OBJECTIVES: PROs are used in prostate cancer clinical trials to measure therapeutic impact. We explored the temporal relationship between changes in PROs and subsequent clinical outcomes in chemotherapy-naïve mCRPC. METHODS: COU-AA-302 was a multinational, double-blind, randomized phase 3 trial of abiraterone acetate plus prednisone compared with prednisone alone in asymptomatic or mildly symptomatic mCRPC patients without previous chemotherapy. Using data from the entire  COU-AA-302 patient population (N = 1088) over the first 181 days of treatment, we explored the relationships between clinical time-to-event end points and changes in PROs measuring pain, physical well-being (PWB), functional well-being (FWB), and prostate cancer–specific signs and symptoms. Cox regression models were developed to assess the relationship between each PRO (separately and for all 4 simultaneously), and radiographic progression-free survival (rPFS) as the dependent variable, adjusting for important baseline clinical and PRO characteristics. RESULTS: In each individual model, patients with worsening PROs were at greater risk of radiographic progression compared with patients whose PRO scores improved or remained stable during the follow-up period. Hazard ratios (95% confidence intervals) for worsening pain intensity, PWB, FWB, and prostate cancer–specific symptoms were 1.68 (1.28-2.21), 2.08 (1.60-2.71), 1.35 (1.04-1.74), and 1.52 (1.18-1.95), respectively (all p ≤ 0.02). When all 4 PRO end points were included in a single multivariate model, a worsening in PWB was the most significant factor associated with worse rPFS. There were too few events at the time of analysis cutoff to explore the relationship between survival and PROs. CONCLUSIONS: These results demonstrate a significant temporal relationship between PROs and disease progression. Worsening of PROs was associated with an increased likelihood of radiographic progression. In addition to their traditional utility in describing patient-relevant outcomes in clinical trials, PROs may be valuable clinical monitoring tools when following patients for disease progression.