Background: The treatment for patients with metastatic RCC is evolving. The current standard of care for patients presenting with de novo metastatic disease is combination immunotherapy (IO)-based treatment. At the time of this shift in the systemic treatment strategy, the role of immediate cytoreductive nephrectomy has also been in flux. For patients with de novo disease, there has been a shift towards initiation of upfront systemic rather than immediate cytoreductive nephrectomy. SABR is a highly focused radiation technique that delivers a high dose of radiation over a limited number of fractions. The SAMURAI trial seeks to evaluate SABR as an alternative approach to treat the primary tumor in patients with metastatic RCC receiving IO, who are not recommended for surgery, or who decline surgery. Methods: This is a randomized phase II trial for patients with metastatic RCC with an intact primary tumor. Eligible patients include those with any histology RCC who are candidates to receive standard IO combination treatment and are those not recommended for upfront surgery or decline surgery. Patients will be randomized to SABR + IO combination versus IO combination alone. The primary objective of the study is to determine whether the addition of SABR to the primary tumor in combination with IO improves outcomes compared to IO alone in patients with metastatic, unresected, RCC. The primary endpoint is nephrectomy and radiographic progression-free survival (nrPFS) with progression determined as per iRECIST criteria. Patients are eligible if they are not recommended for upfront surgery, have a primary tumor treatable with SABR, and are candidates for IO. Choice of IO combination regimen will be at the discretion of the treating physician and will include either IO-IO or regimens of IO in combination with a VEGF inhibitor (IO-VEGF). 240 patients will be randomized in a 2:1 ratio favoring SABR plus IO combination (n=160) as compared to standard of care IO combination alone (n=80). The sample size will provide 90% power at a one-sided alpha level of 0.05 to detect a hazard ratio for nrPFS of 0.62, i.e., an approximate 40% reduction in the rate of events. Secondary endpoints include objective response rate by iRECIST and RECIST, radiographic progression free survival by RECIST and iRECIST, time to second line therapy, rate of cytoreductive nephrectomy, treatment free survival, and overall survival. Exploratory analyses will assess potential prognostic and predictive biomarkers. The trial is currently open and accruing through the NRG oncology cooperative group (NCT05327686) and study information can be found through the Cancer Trials Support Unit website www.ctsu.org. Clinical trial information: NCT05327686.