Background: The first planned interim analysis of ENZAMET, with 243 deaths after a median follow-up of 34 months, revealed a clinically meaningful overall survival benefit in mHSPC with the addition of enzalutamide to standard of care (hazard ratio 0.67, 95% CI 0.52 to 0.86, p=0.002, Davis et al, NEJM 2019). We now present updated overall survival (OS) findings from the prespecified analysis triggered to occur after 470 deaths. Methods: We randomly assigned participants (pts) with mHSPC to treatment with testosterone suppression (TS) plus either a conventional non-steroidal anti-androgen (NSAA) or enzalutamide. Stratification factors included age, volume of disease (high vs low according to the CHAARTED definition), and planned use of concurrent docetaxel assigned by the treating physician (docetaxel yes vs no). Results: We randomized 1125 pts with a median age of 69 years, including 503 in the docetaxel stratum, and 602 with high volume metastatic disease. OS results in the table below are based on 476 deaths, a median follow-up of 68 months, and a cut-off date of 19JAN2022. The hazard rate for death was 30% lower among all those assigned enzalutamide versus control (p<0.0001). Outcomes by volume status are shown (Table) as well as the subgroups of interest with M1 high or low volume disease at diagnosis selected for concurrent docetaxel. Conclusions: Enzalutamide added to TS, compared with an active comparator of NSAA, provided clinically meaningful improvements in OS for the combined overall cohort, which persisted with an additional 3 years of follow-up. The benefits were more pronounced in pts with low volume disease, and were also seen in the subgroup with M1 high volume mHSPC despite the relatively high survival with TS+docetaxel+NSAA. ENZAMET was led by ANZUP Cancer Trials Group and the University of Sydney NHMRC Clinical Trials Centre, with funding support from Astellas. Clinical trial information: NCT02446405.