer (CRPC), although flutamide (FLU) is still used as an alternative anti-androgen therapy after bicalutamide-CAB. Methods: The multicenter open-label phase 2 trial OCUU-CRPC (NCT02346578) randomized patients (1:1) with CRPC after bicalutamide-CAB to ENZA (160 mg/day) or FLU (375 mg/day). Patients were stratified according to distant metastases. The primary endpoint was the prostate-specific antigen (PSA) response rate (≥50% decrease) at 3 months. The endpoints of this follow-up observational study include PSA progression-free survival of ENZA therapy (PSA-PFS-ENZA), time to treatment failure of ENZA therapy (TTF-ENZA), and overall survival (OS). Results: In total, 103 patients were randomized to ENZA (n = 52) and FLU (n = 51). Overall, 67% had distant metastases and 10% had prior radical therapy. Twenty-five (48%) and 38 (75%) patients, respectively, discontinued their assigned treatment because of progressive disease or adverse events (AEs) and were treated by standard of care. Of the 38 patients that discontinued FLU, 34 (89%) received ENZA as subsequent therapy. The median follow-up time was 14 months (ENZA, interquartile range (IQR): 9.5-24.8) and 17.2 months (FLU, IQR: 9.8-24.9). PSA-PFS-ENZA was longer in patients not treated with FLU (hazard ratio (HR), 0.29; 95% confidence interval (CI), 0.14 to 0.63; p < 0.001), but there was no significant difference in TTF-ENZA (HR, 1.27; 95% CI, 0.73 to 2.19; p = 0.397)and OS (HR, 0.77; 95% CI, 0.31 to 1.89; p = 0.567) between the two groups. The AEs of ENZA were consistent with those observed in prior phase 3 trials. Conclusions: ENZA after bicalutamide-CAB resulted in greater PSA-PFS than sequential FLU and ENZA therapy. No differences were observed in TTF-ENZA and OS between ENZA after bicalutamide-CAB and sequential FLU and ENZA therapy. Clinical trial information: NCT02346578. [Table: see text]