Feasibility and Implementation of INTERVAL-GAP4: A Global Randomised Controlled Trial of Intense Hybrid-supervised/Self-managed Versus Self-directed Exercise for Metastatic Prostate Cancer.

Background and objective: Physical activity is associated with a lower risk of mortality in men with prostate cancer (PC); yet, randomised controlled trials with survival endpoints are nonexistent. INTense ExeRcise for surviVAL-Global Action Plan 4 (INTERVAL-GAP4) was a global phase 3 trial designed to test whether structured, hybrid-supervised/self-managed exercise improves survival in men with metastatic PC. The trial was stopped early due to poor accrual. This paper reports feasibility and implementation outcomes. Methods: Men with metastatic PC were randomised (1:1) to a supervised/self-managed moderate- to high-intensity resistance and aerobic programme (three sessions per week for 2 yr) or to self-directed exercise. We evaluated site activation, recruitment, year 1 adherence, adverse events, and barriers to global trial feasibility. Efficacy outcomes-including survival, physical fitness, and biomarker results-will be reported separately. Key findings and limitations: Of 21 activated sites across seven countries, 13 (62%) randomised patients. Of 938 patients approached, 232 (25%) consented and 145 (15%) were randomised (75 in the intervention and 70 in the control group) between April 2016 and February 2023. The median age was 70 yr (range: 44-89 yr). The study closed early after reaching 17% of the intended target. The median adherence in the intervention arm was 84% (interquartile range: 61-95%), with no difference between metastatic castrate-resistant and hormone-sensitive PC. At 12 mo, 58% of intervention participants met exercise guidelines versus 24% of controls. In year 1, 162 adverse events occurred in the intervention group and 109 in the control group; 19 adverse events were study related, all in the intervention arm. The major feasibility challenges included administrative burden, infrastructure limitations, logistics of supervised exercise delivery, and coronavirus disease 2019 disruptions. Conclusions and clinical implications: While high adherence to a demanding exercise programme was achieved in selected metastatic PC patients, global recruitment proved difficult. Future large-scale exercise-oncology trials require streamlined protocols, realistic timelines, and greater alignment with site resources. Implementation science research is needed to support integration of exercise into routine advanced cancer care. A forthcoming paper will present the trial's survival and physical fitness efficacy outcomes. Patient summary: In this report, we describe the feasibility of a centrally coordinated, global clinical trial of hybrid-supervised/self-managed versus self-directed exercise for men with metastatic prostate cancer. We report trial implementation as mixed across the world, while exercise session adherence was high among men receiving the intervention. However, of the patients approached, 53% declined to participate in the study, and those enrolled were likely more motivated and willing to exercise. Those who participated varied in age, had other health conditions, were receiving multiple medications, and were at different treatment stages after a diagnosis of metastatic prostate cancer. Recent guidelines provide a framework for integrating exercise programming into clinical care for patients with advanced cancer. Further implementation science research is needed to help patients with advanced cancer exercise safely and effectively as part of their cancer care.