NIAGARA Trial: Perioperative Durvalumab for MIBC (Full Video)
Key Points
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Based on the NIAGARA trial, the FDA approved perioperative durvalumab plus neoadjuvant chemotherapy and radical cystectomy for eligible patients with muscle-invasive bladder cancer (MIBC).
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NIAGARA analyses showed that adding durvalumab improved event-free survival (EFS) and overall survival (OS), regardless of pathologic complete response (pCR) status.
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Lack of circulating tumor DNA (ctDNA) clearance was significantly associated with lack of pCR.
Expert Insights From the NIAGARA Trial
Based on the NIAGARA trial, the FDA approved perioperative durvalumab with neoadjuvant cisplatin-based chemotherapy and radical cystectomy for MIBC. The NIAGARA regimen is now the standard of care for cisplatin-eligible patients with MIBC who are fit for surgery.
At the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting, Rahul Gosain, MD, MBA, of Wilmot Cancer Institute, and Rohit Gosain, MD, of Roswell Park Comprehensive Cancer Center, met with Joshua Meeks, MD, PhD, of Northwestern Medicine; Karine Tawagi, MD, of University of Illinois Cancer Center; Neal Shore, MD, FACS, of Carolina Urologic Research Center; and Petros Grivas, MD, PhD, of Fred Hutchinson Cancer Center and UW Medicine, to discuss the impact of the trial.
Primary NIAGARA Trial Outcomes
In the phase 3 NIAGARA trial, 533 patients were randomized to neoadjuvant durvalumab and gemcitabine plus cisplatin every 3 weeks for 4 cycles, followed by radical cystectomy and adjuvant durvalumab every 4 weeks for 8 cycles. The comparison arm included 530 patients randomized to neoadjuvant gemcitabine plus cisplatin followed by radical cystectomy alone.
In the initial publication, the estimated 24-month EFS was 67.8% (95% CI, 63.6-71.7) in the durvalumab arm versus 59.8% (95% CI, 55.4-64.0) in the comparison arm (hazard ratio [HR], 0.68; 95% CI, 0.56-0.82; P < .001). The estimated 24-month OS was 82.2% (95% CI, 78.7-85.2) in the durvalumab arm versus 75.2% (95% CI,71.3-78.8) in the comparison arm (HR, 0.75; 95% CI, 0.59-0.93; P = .01).
“It’s very exciting to show OS data and benefit with an agent in the [perioperative] setting because we know it’s a high bar, and the previously conducted trials in the purely adjuvant setting… have not as of yet shown a conclusive OS benefit,” said Dr. Grivas.
Additional and Exploratory NIAGARA Analyses
An update presented at the 2025 ASCO Genitourinary Cancers Symposium reported that the addition of durvalumab reduced the risk of distant metastases or death by 33% (HR, 0.67; 95% CI, 0.54-0.83; P < .001) compared with neoadjuvant chemotherapy and cystectomy alone. Additionally, the analysis showed that 37% of patients in the durvalumab arm achieved pCR at the time of surgery, compared with 28% in the comparison arm.
In patients with pCR, the 24-month EFS rates were 92% (95% CI, 87-95) and 86% (95% CI, 79-91; HR, 0.58; 95% CI, 0.33-1.00) and the 24-month OS rates were 96% (95% CI, 92-98) and 91% (95% CI, 85-95) in the durvalumab and comparison arms, respectively. In patients without a pCR, the 24-month EFS rates were 53% (95% CI, 48-59) and 50% (95% CI, 44-55; HR, 0.77; 95% CI, 0.63-0.95) and the 24-month OS rates were 74% (95% CI, 69-79) and 69% (95% CI, 64-73; HR, 0.84; 95% CI, 0.66-1.07) in the durvalumab and comparison arms, respectively.
In MIBC and other cancers, the necessity of adjuvant immunotherapy is unclear, especially in patients who achieve pCR with neoadjuvant treatment and surgery. The improved survival outcomes, regardless of pCR status in NIAGARA, suggest a benefit from adjuvant durvalumab, though the question of whether some patients could forego adjuvant therapy remains, said Dr. Tawagi.
The Impact of ctDNA Status in NIAGARA
Available data indicate that ctDNA is a highly prognostic biomarker, though its value for predicting immunotherapy benefit remains uncertain. The 2025 ASCO Annual Meeting presentation from NIAGARA covered an exploratory analysis of associations between ctDNA and clinical outcomes in evaluable patients. Included patients had plasma ctDNA assessed at baseline (n=460), after neoadjuvant treatment before surgery (n=422), and at the start of adjuvant therapy (n=345).
Overall, the ctDNA-positive rate was 57% at baseline, 22% presurgery after neoadjuvant treatment, and 9% postsurgery. The rate of ctDNA clearance from baseline to presurgery was 41% in the durvalumab arm versus 31% in the comparison arm. Notably, 86 of 89 patients (97%) who were ctDNA-positive pre-surgery did not achieve a pCR.
NIAGARA Takeaways for Clinical Practice
NIAGARA showed that neoadjuvant durvalumab did not compromise the ability of patients with MIBC to receive radical cystectomy, which has not been the case for perioperative approaches in other disease sites, said Dr. Rahul Gosain. Nonetheless, the panel emphasized that using the NIAGARA regimen requires multidisciplinary coordination between urologists and medical oncologists to maximize the benefit of neoadjuvant therapy and determine when patients are sufficiently recovered from surgery to start adjuvant therapy.
A follow-up trial, NIAGARA-2, aims to optimize the neoadjuvant chemotherapy backbone component by comparing the two approved regimens, gemcitabine plus cisplatin and dose-dense MVAC (methotrexate, vinblastine, doxorubicin, and cisplatin).