Role of circulating tumor DNA (ctDNA) in locally advanced (LA) and metastatic urothelial cancer (mUC).

685 Background: The role of ctDNA is emerging as an adjunctive prognostic tool for survival in the laUC setting, but its role is evolving in mUC. We aimed to analyze ctDNA in the real-world setting and correlate its trend with available clinical, radiographic, and next generation sequencing (NGS) data. Methods: Patients with a diagnosis of laUC and mUC were included in the analysis of an IRB-approved protocol. Clinical/pathologic stage, systemic therapy received, NGS (TEMPUS) results, and tumor-informed detection and quantification (Signatera, Natera, Inc) was analyzed with baseline ctDNA data (positive + vs. negative -). Mean tumor molecules (MTM) levels were obtained and time to radiographic progression (TTrP), radiographic progression-free survival (rPFS) and overall survival (OS) evaluated. If baseline ctDNA was negative (ctDNA-), time to initial ctDNA+ was recorded. Analyses of time in days (d) from ctDNA- to ctDNA+ with regard to radiographic progression and OS was analyzed using Kaplan-Meier method and between group comparison by Log-rank test. Descriptive statistics were used to evaluate ctDNA trends in patients receiving various systemic therapies. Results: 47 patients (n=24 laUC; n=23 mUC) were included in analyses; 34 Male, 14 Female. The median rPFS in patients with baseline ctDNA+ was 189d. Higher baseline levels did not significantly affect rPFS (p=0.0518, HR=1.007) or TTrP (p=0.2718, HR=1.004). The median rPFS in baseline ctDNA- level was 553d. The overall TTrP was worse in mUC baseline ctDNA+ vs baseline ctDNA- (log-rank p=0.037). Median OS in baseline ctDNA+ was 266d and ctDNA- was not evaluable. Patients who received immunotherapy-based treatment or antibody-drug-conjugate based therapy had a decline in baseline ctDNA at 1 month follow up. Lack of response or clearance of ctDNA served as predictor of mortality. Of the mUC patients who had baseline ctDNA +, mortality was as high as 70% at the time of follow up. No correlation with specific NGS findings were seen. Conclusions: The use of ctDNA allowed for identification of earlier disease relapse than radiographic imaging alone which allows for earlier switch in therapeutic management. Obtaining a baseline positive ctDNA result without conversion to a negative value portends a poor prognosis in mUC.