Salvage prostatic bed radiotherapy (PBRT) is a standard in case of biochemical recurrence following radical prostatectomy (RP) for prostate cancer (PC). 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 radiosensitising 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.

We conducted a prospective, non-randomised, open-label, multicentre, dose escalation, phase I/II study involving a minimum of 44 patients. Eligible patients must have biochemical recurrence (Prostate Specific Antigen (PSA)>0.2 ng/mL and confirmed ascending trend in at least two successive assays), occurring at least 2 years after PBRT and prior RP for PC (including low, intermediate and high risk with a single risk factor) and no Common Terminology Criteria for Adverse Events (CTCAE) grade>=2 toxicity following PBRT. The recurrence should be visible on MRI and/or Positron Emission Tomography (PET) Choline and/or PET PSMA, without evidence of pelvic lymph node recurrence or metastatic disease. The primary objective of phase I is to determine the optimal SBRT dose (5x6, 6x6, or 5x5 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 (OS).

Ethical approval has been obtained from the Ethics committee "SUD EST III Bron" Ref.CPP 2020-042B (20.05.07.72735) and the National Agency for the Safety of Medicines (ANSM) Ref. ANSM MEDAECNAT-2020-05-00009. The ethics approval obtained covers all the sites that will take part in this study. The study’s findings will be disseminated through publications and conference presentations.

NCT04536805, Registration Date: 2020-08-17