Prognostic value of post-operative circulating tumor DNA (ctDNA) in real-world treatment and outcomes among patients (pts) with muscle invasive (MIBC) and locally advanced (LA) bladder cancer (BC).

4600 Background: BC has high recurrence risk despite curative intent surgery and perioperative therapy. As ctDNA guided strategies are investigated in trials, evidence from routine practice is needed to understand treatment decisions and how post-surgery ctDNA status relates to outcomes. This study evaluated real-world survival outcomes and treatment patterns by post-surgery ctDNA status among pts with MIBC/LA BC and assessed prognostic value beyond pathologic response (pCR). Methods: This retrospective study used the US-based, EHR-derived deidentified Flatiron Health Research Database (cutoff 08/31/25). Pts with MIBC or LA BC diagnosed on or after January 2015 who underwent surgery and ctDNA testing were included. Pt characteristics were summarized, including ctDNA testing patterns. Adjuvant therapy initiation was described by post-surgery ctDNA status. Real-world overall survival (rwOS) and disease-free survival (rwDFS) were estimated from the date of surgery using Kaplan–Meier methods, stratified by pCR status and post-surgery ctDNA status (results within 90 days post-surgery), and summarized descriptively with landmark survival probabilities. Results: Among 388 pts in the study population who underwent surgery and received ctDNA testing, median age at diagnosis was 70 years (IQR: 63.8-75.0); 63% received neoadjuvant therapy, 49% received adjuvant therapy, and 11% had residual disease post-surgery. Use of ctDNA testing increased substantially over time in the study cohort, from 2.6% (10/388) in 2021 to 57% (223/388) in 2025. Of ctDNA-tested pts, 97 pts had evaluable post-surgery ctDNA results (ctDNA+: 10.3% [n=40]; ctDNA–: 14.7% [n=57]). Of these, adjuvant therapy was given to 43% of post-surgery ctDNA+ pts and 35% of ctDNA− pts. The 12-month rwOS (95% CI) was 69.4% (53.8%-89.6%) for ctDNA+ vs 96.5% (91.8%-100.0%) for ctDNA–; 12-month rwDFS (95% CI) was 34.4% (20.8%-56.8%) vs 72.7% (61.2%-86.4%), respectively. Stratified by pCR, outcomes were favorable among pts achieving pCR. Although limited by small sample sizes, ctDNA status appeared to further differentiate prognosis within each stratum, particularly among pts without pCR, where ctDNA+ pts had worse rwOS (43.2% vs 100.0%, P < .01) and worse rwDFS (9.9% vs 64.2%, P = .014) over time compared with ctDNA– pts. Conclusions: Rapid growth in ctDNA testing highlights increasing clinical adoption. Post-surgery ctDNA positivity was linked to worse rwOS/rwDFS in pts with MIBC/LA BC and further stratified prognosis beyond pCR. Importantly, ctDNA may complement pathologic response in identifying pts at highest risk for recurrence and informing post-surgical management. Future work is needed to translate these findings into clinically actionable insights and treatment strategies.