5036 Background: ABI + P and ENZA treatments are associated with side effects that may impair QOL. ENZA has been associated with cognitive and memory impairment. There has been no direct comparison between these agents and their effect on these domains. Methods: Randomized phase II trial of ABI + P vs ENZA as 1st-line therapy for mCRPC (ClinicalTrials.gov: NCT02125357). FACT-P QOL questionnaire, patient health questionnaire (PHQ-9) and Montreal Cognitive Assessment (MoCA) were completed throughout the study. The proportion of patients with a clinically significant change in FACT-P (10 points total FACT-P score, 3 points FACT-P subscales), worsening of PHQ-9 depression symptom severity (none = 0-4, mild = 5-9, moderate = 10-14, moderate-severe = 15-19, severe ≥20) and decline in MoCA cognitive impairment level (normal = 27-30, mild = 18-26, moderate = 10-17, severe ˂ 10) at week 12 was compared between study arms for this analysis. Results: From 202 patients (pts) accrued, there were 162, 145 and 142 pts with baseline and 12-week FACT-P, PHQ-9 and MoCA assessment. Median baseline FACT-P, PHQ-9 and MoCA scores were similar in both arms. From baseline to 12 weeks, the median total FACT-P score improved in the ABI + P arm (115 to 128, P = 0.02), but there was no change in the ENZA arm (114 to 114, P = 1.00). There was a higher rate of significant worsening for the physical well-being (PWB) subscale for ENZA vs ABI + P (TABLE), but not for the other FACT-P subscales. There was a higher rate of worsening in depression severity in the ENZA arm (TABLE), although worsening to a moderate-severe/severe level occurred in only 2 patients. There was also a trend for worsening in cognitive impairment for the ENZA arm (TABLE). Conclusions: These data suggest there are distinct differences between ABI + P vs ENZA and their effects on QOL, mood symptoms and cognitive function. Clinical trial information: NCT02125357. [Table: see text]