Background: Kidney cancer presenting with synchronous primary tumor and metastases has demonstrated shorter survival outcome, as compared to the patients relapsing later with metastases after nephrectomy. CARMENA trial demonstrated no change in overall survival with addition of nephrectomy to sunitinib therapy. Immune checkpoint based combination therapy has now become the standard of care in frontline setting for RCC. The role of cytoreductive nephrectomy (CN) or primary resection has not been evaluated in the setting of immune checkpoint based systemic therapy. The PROBE study design attempts to answer the question whether CN has an impact on overall survival outcomes in advanced RCC within the context of immune checkpoint based combination regimens. The underlying mechanism is that the broader antigen spread and higher neoantigen load enabled by the primary tumor would enhance the efficacy of the immune therapy. CN after initial systemic therapy will potentially enable eradication of the immune resistant clones within the primary. Methods: Eligible patients with primary tumor and metastases are treated with one of the FDA approved ICI based combinations: ipililumab and nivolumab, axitinib and pembrolizumab, or axitinib and avelumab. Cabozantinib + nivolumab and lenvatinib + pembrolizumab combinations are being added into the next amendment. Urology evaluation and response assessment is required. Randomization occurs between 10-14 weeks of therapy; 1:1 to receive CN followed by systemic therapy or to continue on systemic therapy. The primary endpoint is overall survival. We estimate the median survival from time of randomization for the non-surgical arm will be 25 months. The study hypothesis is that CN will result in improvement in OS outcomes in advanced synchronous RCC post-initial systemic immune checkpoint based combination therapy. With a sample size of 302 eligible, randomized participants (151 per arm) and a one-sided alpha = 0.025, the study has 85% power to detect a 47% improvement in median survival (HR = 0.68; 1/0.68 = 1.47) Clinical trial information: NCT04510597.