REPAIR_GETUG P16 - Relapse in previously irradiated Prostate bed: a phase I/II study of stereotactic Ablative reirradiation potentiated by Metformine study protocol

Abstract Introduction: Salvage prostatic bed radiotherapy (PBRT) is a standard in case of biochemical recurrence following radical prostatectomy (RP) for prostate cancer. The management of isolated prostatic bed recurrence following RP and PBRT is debated. Reirradiation within stereotactic body radiotherapy (SBRT) guided by metabolic imaging could be a relevant option in this case. In parallel, metformin, an economically viable and well-tolerated oral antidiabetic agent, has demonstrated its radiosensitizing properties. This phase I/II clinical trial aims to i) determine the optimal dose for SBRT reirradiation, ii) conduct safety assessments, and iii) evaluate the efficacy of the metformin and SBRT combination. Methods and Analysis: We conduct a prospective, non-randomized, open-label, multicenter, dose escalation, phase I/II study involving a minimum of 44 patients. Eligible patients must have biochemical recurrence (PSA > 0.2 ng/ml and confirmed ascending trend in at least 2 successive assays), occurring at least 2 years after PBRT and prior RP for prostate cancer (including low, intermediate, and high risk with a single risk factor) and no CTCAE grade >=3 toxicity following PBRT. The recurrence should be visible on MRI and/or PET Choline and/or PET PSMA, without evidence of pelvic lymph node recurrence or metastatic disease. The primary objective of the phase I is to determine the optimal SBRT dose (5×6, 6×6, or 5×5 Gy) based on dose-limiting toxicity (DLT). The dose will be chosen using a time-to-event continual reassessment method based on DLT, defined as CTCAE grade ≥3 gastrointestinal or genitourinary toxicity, or any other grade 4 adverse event. The primary outcome of the phase II is to estimate the efficacy of SBRT in combination with metformin in terms of biological relapse-free survival (bRFS) rate at 3 years. Secondary outcomes include 5-year bRFS rate, early/late genitourinary and gastrointestinal toxicities, quality of life, biochemical response rate, clinical progression-free survival, and overall survival. Ethics and Dissemination: Ethical approval has been obtained from the Ethics committee "SUD EST III Bron" and the National Agency for the Safety of Medicines (ANSM). The study's findings will be disseminated through publications and conference presentations.