Background: Genomic alterations (GA) of EGFR, are well recognized as druggable oncogenic drivers in NSCLC, but the druggable GA EGFR L858R and exon 19 deletion (ex19del), are rarely observed in genitourinary cancer. We reviewed the genomic landscape of advanced upper tract and bladder UC (UTUC and BUC) to assess the frequencies of druggable EGFR GA. Methods: Tissue specimens from patients with UTUC (407) and BUC (2,402) were assayed using hybrid capture-based comprehensive genomic profiling (CGP). Tumor mutational burden (TMB) was determined on up to 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 95 or 114 loci. Results:EGFR alterations (EGFR_alt) were present in 17 UTUC and 93 BUC (4.2% and 3.9%). Age distribution between the two subgroups was similar, but UTUC was more prevalent in female patients (47% v 29%). BUC had a higher median TMB (5.2mut/mb v 7.8 mut/mb; p = 0.046) and the prevalence of MSI-H cases was not significantly different. TERT (55% v 71%) and TP53 (59% v 74%) were the most frequently mutated genes in EGFR_alt UTUC and BUC. Within EGFRalt, amplifications were the most common alterations in both UTUC and BUC (13/17, 76%; 57/93, 61%). Amplifications were mutually exclusive from cases with EGFR short variants (SV) in BUC (0/34, 0%), and co-occurred with EGFR SV in four UTUC cases (4/8 50%). The majority of EGFR SV were EGFR exon 20 insertions (EGFR_exon20), which made up a larger proportion of EGFRalt in UTUC than BUC (7/17, 41% v 13/93, 14%; p = 0.01). Compared to other EGFR_alt, EGFR_exon20 trended towards mutual exclusivity of GA in commonly altered UC genes: TP53 (UTUC EGFR_exon20 v EGFR_alt other: 0% v 100%, p = 5.1E-5; BUC EGFR_exon20 v EGFR_alt other: 0% v 86%, p = 2.2E-7), PIK3CA (14% v 10%; 0% v 19%), RAF1 (0% v 10%; 0% v 16%), or FGFR3 (0% v 10%; 0% v 6.3%) alterations. Only 2.2% (2/93) of BUC EGFR_alt were L858R mutations and none were ex19del (0/93), while neither mutation was detected in UTUC. Conclusions:EGFR_exon20 defines a subset of UC cases, and is the most common non-amplification GA seen in EGFR in UC, with some enrichment in UTUC. Consideration should be given to developing a trial for EGFR exon20 UC patients given the recent investigational work on inhibitors with activity against EGFRexon20, such as poziotinib and TAK-788.