Background: The standard management of MIBC involves neoadjuvant cisplatin-based chemotherapy followed by radical cystectomy and pelvic lymph node dissection. Approximately 40% of patients with MIBC are cisplatin ineligible, the standard of care (SoC) for these patients is to proceed directly to cystectomy as there are no effective or approved neoadjuvant therapies in this setting. Only nivolumab has been approved as adjuvant treatment for patients who are at high risk of recurrence after radical resection. Given this, there remains an unmet need. D (anti–PD-L1 antibody) +T (anti–CTLA-4 antibody) have demonstrated a manageable safety profile with clinical activity in metastatic urothelial carcinoma and in a phase 2 neoadjuvant trial, D+T showed anti-tumor activity, including meaningful pathologic complete responses (pCR), in cisplatin-ineligible MIBC with high-risk features. Targeted cytotoxic antibody drug conjugates (ADCs) are known to have the potential to induce immunogenic tumor cell death, which promotes activation and recruitment of immune cells. EV is a vedotin ADC comprising an antibody against Nectin-4 linked to a microtubule-disrupting agent MMAE that has demonstrated efficacy in, and is approved for, advanced urothelial cancer. Thus, we hypothesize that EV in combination with PD-L1 inhibition, with or without CTLA-4 inhibition, may improve outcomes in patients with MIBC by downstaging of disease before cystectomy and that adjuvant therapy with D or D+T may further improve time to disease relapse. Methods: VOLGA (NCT04960709) is a phase 3, randomized, open-label, multicenter, international trial that will enroll ̃830 patients with MIBC. Eligible patients include those aged ³18 years with histologically or cytologically documented MIBC (transitional and mixed transitional cell histology), who are cisplatin ineligible and with a clinical stage of T2-4aN0-N1M0. Patients will be randomized to 3 arms to receive 3 cycles of neoadjuvant therapy Q3W as follows: (Arm 1) D (1500 mg day 1) +T (75 mg day 1) +EV (1.25 mg/kg Days 1 & 8); (Arm 2) D (1500 mg day 1) +EV (1.25 mg/kg Days 1 & 8); or (Arm 3) no neoadjuvant treatment (SoC). A safety run-in study is included. Following radical cystectomy, patients will then receive: (Arm 1) 1 cycle of T on Day 1 plus 9 cycles of D Q4W; (Arm 2) 9 cycles of D Q4W; or (Arm 3) either no adjuvant treatment (observation only) or adjuvant nivolumab in high-risk patients where available and approved (planned amendment). The dual primary endpoints are pCR and event-free survival. Secondary endpoints include overall survival, disease-free survival, pathologic downstaging rate to < pT2, disease-specific survival, quality of life, immunogenicity, and pharmacokinetics. The study is actively enrolling. Clinical trial information: NCT04960709.