4526 Background: Clinically advanced metastatic urothelial carcinoma (UC) is a devastating disease lacking effective systemic therapies. Herein, we present a comprehensive genomic profile-based (CGP) study of UC designed to detect clinically relevant genomic alterations (CRGA) that could inform the selection of established and novel targeted therapies. Methods: DNA was extracted from 295 consecutive cases of relapsed/metastatic UC. CGP was performed on hybridization-captured, adaptor ligation based libraries to a mean coverage depth of 688X for 236 cancer-related genes. The CGP assay included base substitutions (SUB), INDELs, copy number alterations (CNA) and fusions/rearrangements. CRGA were defined as GA linked to drugs on the market or under evaluation in mechanism driven clinical trials. Results: There were 75% male and 25% female patients with a mean age of 66 years. 295/295 (100%) of UC were high grade and advanced stage (III and IV). 294/295 (99.7%) UC had at least 1 GA on CGP with a mean of 6.4 GA...