Background: Genomic stratification may help to improve the management of patients with metastatic urothelial cancer (mUC) given the recent identification of targetable molecular alterations in this disease. However, collecting tissue samples in mUC remains challenging. We assessed the clinical utility of plasma circulating tumor DNA (ctDNA) sequencing in mUC. Methods: mUC patients were prospectively enrolled in the STING trial (NCT04932525) whereby ctDNA was profiled using the FoundationOne Liquid CDx Assay (324 genes, tumor mutational burden [TMB], microsatellite instability status). Each individual genomic report was reviewed and discussed weekly by a multidisciplinary tumor board (MTB). Actionable targets were classified by ESCAT tier leading to molecular-based treatment suggestions whenever it was possible. Results: Between January 2021 and June 2022, 140 mUC patients underwent molecular profiling. Median time to assay results was 20 days. ctDNA abundance was correlated with number of prior lines and number of metastatic sites. ctDNA analysis reproduces the somatic genomic landscape reported by previous tissue-based cohorts. Concordance for serial tumor tissue was moderate (r=0.545 CI95: [0.121-0.801], p= 0.016). At least one actionable target was detected in 63 patients (45 %) with a total of 35 actionable alterations including TMB high (≥12 mutations/Mb) (N= 39, 21.1%), FGFR3 (N= 20, 10.8%) and HRD alterations (N= 14, 7.6%). The MTB recommended a matched therapy for 63 patients (45.0%). In total, 8 patients (5.7 %) were treated with an overall response rate of 50% (95%: 15.70-84.30) and a median PFS of 5.2 months (CI95%: 4.1 - NR). FGFR3 alterations were associated with lower progression-free survival in patients treated with immunotherapy. Conclusions: Overall, our analysis demonstrates that genomic profiling with a large panel of ctDNA in mUC is a reliable and feasible approach to timely initiate genotype-matched therapies. Clinical trial information: NCT04932525.