PROSTVAC is a therapeutic cancer vaccine, comprises two recombinant viral vectors, each encoding transgenes for PSA, and three immune costimulatory molecules (B7.1, ICAM-1 and LFA-3). In a Phase II controlled-randomized trial, 82 patients received PROSTVAC-VF and 40 received control vectors. The primary end point was PFS, which was similar in the two groups (p = 0.6). However, at 3 years poststudy, PROSTVAC-VF patients had a better OS with 25 (30%) out of 82 patients alive versus seven (17%) out of 40 controls, longer median survival by 8.5 months (25.1 vs 16.6 months for controls), an estimated hazard ratio of 0.56 (95% CI: 0.37–0.85) and stratified log-rank p = 0.006. These provocative data provide preliminary evidence of clinically meaningful benefit to undergo PROSTVAC Phase III clinical trials. The PROSPECT study is currently recruting patients (ClinicalTrials.gov identifier: NCT01322490). The purpose of this study is to determine whether PROSTVAC alone or in combination with granulocyte–macrophage colony-stimulating factor is effective in prolonging overall survival in men with few or no symptoms from mCrPC.