Background: MIBC is a systemic disease as >40% of patients (pts) ultimately develop recurrence after radical cystectomy (RC). For pts who cannot receive or refuse cisplatin-based chemotherapy there is no standard-of-care neoadjuvant therapy. Single-agent pembrolizumab, given neoadjuvantly in patients with T2-4N0M0 MIBC, documented a 42% pathologic complete response-rate (ypT0N0) in our previous trial (PURE-01, NCT02736266). However, there is a huge proportion of pts who do not benefit from single-agent immune-checkpoint inhibitors (ICI). SG is an antibody-drug conjugate (ADC) composed by a humanized anti-Trop-2 antibody, SN-38 payload (a parent compound of irinotecan), and a hydrolysable linker for SN-38 release. Based on preliminary data from TROPHY-U-01 trial, SG got fast-track designation for urothelial carcinoma (UC) by the United States Food and Drug Administration (US-FDA). In SURE trial we aim to evaluate the efficacy of neoadjuvant SG either as a single-agent (SURE-01) or combined with pembro (SURE-02), before RC. Methods: This phase II, open-label trial will test the safety, tolerability, activity, of SG and SG+Pembro. This study will enroll pts sequentially in the 2 cohorts. Pts should have a histopathologically-confirmed predominant UC, be fit and planned for RC, have a clinical stage T2-T4N0M0 MIBC, be ineligible (Galsky criteria) or refuse to receive cisplatin-based chemotherapy. Eligible pts will receive 4 cycles of 10 mg/Kg SG IV, on days 1, 8, of each 21 day cycle (SURE-01) and SG plus Pembro on day 1, every 21 days, at the standard dose of 200 mg intravenously (SURE-02). Surgery is planned at the time of study inclusion to be performed within 2 weeks of the last dose of study drug. After surgery patients will be managed and the surgical safety data will be recorded according to the European Association of Urology (EAU) guidelines. In SURE-02, an adjuvant phase of 13 postoperative cycles of pembrolizumab will be administered. The primary endpoint of the study is to assess the proportion of ypT0N0. The total sample size of SURE is of 77 pts, distributed as 56 pts in SURE-01 and 48 in SURE-02. The assumptions include a ypT0N0 ≤20% as H₀ and ≥45% as H₁ in a single-stage A’Hern’s design for SURE-01 and a 2-stage design for SURE-02 assuming a ypT0N0 ≤30% as H₀ and ≥45% as H₁. In SURE-02 a safety lead-in phase will be conducted including 10 subjects. An external Review Committee will evaluate the safety outcomes in this phase and the occurrence of pre-defined study-limiting events. Biomarker analyses will include assessment of transcriptomic clustering, immune-gene signature, next generation sequencing on tumor circulating tumor DNA (ctDNA), including single-cell RNA sequencing on frozen tumor samples, before and after treatment. Clinical trial information: 2020-004844-27.