Biochemical Recurrence Irradiation or Observation ( <scp>BRIO</scp> ) in patients with prostate cancer: protocol for a randomised control trial

BACKGROUND: The optimal management of biochemical recurrence (BCR) after radical prostatectomy (RP) remains controversial, particularly in the absence of clinical or radiographic evidence of disease. Salvage radiotherapy (SRT) remains standard of care, but it is unclear whether SRT benefits patients when modern imaging with a multiparametric magnetic resonance imaging (mpMRI) and prostate-specific membrane antigen-positron emission tomography/computed tomography (PSMA-PET/CT) are negative for local recurrence. Retrospective data comparing SRT to observation for such patients is fraught with selection bias, underscoring the need for a prospective randomised controlled trial. STUDY DESIGN AND METHODS: The Biochemical Recurrence Irradiation or Observation (BRIO) is a randomised study under the DIVINE trial framework (NCT06378866) enrolling men with BCR (prostate-specific antigen [PSA] level ≥0.2, up to 1.5 ng/mL) after RP with no radiographic evidence of recurrence on mpMRI and PSMA-PET/CT. Major inclusion criteria include age ≥18 years, biochemically recurrent prostate cancer after RP with a PSA level between 0.2 and 1.5 ng/mL, and no local or metastatic recurrence on imaging. A total of 312 patients will be enrolled. Participants are randomised 1:1 to standard-of-care SRT followed by surveillance (Group A), or initial observation with subsequent image-guided therapy at radiographic progression (Group B). Based on historical analysis, a total of 30 metastasis events provides 80% power to detect a significant improvement (hazard ratio 0.5 corresponding to a 5-year metastasis-free proportion of 80.7% in the control group and 89.8% in the experimental group with one-sided type I error rate of 0.15). All participants undergo baseline blood collection to measure prostate cancer-extracellular vesicles and cell-free DNA for biomarker development. Participants are followed in a 16-week cycle with serial PSA measurements, repeat imaging if PSA doubles, safety assessment, and patient-reported outcomes. ENDPOINTS: The primary endpoint is distant recurrence-free survival at 5-years using a 12-month landmark to mitigate bias arising from differing assessment schedules for patients receiving optional 6 months of androgen deprivation therapy. Key secondary outcomes include time to hormone therapy, quality of life measures, adverse effects, and novel blood and urine biomarkers. CONCLUSION: The BRIO study will clarify the clinical benefit of immediate SRT vs observation with image-guided intervention in mpMRI and PET-negative BCR after RP.