Background: Salvage radiotherapy (SRT) is as a potentially curative treatment for prostate cancer (CaP) patients presenting biochemical relapse after radical prostatectomy (RP). Metformin is a well-known antidiabetic drug that has demonstrated anti-cancer and radio-sensitizing effects. We aim to study whether metformin combined with SRT will improve cancer control by prolonging time to progression (TTP). Methods: This is a multicenter, randomized (1:1) phase II trial of SRT (70Gy/35fr to the prostate bed) with or without metformin (850mg BID for 52 wks) (NCT02945813). Metformin 850mg q.d. is started 4 wks prior to SRT. Stratification variables include Gleason score, PSA at randomization, surgical margin status and ADT use (allowed if PSA > 0.5, R0, post-RP PSA-DT < 6 mos or pT3b). Major eligibility criteria include: histologically proven CaP adenocarcinoma pT2a-3b, pN0 or cN0, M0; RP > 12 wks before registration; PSA progression after RP defined as 2 consecutive rises with final PSA > 0.1 ng/mL or 3 consecutive rises; and PSA ≤ 2 ng/mL within 14 days prior to registration. A sample size of 170 patients (85 per arm) is planned based on the primary endpoint TTP. Using a type I error of 5% and a power of 80%, 62 events are needed to show superiority of the treatment arm under the alternative hypothesis that the hazard ratio (HR) is 0.65 (TTP at 18 mos of 80% in the control arm vs. 86.5% in the treatment arm). All efficacy endpoints will be analyzed based on the full analysis population. The treatment effect will be assessed using Cox regression with the treatment arm as independent variable and the stratification factors as strata. Correlative studies including prostate tissue, blood (metabolic parameters), saliva and feces (microbiota) will be performed. Conclusion: Centers in Switzerland, Germany and France (GETUG) will recruit patients for this study. If positive, these results could help elucidate the role of metformin in CaP and determine the design of a subsequent phase III trial. Clinical trial information: NCT02945813