Background: Cisplatin-based neoadjuvant chemotherapy (CT) followed by cystectomy improves overall survival in patients (pts) with MIBC. Immune checkpoint inhibitors as single agents are approved in pts with advanced UC. Combination of both programmed cell death ligand-1 (PD-L1) and cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) checkpoints might be synergistic. Durvalumab (DU) is a selective, engineered, human IgG1 monoclonal antibody (mAb) that blocks PD-L1 binding to PD-1 and CD80. Tremelimumab (TRE) is an anti-CTLA-4 mAb of the lgG2 isotype. Pembrolizumab and atezolizumab, have shown a promising activity (including significant pathologic complete responses (pT0)) in MIBC pts candidate to cistectomy, with better results in those pts with PD-L1 overexpression. It is expected that the dual targeting of the immune system with an anti-PDL1 + antiCTLA4 such as DU and TRE in the neoadjuvant setting may improve these outcomes. In addition, the most precise selection of pts according to a molecular INF-gamma signature is intended to increase the efficacy. Methods: This is a prospective and randomized phase II, open-label study conducted in urothelial MIBC pts diagnosed of T2-T4 and/or N+ candidates to cystectomy, ECOG 0-1 and adequate organ function. Pts will be treated according to the score of a pro-inflammatory signature (PIS) determined with Nanostring technology. Pts with a low PIS will receive standard cisplatin-based neoadjuvant therapy (22 pt). Pts with a high PIS will be randomized 1:1 to receive cisplatin-based neoadjuvant therapy (22 pt) or DU 1500 mg + TRE 75 mg every 4 weeks x 3 cycles (22 pt). If more than 8 responses (pT0) are observed in first 22 pts included in DU+TRE arm, 24 additional pts will be recruited in this arm. Primary objective is to assess the antitumor activity of DU+TRE measured as pT0 rate in pts with a positive PIS. Disease free survival and safety profile will be also evaluated. Tissue, plasma and urine samples will be collected for translational studies. Clinical trial information: NCT03472274