Background: Cisplatin-based CT is the standard first-line treatment for metastatic UBC and carboplatin-based regimens are utilized for cisplatin-ineligible pts. Despite a relatively high response rate, responses are generally short-lived and almost all pts experience disease progression highlighting a major unmet medical need in UBC. Immune checkpoint blockade has shown activity in pts with CT-resistant UBC, and evidence suggests targeting both programmed cell death-1 (PD-1) and cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) checkpoints provides for non-redundant pathway blockade and synergy. Durvalumab is a selective, high affinity, engineered human IgG1 mAb that blocks programmed cell death ligand-1 (PD-L1) binding to PD-1 and CD80. Tremelimumab is an anti-CTLA-4 mAb of the lgG2 kappa isotype. In a Phase 1/2 study (NCT01693562), single-agent durvalumab showed preliminary evidence of antitumor activity across several tumor types, including UBC. Encouraging clinical activity and manageable tolerability were reported in a Phase 1b study of durvalumab + tremelimumab in NSCLC (NCT02000947). Methods: DANUBE is a randomized, open-label, multicenter, global Phase 3 study (NCT02516241) of durvalumab ± tremelimumab versus SoC CT in treatment-naïve pts with unresectable and/or metastatic UBC. Pts will be randomized 1:1:1 to receive durvalumab 1500 mg i.v. every 4 wks (q4w) for up to 12 mos; durvalumab 1500 mg i.v. q4w + tremelimumab 75 mg i.v. q4w for 4 doses, followed by durvalumab 1500 mg i.v. q4w for up to 12 mos; or SoC (cisplatin + gemcitabine or carboplatin + gemcitabine) for up to 6 cycles. Pts will be stratified according to cisplatin eligibility, PD-L1 status (PD-L1⁺: ≥ 25% tumor membrane or tumor-associated immune cells stained), and visceral metastasis. The primary endpoint is PFS using investigator assessment (RECIST v1.1). Secondary endpoints include OS; proportion of pts alive and progression free at 12 mos, ORR, DOR, and DCR using investigator assessment; time to second progression; HRQOL; PK; immunogenicity; and safety and tolerability. Recruitment is ongoing. Clinical trial information: NCT02516241