Background: PRESIDE (NCT02288247) evaluated the benefit of continued ENZA + androgen deprivation therapy (ADT) with DOC + PDN in men with mCRPC who progressed on ENZA + ADT. Methods: PRESIDE (Dec 2014–Apr 2020) enrolled chemotherapy-naïve men with mCRPC and disease progression while on a luteinizing hormone-releasing hormone (LHRH) agonist/antagonist (ADT) or after bilateral orchiectomy. Pts received open-label ENZA (160 mg) + ADT in Period 1 (P1). Those with a prostate-specific antigen (PSA) response of ≥50% change from baseline to week (wk) 13 and later progression were eligible for Period 2 (P2). P2 pts received DOC (75 mg/m²), PDN (10 mg), and ADT, and were randomized to ENZA (160 mg) or PBO. The primary endpoint was progression-free survival (PFS) in P2 (from randomization to radiographic/clinical progression or death). Secondary endpoints included time to PSA progression (TTPP) [≥25% increase; absolute increase ≥2 ng/mL] and PSA response in P2. Hazard ratios (HRs) were from a Cox proportional hazards model with covariates for treatment and P1 progression. Adverse events (AEs) were recorded to assess safety. Results: 687 pts received ENZA in P1; 273 pts were randomized and 271 were treated in P2. Baseline demographics and characteristics were balanced between P2 arms. Median ENZA exposure was 62.6 wks in P1 and 36.1 and 30.1 wks in P2 with ENZA and PBO, respectively. At P2 data cut-off (Apr 30, 2020), 269 (99.3%) pts had discontinued therapy; 93 pts in each arm (ENZA, 74.4%; PBO, 75.6%) had progression. PFS was significantly improved with ENZA (HR 0.72; 95% confidence interval [CI] 0.53, 0.96; p = 0.027), with a higher median PFS with ENZA (9.53 months; 95% CI 8.25, 10.87) than with PBO (8.28 months; 95% CI 6.28, 8.71). ENZA also significantly delayed TTPP (8.44 vs. 6.24 months with PBO; HR 0.58; 95% CI 0.41, 0.82; p = 0.002) and improved PSA response at any time (ENZA, n = 76 [55.9%]; PBO, n = 50 [37.0%]). There were 46 (6.7%) deaths in P1 and 20 (ENZA, n = 13 [9.6%]; PBO, n = 7 [5.2%]) in P2. In P2, 264 (97.4%) pts had a treatment-emergent AE (TEAE) [ENZA, n = 133 (97.8%); PBO, n = 131 (97.0%)]. Grade 3/4 TEAEs were reported by 84 (61.8%) pts on ENZA and 84 (62.2%) on PBO, and 12 (8.8%) and 9 (6.7%) pts, respectively, had TEAEs leading to discontinuation. Neutropenia (ENZA, 16.9%; PBO, 20.7%) was the most common grade 4 TEAE. Drug-related TEAEs (ENZA, 46.3%; PBO, 41.5%) were similar, and 90.4% of pts in each arm reported DOC-related TEAEs. Conclusions: Continued ENZA therapy in men with mCRPC who progressed on ENZA + ADT and received post-progression DOC + PDN significantly improved PFS compared to PBO. Treatment was well tolerated and ENZA AEs were consistent with its known safety profile. Clinical trial information: NCT02288247.