Circulating tumor DNA (ctDNA) in patients with muscle-invasive bladder cancer (MIBC) who received perioperative durvalumab (D) in NIAGARA.

4503 Background: In the phase 3 NIAGARA trial (NCT03732677) of patients (pts) with cisplatin-eligible MIBC, addition of perioperative D to neoadjuvant chemotherapy (NAC) demonstrated a statistically significant and clinically meaningful improvement in event-free survival (EFS) and overall survival compared with NAC alone, and a 10% higher pathological complete response (pCR) rate, with a manageable safety profile and no impact on the feasibility of surgery. Here, we report a planned exploratory analysis of ctDNA and association with clinical outcomes from NIAGARA. Methods: NIAGARA enrolled cisplatin-eligible pts with MIBC (cT2-T4aN0/1M0) planned for radical cystectomy (RC). Pts were randomized 1:1 to receive either neoadjuvant D (1500 mg IV Q3W) and NAC (cisplatin + gemcitabine IV Q3W) for 4 cycles followed by RC, then adjuvant D monotherapy (1500 mg IV Q4W) for 8 cycles (D arm), or NAC followed by RC alone (comparator [C] arm). Dual primary endpoints were pCR and EFS. Disease-free survival (DFS) was a secondary endpoint. Plasma ctDNA was assessed using the Signatera personalized, tumor-informed molecular residual disease (MRD) assay (Natera, Inc, Austin, TX, USA). ctDNA was assessed at baseline (screening or neoadjuvant C1D1, n = 460), after neoadjuvant treatment prior to RC (pre-RC, n = 422), and at C1D1 of the adjuvant phase (post-RC, n = 345). Results: Of 1063 randomized pts, 462 comprised the biomarker-evaluable population (237 D arm; 225 C arm). Patient characteristics were similar to the ITT population. Overall, the ctDNA+ rate at baseline was 57% (260/460) and decreased to 22% (94/422) after neoadjuvant treatment at pre-RC. ctDNA clearance rates from baseline to pre-RC were 41% in the D arm and 31% in the C arm. The non-pCR rate was 97% (86/89) among pts with pre-RC ctDNA+ status. Overall ctDNA+ rate post-RC was 9% (31/345). EFS benefit in the D arm vs the C arm was observed in both the baseline ctDNA+ and ctDNA− groups (Table). DFS benefit with perioperative D was observed in post-RC ctDNA+ and ctDNA− groups (Table). Conclusions: In this exploratory analysis, ctDNA+ status at pre-RC was associated with non-pCR. Higher ctDNA clearance from baseline to pre-RC in the D arm indicated the additional benefit of D plus NAC vs NAC alone. Perioperative D provided an EFS benefit to both pts with ctDNA+ and ctDNA− status at baseline; a similar trend was observed with DFS based on ctDNA status post-RC. These results further support the perioperative D regimen for pts with MIBC. Funding : AstraZeneca. Clinical trial information: NCT03732677 . EFS DFS Baseline ctDNA+ Baseline ctDNA- Post-RC ctDNA+ Post-RC ctDNA- D C D C D C D C n 137 123 99 101 9 8 129 126 Median (95% CI), months NR (NR–NR) 32.3(24.3–NR) NR(NR–NR) NR(NR–NR) 9.5(2.8–NR) 6.2(2.9–NR) NR(NR–NR) NR(NR–NR) Hazard ratio(95% CI) 0.73(0.51–1.06) 0.45(0.25–0.84) NC* 0.49(0.28–0.84) CI, confidence interval; NC, not calculable; NR, not reached. *NC due to <20 events between arms.