NIAGARA: ctDNA analysis highlights durvalumab’s impact in MIBC

Findings of an exploratory analysis of the phase 3 NIAGARA trial (NCT03732677) evaluating perioperative durvalumab (Imfinzi) plus neoadjuvant chemotherapy (NAC) with radical cystectomy vs NAC with radical cystectomy alone appear to support the utility of circulating tumor DNA (ctDNA) as a biomarker in the neoadjuvant setting.¹

The findings also lend further credence to this muscle-invasive bladder cancer treatment regimen, investigators reported at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, Illinois.

Thomas B. Powles, MBBS, MRCP, MD

“Essentially, what we showed was, at all points, ctDNA was really strongly prognostic. We also showed quite high levels of ctDNA clearance, and these levels of ctDNA clearance were higher when you added durvalumab to neoadjuvant chemotherapy,” said Thomas B. Powles, MBBS, MRCP, MD, director of the Barts Cancer Centre at St. Bartholomew’s Hospital in London, United Kingdom.

During his ASCO 2025 presentation, Powles provided a summary of NIAGARA, the results of which were published in The New England Journal of Medicine. The investigators reported that perioperative durvalumab plus NAC with radical cystectomy vs NAC with radical cystectomy alone was associated with improved event-free survival (EFS) (HR=0.68; 95% CI: 0.56-0.82, P <. 0001) and overall survival (HR=0.75; 95% CI: 0.59-0.93, P = .0106), a pathological complete response rate of 37.3% vs 27.5%, radical cystectomy rates of 88% vs 83%, and a tolerable and manageable safety profile.² The FDA approved neoadjuvant durvalumab in combination with gemcitabine and cisplatin, followed by adjuvant durvalumab monotherapy following radical cystectomy, for adult patients with muscle-invasive bladder cancer on March 28, 2025.³

“There's been increased attention to circulating tumor DNA recently,” said Powles, although he noted that much of the data reported to date have been in the adjuvant setting as opposed to the neoadjuvant setting.

Powles explained that ctDNA was assessed with the Signatera assay, and it was measured at baseline (prior to therapy), after NAC/prior to cystectomy, and following cystectomy. Of 1063 patients in NIAGARA’s intent-to-treat (ITT) population, the total biomarker evaluable population (BEP) was 462, and then 460 at baseline, 422 pre-cystectomy, and 345 post cystectomy. Compared to the ITT population, the baseline characteristics of the BEP were found to be generally similar. More patients (95) in the BEP underwent cystectomy compared with the ITT population (86).

Powles reported a decrease of ctDNA-positivity through the course of the study. At baseline, 57% of the BEP was ctDNA-positive; after NAC, 22% was ctDNA-positive; and 9% was ctDNA-positive following cystectomy. For the durvalumab arm, these figures were 58%, 19%, and 10%, respectively, whereas in the comparator arm the rates were 55%, 26%, and 8%, respectively.

According to Powles, at baseline, ctDNA detection was prognostic for EFS (HR=0.42; 95% CI: 0.30-0.60). Treatment with durvalumab appeared to confer EFS benefit to patients regardless of ctDNA status, with an HR of 0.45 (95% CI: 0.24-0.84) for ctDNA-negative patients and 0.73 (95% CI: 0.51-1.05) for ctDNA-positive patients.

The investigators also assessed ctDNA clearance rate, with Powles reporting a rate of ctDNA clearance from baseline to pre-cystectomy of 70% in the durvalumab arm vs 57% in the comparator arm. In addition, EFS was better in patients who cleared ctDNA pre-cystectomy (HR=0.32; 95% CI: 0.22-0.47).

Fifty-one percent of patients who were ctDNA-negative prior to cystectomy achieved a pathological complete response, indicating that ctDNA-negative status was not associated with pathological complete response. By contrast, 3% of patients who were ctDNA-positive prior to cystectomy achieved a pathological complete response, indicating that “ctDNA+ status was highly correlated with non-[pathological complete response],” according to the investigators.

Following cystectomy, ctDNA detection was found to be prognostic for disease-free survival.

“10% of patients were ctDNA-positive at this time point. So the vast majority, 90%, are ctDNA-negative. Clearly, being ctDNA-positive post-neoadjuvant chemotherapy and cystectomy, with or without durvalumab, is a bad thing. And indeed, when you look at the impact of durvalumab in these 2 populations, particularly that 90% of patients who are ctDNA-negative, as you would expect, because it's 90% of the population, those patients are benefiting from durvalumab, with a hazard ratio of 0.49,” Powles said.

Powles also reported that in ctDNA-negative patients, DFS prognosis was better for patients with a pathological complete response.

“We've shown the Signatera assay is associated with a 57% ctDNA positivity at baseline, dropping to 22%, post-neoadjuvant chemotherapy/pre-cystectomy, and then down to about 10% post-cystectomy. I think we fairly conclusively showed that being ctDNA-positive at any of these time points is bad news…I think these analyses do support the use of ctDNA in urothelial cancer in the neoadjuvant and the perioperative space. I also think it does further support durvalumab in combination with chemotherapy prior to cystectomy in urothelial cancer,” Powles concluded.

REFERENCES

1. Powles T, Van der Heijden M, Wang Y, et al. Circulating tumor DNA (ctDNA) in patients with muscle-invasive bladder cancer (MIBC) who received perioperative durvalumab (D) in NIAGARA. J Clin Oncol. 2025;43(suppl 17):4503. doi:10.1200/JCO.2025.43.16_suppl.4503

2. Powles T, Catto JWF, Galsky MD, et al. Perioperative durvalumab with neoadjuvant chemotherapy in operable bladder cancer. N Engl J Med. 2024;391(19):1773-1786. doi:10.1056/NEJMoa2408154

3. FDA approves durvalumab for muscle invasive bladder cancer. News release. US Food & Drug Administration. March 28, 2025. Accessed June 1, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-durvalumab-muscle-invasive-bladder-cancer