Background: Prostate specific antigen (PSA) and bone scan changes are often used as components of primary endpoints in phase II trials of mCRPC. However, they do not reliably capture drug activity, as suggested by multiple phase III trials that failed to validate promising activity in phase II trials. Recently, an association between RECIST 1.0 changes and overall survival (OS) in men with mCRPC receiving docetaxel was observed. We externally validated the prognostic impact of RECIST 1.0 changes on OS. Methods: S0421 was a phase III trial in men with mCRPC men treated with docetaxel and prednisone plus either placebo or atrasentan. Individual patient data from both arms of were combined for analysis since no differences in outcomes were observed. Cox proportional hazards regression evaluated the association of RECIST outcomes within 120 days, i.e. unconfirmed partial response (PR), stable disease (SD) and progressive disease (PD) with OS from day 120. The analysis was adjusted for selected major baseline prognostic factors: hemoglobin, alkaline phosphatase, PSA, treatment arm, performance status, visceral disease, progression type, pain and Gleason score. All tests were two-sided and P≤ 0.05 was considered statistically significant. Results: Of 1038 eligible patients on S0421, 469 had measurable disease. Of these, 377 had RECIST assessments within 120 days after starting therapy. From day 120, 23 patients had PD, 230 had SD, and 73 had ≥ PR (n = 73). Median OS of was 7.1, 13.4 and 16.3 months, respectively (p = 0.004). After adjusting for baseline factors, RECIST changes remained significantly associated with OS (p = 0.002). For every 10% increase in lesion size, the hazard of dying after day 120 increased by 6.3% (95% CI: 2.3% to 10.5%, p = 0.0018), after adjusting for prognostic factors. Conclusions: This analysis provides external validation of the association of RECIST 1.0 changes with OS in men with mCRPC receiving docetaxel-based chemotherapy. Given that current imaging is increasingly detecting measurable disease, a robust and objective signal of activity represented by RECIST changes should be shown in phase II trials before launching phase III trials.