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Background and Importance The European Medicines Agency recently approved new treatments such as enfortumab vedotin plus pembrolizumab (EV-Pembrolizumab) and nivolumab in combination with gemcitabine-cisplatin (Nivolumab-CT) for urothelial carcinoma (UC). Indirect comparisons between these regimens might support the therapeutic positioning of the schemes in this clinical context.Aim and Objectives To evaluate whether EV-pembrolizumab and nivolumab-CT are equivalent therapeutic alternatives (ETA) in untreated carcinoma patients with UC through an indirect comparison.Material and Methods A bibliographic search was conducted in PubMed database until September-2025. Inclusion criteria: phase III, randomised clinical trials (RCTs) involving untreated patients with unresectable locally advanced or metastatic UC. Exclusion criteria: RCTs without a comparator common to alternatives considered. Overall survival (OS) was selected as the main variable. We conducted adjusted indirect comparison using Bucher method. ESMO-Magnitude of Clinical Benefit Scale was used to define the maximum acceptable difference as a clinical non-inferiority standard Delta (∆). Selected ∆ margins were 0.70 and 1.43. To establish positioning, the criteria of the ETA guidelines were applied.Results Two RCTs were found. EV-302 trial evaluated EV-pembrolizumab vs chemotherapy (HR 0.47; 95% CI 0.38-0.58; p <0.001) and CheckMate 901 trial assessed Nivolumab-CT vs chemotherapy (HR 0.78; 95% CI 0.63-0.96; p=0.02). Chemotherapy (gemcitabine plus cisplatin) was adopted as common comparator. Limitations identified in the RCTs: follow-up (17.2 months in EV-302 trial and 33.6 months in CheckMate 901 trial), patients over 65 years of age (67.47% and 49.70%, respectively) and metastatic stage (95.20% and 85.90%, of patients). Indirect comparison obtained a value of HR 0.60 (95% CI, 0.45-0.81; p=0.0009) between EV-Pembrolizumab versus Nivolumab-CT. According to the ATE guide, these treatments presented a degree of equivalence F (probably relevant difference), since statistically significant and clinically relevant differences were found (most of the 95% CI is outside the equivalence interval).Conclusion and Relevance Our indirect comparison provides comparative efficacy data between therapeutic alternatives for untreated patients with unresectable locally advanced or metastatic UC. EV-pembrolizumab and nivolumab-CT showed clinically relevant differences and could not be considered ETA.Conflict of Interest No conflict of interest