OBJECTIVES: Enzalutamide has a positive impact on outcomes assessed by the Functional Assessment of Cancer Therapy-Prostate (FACT-P) instrument, including slower overall decline in total FACT-P scores among patients with metastatic castration-resistant prostate cancer (mCRPC). This research aimed to describe specific benefits of enzalutamide through novel exploratory analyses of individual symptom and functioning items of FACT-P in mCRPC clinical trials. METHODS: FACT-P was administered at baseline and every 12 weeks during placebo-controlled trials of enzalutamide in chemotherapy-treated (AFFIRM) and chemotherapy-naïve (PREVAIL) mCRPC patients. Scores on FACT-P 0–4 scales were transformed to 0–100% to facilitate interpretation; higher scores indicated reduced symptoms and better functioning. Descriptive analyses were performed on change from baseline scores. RESULTS: In both trials, the impact of enzalutamide on items related to pain was relatively robust compared with other symptom items. In AFFIRM, at week 25, men receiving enzalutamide reported a median decrease (deterioration) of 3% across all FACT-P pain items, compared with a 16% decrease in those receiving placebo. Throughout both studies, enzalutamide delayed worsening in various aspects of social, physical, and emotional functioning versus placebo, including ability to work and enjoy life, worrying about dying, and feeling sad. Throughout both trials, there was little impact of enzalutamide on symptom and functioning items assessing urinary and sexual symptoms compared with placebo. CONCLUSIONS: The exploratory analysis indicates enzalutamide preserves mCPRC patients’ level of symptomatology and physical functioning, supporting overall health-related quality-of-life scores previously reported. The analyses suggest enzalutamide may prevent a progression in pain and preserve patients’ standard of living, ability to work, and emotional views of their disease. Given a lack of decline in the context of a chronic condition, patients may deem these effects as positive. Analyses of individual items are an innovative and valuable approach to interpreting treatment effects from broad patient-reported outcome measures.