Background: Pre-clinical and retrospective clinical data support an interaction of metformin (MET) and radiotherapy. Thus, MET may represent a cost-effective means to improve radiotherapy outcomes. We sought to investigate whether MET increases time to progression (TTP) when combined with salvage radiation therapy (SRT) in men with recurrent prostate cancer after radical prostatectomy (RP). Methods: Non-diabetic men with biochemical recurrence after RP were enrolled into an open label, randomized, phase 2 study in 17 hospitals in Switzerland, France, and Germany. The randomization (1:1) was stratified by Gleason score (<8 vs ≥8), surgical margin status (R0 vs R1), PSA at randomization (PSA > 0.5 vs ≤ 0.5 ng/mL), ADT use, and evidence of local recurrence. Following randomization, patients received either prostate bed SRT (70Gy) or prostate bed SRT (70Gy) + MET. MET 850mg PO QD was given for 4 weeks before SRT, then 850mg PO QD for 48 weeks. The primary endpoint was TTP. Secondary endpoints were progression-free survival, undetectable PSA under normal testosterone levels, 50% PSA response, clinical progression-free survival, time to further systemic therapy, prostate cancer-specific survival, overall survival, and adverse events (AE). The trial design was powered for a HR 0.65 with planned enrollment of 170 patients. The trial was prematurely closed by the sponsor due to financial reasons. Data is reported after patients reached a minimum follow-up of 12 months after SRT and corresponds to the final analysis. Results: A total of 111 patients were randomized (106 evaluable) between 10/2017 and 11/2020. The median PSA at randomization was 0.3 ng/mL (range, 0.03-1.5 ng/mL), 19 patients (17.9%) had Gleason ≥8, 54 (50.9%) pT3 disease, and 50 (47.2%) positive surgical margins. Twenty-four patients (22.6%) used short-term ADT. Trial arms were well balanced. At a median follow-up of 27.1 months (95% CI: 26.7-27.8), a total of 16 progression events occurred. The median TTP was not reached in either treatment arm. The hazard ratio adjusted by stratification factors was 1.25 (95% CI: 0.40-3.94; one-sided 80% CI: 2.05; log-rank p=0.62). Two-year TTP was 89% (95% CI: 76%-96%) in the SRT arm vs 82% (95% CI: 67%-91%) in the SRT + MET arm. No statistically significant differences were found for the secondary endpoints. Most common AE during treatment was grade 1-2 diarrhea (24.1% SRT vs 54.6% SRT + MET). Grade 2 and 3 AE (gastrointestinal and/or urinary) were 25.9% and 3.7% with SRT vs 34.5% and 7.3% with SRT + MET (p=0.41 and p=0.68), respectively. Conclusions: Adding MET to SRT did not result in a significant improvement in TTP in non-diabetic men with recurrent prostate cancer post-RP. Because of early trial closure and fewer than expected events, the trial may have been underpowered for this endpoint. Additional correlative studies will be pursued. Clinical trial information: NCT02945813.