Prognostic Implications of Personalized Circulating Tumor DNA Testing in Patients with Advanced Urothelial Carcinoma Treated with Enfortumab Vedotin ± Pembrolizumab

BACKGROUND AND OBJECTIVE: Enfortumab vedotin (EV) plus pembrolizumab (P) is the preferred first-line therapy for locally advanced or metastatic urothelial carcinoma (la/mUC); however, responses remain heterogeneous, and biomarkers are limited. We evaluated longitudinal tumor-informed circulating tumor DNA (ctDNA) as a potential real-time prognostic biomarker in patients with la/mUC initiating EV with or without P (EV±P). DESIGN, SETTING AND PARTICIPANTS: This is an exploratory, real-world retrospective, multicenter analysis of patients with la/mUC who received personalized, tumor-informed ctDNA testing (Signatera, Natera, Inc.) coinciding with their EV±P treatment. RESULTS AND LIMITATIONS: Across 545 plasma samples from 110 patients (median follow-up 60.6 weeks (wk)), baseline ctDNA was detected in 93.6% and declined or cleared within 12 wk in 75.8% and 33.9%, respectively. In all evaluated time intervals, ctDNA positivity on-treatment was consistently associated with inferior progression-free survival (PFS) and overall survival (OS) compared to ctDNA negativity (PFS 4-12 wk: hazard ratio [HR] = 10.08; p < 0.001; 12-24 wk: HR = 11.84; p < 0.001; >24 wk: HR = 6.77; p < 0.001; OS 4-12 wk: HR = 6.53; p = 0.013; 12-24 wk: HR = 7.22; p = 0.0083; >24 wk: HR = 3.81; p = 0.025) and remained independently prognostic on multivariable analyses. ctDNA dynamics relative to baseline were similarly prognostic: persistent positivity within 12 wk was associated with shorter PFS (HR = 8.96; p = 0.0004) and OS (HR = 4.58; p = 0.016), whereas early ctDNA clearance was enriched among radiographic responders (p < 0.001). Limitations include the retrospective design, non-standardized ctDNA sample collection, and heterogeneity in evaluation and treatment approaches. CONCLUSIONS: Personalized, tumor-informed ctDNA testing can indicate response to EV±P and is prognostic of survival benefit in patients with la/mUC receiving EV±P.