Background: First-line platinum-based chemotherapy followed by maintenance avelumab (Av) is the current preferred standard of care in patients (pts) with mUC who do not progress after platinum-based chemotherapy. There is an unmet need to further improve outcomes by combining Av with an effective, non-cross resistant therapy with non-overlapping toxicity. Cabozantinib (CABO) is an oral inhibitor of MET, VEGFR and TAM family receptors involved in tumor growth, angiogenesis and immune cell regulation and has shown efficacy in UC in combination with PD-1/PD-1L1 inhibitors. We hypothesize that CABO-Av combination will be synergistic in pts with mUC with an acceptable safety profile and will improve upon the benefit seen with Av maintenance in mUC. Methods: MAIN-CAV is a phase III randomized, multicenter, international trial for locally advanced/mUC pts (including N3 only disease) who do not progress after 4-6 cycles of any platinum-based chemotherapy (gem-cis, gem-carbo, MVAC or ddMVAC). 654 adult pts will be randomized 1:1 within 3-10 weeks (wk) after last dose of chemotherapy to receive Av 800 mg IV every 2 wk or combination of Av and CABO 40 mg orally daily for up to 2 yrs. Key eligibility criteria include ECOG PS 0-1, no prior use of immunotherapy (exception of BCG), no central nervous system metastases, no major surgery within 4 wk, no uncontrolled hypertension or cardiovascular disorders. Pts will be stratified based on 1) best response to 1L therapy: complete response vs partial response vs stable disease and 2) presence or absence of visceral metastases. The primary endpoint is overall survival (OS) with assumptions of one-sided alpha of 0.025, power of 80%, median OS of 21 months (mo) on Av arm and hazard ratio (HR) of 0.75, thus hypothesizing a median OS of 28 mo on CABO-Av combination arm. Key secondary endpoints include progression-free survival, safety, tolerability, and activity of CABO-Av compared to Av alone based on RECIST 1.1 and iRECIST criteria and PD-L1 status of pts’ tumors. Quality of life (QOL) will be assessed using EQ-5D-5L, PROMIS-Fatigue 4a, EORTC QLQ-C30, EORTC QLQ-BLM30 between pts on CABO-avelumab vs avelumab alone. Biomarkers of response and resistance to Av will be assessed using baseline archival tissues, baseline and serial blood, ctDNA, stool and urine. Imaging studies will test correlation of established and new radiomic signatures with OS, adverse events and QOL and incorporate both radiologic and biologic features to predict outcomes. This trial would be the first to systematically address whether adding a multitargeted TKI, CABO to Av leads to improved clinical outcomes compared to Av alone. Support: U10CA180821, U10CA180882, U24CA196171,U10CA180863 (CCTG); Clinical trial information: NCT05092958.