Background: Cisplatin-containing regimens have been SoC for mUC for nearly 40 years, but durable responses are rare with such treatments. Furthermore, a large proportion of pts with unresectable/mUC are ineligible for cisplatin therapy. Treatment approaches conferring longer-term disease control and extending to broader mUC pt populations are urgently needed. Recently, the programmed death-1 (PD-1) inhibitor, nivolumab, induced durable responses in pts with unresectable/mUC progressing despite platinum-based chemotherapy, and nivolumab combined with ipilimumab (a CTLA-4 inhibitor) demonstrated acceptable safety and clinical activity. This phase 3 study will evaluate nivolumab + ipilimumab and nivolumab + SoC vs SoC in previously untreated pts with unresectable/mUC (NCT03036098). Methods: Key inclusion criteria: cisplatin-eligible and -ineligible pts with measurable disease, no prior systemic chemotherapy for unresectable/mUC, and evaluable tumor biopsy. Key exclusion criteria: active brain metastases, autoimmune disease, and prior treatment with drugs specifically targeting T-cell co-stimulation or checkpoint pathways. Cisplatin-eligible and -ineligible pts will be randomized 1:1 to arm A (nivolumab 1 mg/kg + ipilimumab 3 mg/kg every 3 weeks up to 4 doses, followed by nivolumab 480 mg every 4 weeks until disease progression or unacceptable toxicity) or arm B (gemcitabine-cisplatin or gemcitabine-carboplatin for up to 6 cycles). Additional cisplatin-eligible pts will be randomized to arm C (nivolumab 360 mg + gemcitabine-cisplatin every 3 weeks for up to 6 cycles, followed by nivolumab 480 mg) or arm D (gemcitabine-cisplatin for up to 6 cycles). Stratification factors: PD-1 ligand 1 status, cisplatin eligibility, and liver metastasis. Co-primary endpoints: overall and progression-free survival (OS and PFS) by blinded independent central review (BICR) in cisplatin-ineligible pts receiving nivolumab + ipilimumab vs SoC, and PFS by BICR in cisplatin-eligible pts receiving nivolumab + SoC vs SoC. Enrollment began March 2017 with a target of ~897 pts. Clinical trial information: NCT03036098