Metastasis-directed radiotherapy (MDRT) for men with de novo, oligometastatic prostate cancer treated with long-term androgen deprivation therapy in the STAMPEDE trial (METANOVA): protocol for a multicentre, phase II randomised controlled trial in the USA.

Introduction: Prostate cancer (PCa) is the most commonly diagnosed cancer in men worldwide. A rising proportion of men present with de novo metastatic disease, a state associated with poor survival outcomes and limited curative treatment options. Within this group, a subset of patients exhibit oligometastatic disease, defined by a limited number of metastases, which may represent a distinct clinical entity with potential for long-term disease control. Emerging evidence suggests that metastasis-directed radiotherapy (MDRT), including stereotactic body radiation therapy (SBRT), may improve progression-free survival in this population. However, current evidence is largely limited to phase II trials in the metachronous setting and retrospective studies in the synchronous setting. Furthermore, predictive biomarkers of treatment response in these patients remain undefined. We aim to evaluate, within a large randomised multicentre phase II trial, the efficacy and biological impact of MDRT in men with de novo oligometastatic PCa.

Methods and analysis: Patients with de novo oligometastatic hormone-sensitive prostate cancer (omHSPC), defined as up to 10 sites of metastatic disease by prostate-specific membrane antigen (PSMA) positron emission tomography (PET)/CT or up to five sites of metastatic disease by conventional imaging, are randomised (1:1) to standard of care (SOC) or SOC plus MDRT. SOC includes 12 months of androgen deprivation therapy plus an androgen receptor pathway inhibitor, with definitive treatment to the prostate by radiotherapy (RT). A predefined subset is allowed to undergo radical prostatectomy if clinically appropriate. MDRT involves SBRT to all metastatic sites identified on conventional imaging or PSMA PET/CT. Target enrolment is 200 patients, stratified by diagnostic imaging modality, number of bone metastases, plan to MDRT all sites of metastases and local therapy approach.Prostate RT may be delivered using moderate (20 fractions) or ultra-hypofractionation (five fractions), with optional simultaneous-integrated-boost to dominant intraprostatic lesions. MDRT regimens aim for a biologically effective dose ≥100 Gy (α/β=1.5) using 1-5 fractions. Gross tumour volumes are delineated based on MRI, CT and PSMA PET/CT.The primary endpoint is failure-free survival, defined using cause-specific PCa death. The study is powered at 80% to detect a HR of 0.58 using a one-sided alpha of 0.05. Secondary endpoints include radiographic progression-free survival, overall survival (OS), time to next intervention, time to castration-resistant PCa, PCa-specific mortality and patient-reported outcomes. Biospecimen collection and imaging data will support future translational analyses. Data from this trial is preplanned to be pooled with the STAMPEDE 2 (NCT06320067) trial, a phase III randomised trial to assess OS benefit of MDRT in men with de novo omHSPC.