Background: Several studies have shown that long-term bladder preservation is feasible in selected patients with muscle-invasive bladder cancer, using a multimodal treatment, including transurethral resection (TUR), radiotherapy and chemotherapy. Durvalumab, a fully human monoclonal antibody against PD-L1, has shown activity in patients with advanced pretreated urothelial cancer. A preclinical study showed that the combination of radiation, anti-CTLA4 and anti-PD-L1 overcome- adaptive immune resistance and has superior activity than either therapy alone (Twyman-Saint Victor et al. Nature 2015). The purpose of the present study is to explore feasibility, toxicity and activity in terms of response and bladder preservation of the integration of TUR, immune double checkpoint inhibition with durvalumab and tremelimumab (a fully human monoclonal antibody against CTLA-4), and radiotherapy in the treatment of localized muscle-invasive. Methods: This is a multicenter prospective phase II study of multimodal therapy in patients with localized urothelial carcinoma of the bladder in clinical stages T2-4a N0 M0, ECOG 0- 1, without contraindications to immunotherapy, who either wish for bladder preservation or are ineligible for cystectomy. The primary endpoint is pathological response (≤T1) at post-treatment biopsy. A 2-stage sequential design (response rate P0=5, P1=0.7, α=0.10, β=0.20) requires at least 6 responses in the first 12 pts to expand to a second cohort of 20 patients. The treatment consists of initial TUR of the tumor, followed by durvalumab 1500 mg i.v. plus tremelimumab 75 mg i.v., every 4 weeks for 3 doses. Normofractionated external-beam radiotherapy is started 2 weeks later, at doses of 46 Gy to the minor pelvis and 64-66 Gy to the bladder. Patients with pathological response will be candidates to bladder preservation, whereas those with residual muscle invasive tumor will be candidates to salvage cystectomy. At present time, prespecified activity goal for the first stage of accrual was met; second stage accrual began in December 2019. Clinical trial information: NCT03702179.