Urinary tumor DNA (utDNA) and circulating tumor DNA (ctDNA) in patients (pts) with muscle-invasive bladder cancer (MIBC) who received perioperative durvalumab (D) in NIAGARA.

636 Background: In NIAGARA (NCT03732677), addition of perioperative D to neoadjuvant chemotherapy (NAC) and radical cystectomy (RC) demonstrated a significant improvement in event-free survival (EFS) and overall survival and a numerical increase in pathological complete response (pCR) vs NAC and RC alone in pts with MIBC. In a prior exploratory analysis, negative plasma ctDNA status after neoadjuvant treatment prior to RC (pre-RC) was associated with prolonged EFS but not pCR. Here we assess utDNA as a complementary approach in this setting. Methods: Cisplatin-eligible pts with MIBC (cT2-T4aN0/1M0) were randomized 1:1 to receive perioperative D plus NAC (cisplatin + gemcitabine) and RC (D arm) or NAC and RC alone (comparator C arm). Dual primary endpoints were EFS and pCR. Exploratory analysis of utDNA and ctDNA was completed using the personalized Signatera assay (Natera, Inc, Austin, TX, USA) at baseline (BL; n=205) and pre-RC (n=183). Results: Of 1063 pts, 265 (25%) comprised the biomarker-evaluable population (BEP; 134 D arm; 131 C arm). At BL, lower utDNA levels were associated with longer EFS (low vs high utDNA HR 0.65, 95% CI 0.40−1.04). From BL to pre-RC, utDNA+ rate decreased from 85% to 55%. utDNA clearance was associated with longer EFS (HR 0.24, 95% CI 0.09−0.62) and was 12% higher in the D vs C arm (39% vs 27%). Pre-RC utDNA status was associated with a pCR (utDNA−; 72% 55/76 vs utDNA+; 18% 17/96). Pre-RC utDNA and ctDNA status differentially correlated with disease stage at RC, with utDNA+ correlating with noninvasive disease (<T2N0M0) and ctDNA+ with invasive disease (≥T2N0M0) or systemic spread (N+ and/or M+) (Table). Estimated 24-month EFS rate was highest for pts with dual-negative status at pre-RC (utDNA− ctDNA−; 90%, 95% CI 83–97), followed by pts with utDNA+ only (utDNA+ ctDNA−; 75%, 95% CI 65–87), and was lowest for pts with dual-positive status (utDNA+ ctDNA+; 55%, 95% CI 41–75). Conclusions: This analysis suggests that lower BL levels and pre-RC clearance of utDNA are associated with better EFS and shows the addition of D to NAC increased utDNA clearance. utDNA status at pre-RC was more closely associated with pCR vs prior findings for ctDNA status. Combined pre-RC ctDNA and utDNA analysis was associated with EFS and may provide complementary insights into disease stage at RC. utDNA status could provide clinically relevant information on the primary bladder tumor, particularly in ctDNA− pts, highlighting the potential value of combining utDNA and ctDNA to inform future management of MIBC. Clinical trial information: NCT03732677 . Pre-RC utDNA and ctDNA correlation with disease stage a at RC. Status n T0N0M0 (%) <T2N0M0 (%) ≥T2N0M0 (%) T any N+ M+ (%) ctDNA− utDNA− 72 73.6 12.5 12.5 1.4 ctDNA− utDNA+ 62 24.2 30.7 37.1 8.1 ctDNA+ utDNA− 6 16.7 0.0 0.0 83.3 ctDNA+ utDNA+ 33 6.1 0.0 48.5 45.5 a By locally collected pathological assessment.