Abstract : Abiraterone acetate (ABI) and enzalutamide (ENZ) are considered as clinically relevant comparators among chemotherapy-naïve castration-resistant prostate cancer patients. No clinical trials comparing overall survival (OS) of ABI to ENZ in a head-to-head approach have been published so far. A few observational studies with lack of power suggested a potential benefit of ENZ. Among chemotherapy-naïve castration-resistant prostate cancer patients, we used the French National Health Data System ('SNDS'), to compare OS of new users of ABI and ENZ in 2014-2017, followed through 2018 (the SPEAR cohort, a 2014-2018 cohort study). With an "intent-to-treat" approach, a survival analysis was performed, estimating hazard ratios (HRs) for OS with the inverse probability weighted Cox model method. Among 10 308 new users, 64% were treated with ABI, 36% with ENZ. The crude mortality rate was 25.2 per 100 person-years, 95% CI: 24.4, 26.0 for ABI and 23.7 per 100 person-years, 95% CI: 22.6, 24.9 for ENZ. In the weigthed analysis, ENZ was associated with better OS compared to ABI (HR 0.90, 95% CI: 0.85,0.96; median OS, 31.7 months for ABI and 34.2 months for ENZ). When restricting to 2015-2017 new users, the effect estimate shifted up to HR 0.93, 95% CI: 0.86, 1.01.