Durvalumab Enters the Perioperative Landscape in Muscle-Invasive Bladder Cancer: Reflections from the NIAGARA Trial and ASCO 2025 Updates
The NIAGARA trial represents a major milestone in the treatment of resectable muscle-invasive bladder cancer (MIBC), particularly in cisplatin-eligible patients. By introducing immunotherapy into both the neoadjuvant and adjuvant settings, the study addresses a longstanding gap in improving long-term outcomes for patients undergoing radical cystectomy (RC). The addition of durvalumab to standard cisplatin-gemcitabine chemotherapy demonstrates meaningful clinical and molecular benefits that now redefine the perioperative standard of care.
In this global, randomized, phase 3 trial, patients with cT2–T4a N0/1 M0 MIBC were randomized to receive either perioperative durvalumab (1500 mg IV every 3 weeks) combined with cisplatin-gemcitabine for 4 cycles followed by RC and adjuvant durvalumab (1500 mg IV every 4 weeks for 8 cycles) or standard chemotherapy followed by RC alone. The dual primary end points were pathologic complete response (pCR) and event-free survival (EFS), with disease-free survival (DFS) and overall survival (OS) as key secondary end points.
Importantly, the study permitted enrollment of patients with moderate renal impairment, allowing those with a creatinine clearance as low as 40 mL/min/1.73 m² to receive cisplatin. Randomization was stratified by renal function (40 to < 60 vs ≥ 60 mL/min/1.73 m²). Those with lower clearance (18.9% of patients) received a split-dose cisplatin regimen (35 mg/m² on days 1 and 8 every 3 weeks). This approach underscores the trial’s real-world applicability and broadens the reach of perioperative immunotherapy to patients traditionally considered marginal for cisplatin eligibility.
At the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting, updated molecular and clinical analyses reinforced the therapeutic value of perioperative durvalumab. Circulating tumor DNA (ctDNA) was evaluated using the Signatera assay in a biomarker-evaluable population (BEP) of 462 patients (237 in the durvalumab arm, 225 in the control arm) out of the 1063 total patients.
At baseline, ctDNA was positive in 57% of BEP patients. These rates declined to 22% pre-RC and 9% post-RC overall. When comparing arms, ctDNA positivity dropped from 58% at baseline to 19% pre-RC and then to 10% post-RC in the durvalumab group versus 55% at baseline to 26% pre-RC and then to 8% post-RC in the comparator arm.
In pooled analyses, ctDNA-negative patients had significantly improved EFS (hazard ratio [HR], 0.42; 95% CI, 0.30-0.60). Among patients initially ctDNA-positive, those who cleared ctDNA before RC had markedly better outcomes compared to those with persistent positivity (HR, 0.32; 95% CI, 0.22-0.47). Durvalumab improved EFS across both ctDNA strata, with ctDNA-negative patients deriving greater benefit (HR, 0.45; 95% CI, 0.24-0.84).
Patients treated with durvalumab achieved higher ctDNA clearance from baseline to pre-RC (70% vs 57%), indicating a deeper molecular response. Interestingly, pre-RC ctDNA-negative status did not correlate strongly with pCR (51% pCR vs 49% non-pCR), whereas ctDNA positivity prior to RC was associated with poor pathologic response—97% of such patients did not achieve pCR.
Post-RC ctDNA positivity, though present in only 9% of patients, was highly prognostic of worse DFS (HR, 0.09; 95% CI, 0.05-0.18). However, in this high-risk subgroup, patients in the durvalumab arm experienced a significant DFS benefit (HR, 0.49; 95% CI, 0.28-0.84).
Among ctDNA-negative patients, those who achieved pCR had superior DFS (HR, 0.41; 95% CI, 0.23-0.72). Notably, patients in the durvalumab arm had improved DFS regardless of pCR status, whether they achieved pCR (HR, 0.42; 95% CI, 0.16-1.12) or not (HR, 0.54; 95% CI, 0.28-1.03). These findings underscore the independent and additive value of immunotherapy.
In summary, ctDNA dynamics provided robust prognostic information at baseline and perioperatively. Durvalumab added to neoadjuvant chemotherapy conferred significant EFS benefit, irrespective of baseline ctDNA status. The integration of molecular monitoring enhances the understanding of therapeutic response and risk stratification.
Based on these results, durvalumab became the first immunotherapy approved by the US Food and Drug Administration for perioperative use in resectable MIBC in 2025. This approval marks a paradigm shift toward personalized oncology, where ctDNA clearance may inform future risk-adapted strategies. The NIAGARA trial not only validates the clinical efficacy of perioperative immunotherapy but also exemplifies how real-time molecular surveillance can refine treatment decisions and postoperative monitoring. This trial establishes a new benchmark, transforming durvalumab from an additive option into a foundational component of perioperative bladder cancer care.
References:
Powles T, Catto JWF, Galsky MD, et al; NIAGARA investigators. Perioperative durvalumab with neoadjuvant chemotherapy in operable bladder cancer. N Engl J Med. 2024;391(1):1773-1786. doi:10.1056/NEJMoa2408154
Powles T, Van Der Heijden MS, Wang Y, et al. Circulating tumor DNA (ctDNA) in patients with muscle-invasive bladder cancer (MIBC) who received perioperative durvalumab (D) in NIAGARA. JCO. 2025;43(suppl 16):4503. doi:10.1200/JCO.2025.43.16_suppl.4503