Background: Randomized data from the interferon era demonstrated survival benefits of cytoreductive nephrectomy (CN) in patients with metastatic renal cell carcinoma (mRCC). Results from SURTIME and CARMENA, conducted in the VEGF-targeted therapy era, have challenged the routine use of upfront CN in most IMDC intermediate and poor risk patients. Furthermore, the treatment landscape in mRCC now includes multiple first-line doublet combination immunotherapy approvals. The Checkmate-214 trial showed that intermediate/poor risk patients have improved overall survival and durable objective responses with ipilimumab and nivolumab (I/N) compared to sunitinib. However, patients with a primary kidney lesion in situ appeared to have less benefit than patients with prior nephrectomy. Stereotactic body radiation therapy (SBRT) provides a convenient method for cytoreduction of the primary kidney lesion and may induce an enhanced systemic anti-tumor immune response. We hypothesize that SBRT to the primary kidney mass will enhance the efficacy of I/N compared to standard of care I/N alone in this unique subset of de novo mRCC patients. We also hypothesize that the combination of SBRT and I/N will lead to upregulation of key components of immune modulation as well as unique perturbation of the host gut microbiome compared to I/N alone. Methods: This phase II trial randomizes untreated mRCC patients in a 2:1 fashion to I/N plus SBRT (30-40 Gy in 5 fractions) to the primary kidney mass between cycles 1 and 2 (experimental arm, E), versus standard of care I/N alone (standard arm, S). Eligible patients have biopsy-proven mRCC (any histology) and IMDC intermediate/poor risk disease. Patients with a primary kidney lesion ≥ 20cm, previous abdominal radiation precluding SBRT, or who have a contraindication to I/N are excluded. The primary objective is to compare the efficacy of I/N plus SBRT versus I/N alone, as determined by the hazard ratio for progression free survival (PFS). Secondary objectives include evaluation of safety, overall survival, objective response rate, and health-related quality of life. Exploratory analyses include: (1) immune and genomic profiling of liquid biopsies; (2) transcriptional profiling of baseline tumor biopsies; and (3) interrogation of the gut microbiome and bacterial functionality. Blood and fecal samples will be prospectively collected at baseline, prior to cycle 2 of each arm, and at time of disease progression or the 12-month mark, whichever comes first. Up to 78 patients will be enrolled under the assumption of an improved 12-month PFS from 50% (S) to 75% (E), using a two-sided α=0.1, power=80%, and accounting for loss-to-follow-up and stratification using IMDC criteria 1-2 vs 3-6. Trial is enrolling in Canada and Australia. Clinical trial information: NCT04090710.