Immune checkpoint inhibitors (ICI) have become an integral part of the treatment of locally advanced or metastatic urothelial carcinoma (aUC).1–5 A significant minority of patients (about 15-20%) may achieve durable responses, but unfortunately, this remains the case in only this small subset of patients. Although increased tumor PD-L1 expression and the presence of a high tumor mutation burden (TMB) have been identified as putative predictive biomarkers of response to ICI,6,7 a reliable way to identify these patients is still lacking. The recent approvals of targeted therapies and novel antibody-drug conjugates have further highlighted the need for robust and readily available biomarkers to better identify those patients most likely to benefit from ICI. In the present analysis, we hypothesized that genomic profiling could be used to predict clinical outcomes in patients with aUC treated with an ICI.