Background
Phase III, open-label RCT. 1063 patients with cisplatin-eligible muscle-invasive urothelial bladder cancer (MIBC, cT2–T4aN0M0) planned for radical cystectomy with curative intent. Tested perioperative durvalumab (neoadjuvant + adjuvant) added to standard neoadjuvant cisplatin-based chemotherapy (ddMVAC or GC) followed by cystectomy — a perioperative immunotherapy strategy.
Interventions and follow up
Arm A: Durvalumab 1500mg IV q4wk × 2 cycles during neoadjuvant chemo, then × up to 8 cycles adjuvant post-cystectomy + neoadjuvant cisplatin-based chemotherapy (ddMVAC × 4 cycles or GC × 4 cycles)
Arm B: Neoadjuvant cisplatin-based chemotherapy alone → cystectomy → observation
Primary endpoint: Event-free survival (EFS)
mFollow up: 31.2 mo
Arm B: Neoadjuvant cisplatin-based chemotherapy alone → cystectomy → observation
Primary endpoint: Event-free survival (EFS)
mFollow up: 31.2 mo
Results
EFS: Not reached vs 46.5 mo, HR 0.68, P<.0001
OS: Not reached vs not reached, HR 0.75, P=.0106
pCR rate (ypT0N0): 37.3% vs 27.5%, P=.0028
EFS (PD-L1 high): HR 0.50; EFS (PD-L1 low/neg): HR 0.79
OS: Not reached vs not reached, HR 0.75, P=.0106
pCR rate (ypT0N0): 37.3% vs 27.5%, P=.0028
EFS (PD-L1 high): HR 0.50; EFS (PD-L1 low/neg): HR 0.79
Adverse events
Overall grade ≥3 (neoadjuvant phase): 49.2% vs 48.5% — similar
Overall grade ≥3 (adjuvant phase): 25.1% (durvalumab) vs 10.8% (observation)
Immune-mediated (adjuvant): 44.6% vs 8.2%
Endocrine: hypothyroidism (any grade) 17.9% vs 1.8%
Surgical: complication rates similar between arms (no impairment of operability)
Discontinuation of adjuvant durvalumab due to AEs: 18.1%
Overall grade ≥3 (adjuvant phase): 25.1% (durvalumab) vs 10.8% (observation)
Immune-mediated (adjuvant): 44.6% vs 8.2%
Endocrine: hypothyroidism (any grade) 17.9% vs 1.8%
Surgical: complication rates similar between arms (no impairment of operability)
Discontinuation of adjuvant durvalumab due to AEs: 18.1%
Conclusions
Perioperative durvalumab added to neoadjuvant chemotherapy significantly improved EFS and OS in cisplatin-eligible MIBC, with increased pCR rates and benefit observed across PD-L1 subgroups. NIAGARA provides the first statistically significant OS benefit in the perioperative MIBC setting with an immunotherapy-containing regimen.
Key Limitations
Key Limitations: The perioperative design (neoadjuvant + adjuvant) makes it impossible to isolate whether the benefit comes from neoadjuvant or adjuvant durvalumab — or both. Open-label design may introduce assessment bias. PD-L1-negative subgroup benefit (HR 0.79) is smaller, raising questions about biomarker selection. The adjuvant immune-mediated AE burden (44.6% any grade) is significant. Comparison to AMBASSADOR (adjuvant pembro alone, post-cystectomy) is indirect — both show DFS/EFS benefit but NIAGARA is the only trial with a significant OS result.
Clinical Context
NIAGARA (Lancet 2024) established perioperative durvalumab + neoadjuvant chemotherapy as a new standard of care for cisplatin-eligible MIBC, based on the OS result — a landmark in MIBC treatment. FDA approved durvalumab in this perioperative indication in 2025. The decision between NIAGARA approach (neoadj chemo + peri-op durvalumab) versus EV-neoadjuvant (enfortumab vedotin-based neoadjuvant, SURE SELECT data) is an active clinical and trial design debate. NIAGARA sets a new efficacy benchmark for neoadjuvant chemo-immunotherapy combinations in MIBC.
References
References: Powles T et al, NEJM 2024