Background: Enzalutamide has been approved for the treatment of CRPC in Japan since 2014. This study compared the efficacy and safety of enzalutamide + ADT and flutamide + ADT in the treatment of men with CRPC who progressed despite combined androgen blockade with bicalutamide + ADT. The sequential order of treatment was also investigated. Methods: The open-label, Phase 4 AFTERCAB study (NCT02918968) was conducted from November 2016–March 2020 in Japanese men aged ≥20 years with asymptomatic or mildly symptomatic CRPC (metastatic or nonmetastatic) and an Eastern Cooperative Oncology Group performance status of 0 or 1 who progressed despite bicalutamide + ADT. Patients were initially randomized to enzalutamide (160 mg/day) + ADT (enzalutamide first) or flutamide (375 mg/day [125 mg 3 × daily]) + ADT (flutamide first) as first-line therapy. Following prostate-specific antigen (PSA) progression, other disease progression, or discontinuation of first-line therapy due to an adverse event (AE), patients switched to the other treatment as second-line therapy. The primary endpoint was time to PSA progression with first-line therapy (TTPP1). Secondary endpoints included TTPP2 (TTPP1 + time to PSA progression with second-line therapy). AEs were monitored to assess safety. Results: 206 men were randomized, stratified by study site and disease stage. Baseline demographics and disease characteristics were similar between treatment arms. Median treatment exposure was 14.3 months (range 0.8–35.9) with enzalutamide first and 5.6 months (range 0.3–37.7) with flutamide first. 133 patients transitioned to second-line therapy (n=48 for enzalutamide first and n=85 for flutamide first). TTPP1 was significantly improved with enzalutamide first versus flutamide first; numerically longer TTPP2 was observed with enzalutamide first versus flutamide first (Table). With first-line therapy, 92.2% (n=94) of patients reported treatment-emergent AEs (TEAEs) and 28.4% (n=29) reported serious TEAEs for enzalutamide first. Corresponding numbers for flutamide first were 76.0% (n=79) for TEAEs and 14.4% (n=15) for serious TEAEs. Conclusions: Treatment with enzalutamide + ADT provided a significant improvement in time to PSA progression versus flutamide + ADT as first-line therapy. Both treatments were generally well tolerated, with AEs consistent with the known safety profiles. Clinical trial information: NCT02918968

^aLog-rank test stratified by disease stage; ^bAt 35.9 months as maximum available observation CI, confidence interval; HR, hazard ratio; NR, not reached