In an open-label, randomised phase III NIAGARA study conducted among cisplatin-eligible patients with muscle invasive bladder cancer, perioperative durvalumab plus neoadjuvant chemotherapy with radical cystectomy significantly improved event-free survival (EFS) and overall survival (OS) as compared with neoadjuvant chemotherapy with radical cystectomy alone.
The safety profile was similar, and the safety of surgery was similar in the treatment groups. The findings are presented at the ESMO Congress 2024 along with a simultaneous publication by Prof. Thomas Powles of the Barts Cancer Institute, Queen Mary University of London, Barts Health NHS Trust Biomedical Research Centre in London, UK, and colleagues on 15 September 2024 in The New England Journal of Medicine.
Standard treatment for cisplatin-eligible patients with muscle invasive bladder cancer involves neoadjuvant cisplatin-based chemotherapy followed by radical cystectomy with pelvic lymph node dissection. Approximately 50% of patients with muscle invasive bladder cancer have recurrence within 3 years.
Several phase I/II and phase II studies have assessed the safety and feasibility of combining immunotherapy with platinum-based chemotherapy as neoadjuvant treatment for muscle invasive bladder cancer, and a systematic review showed that the percentage of patients with a response was higher with neoadjuvant immune-chemotherapy than with neoadjuvant chemotherapy alone.
In the adjuvant setting, two phase III studies showed the benefit of immune checkpoint inhibitors as monotherapy in muscle invasive bladder cancer: disease-free survival after surgery for high-risk disease was significantly improved with adjuvant nivolumab as compared with placebo and with adjuvant pembrolizumab as compared with observation.
The authors wrote in the background that perioperative immunotherapy regimens may improve patient outcomes but need to be safe and feasible to deliver. In a single-group, phase II study involving cisplatin-eligible patients with operable muscle invasive bladder cancer, perioperative durvalumab in combination with neoadjuvant gemcitabine–cisplatin followed by radical surgery appeared to be safe and efficacious.
In the phase III NIAGARA study, the researchers assigned, in a 1:1 ratio, cisplatin-eligible patients with muscle invasive bladder cancer to receive neoadjuvant durvalumab plus gemcitabine–cisplatin every 3 weeks for four cycles, followed by radical cystectomy and adjuvant durvalumab every 4 weeks for eight cycles (durvalumab group), or to receive neoadjuvant gemcitabine–cisplatin followed by radical cystectomy alone (comparison group). EFS was one of two primary endpoints, OS was the key secondary endpoint.
In total, 533 patients were assigned to the durvalumab group and 530 to the comparison group. The estimated EFS at 24 months was 67.8% (95% confidence interval [CI] 63.6 to 71.7) in the durvalumab group and 59.8% (95% CI 55.4 to 64.0) in the comparison group (hazard ratio [HR] for progression, recurrence, not undergoing radical cystectomy, or death from any cause 0.68; 95% CI 0.56 to 0.82; p < 0.001 by stratified log-rank test); EFS benefit was broadly consistent across prespecified subgroups.
The estimated OS at 24 months was 82.2% (95% CI 78.7 to 85.2) in the durvalumab group and 75.2% (95% CI 71.3 to 78.8) in the comparison group (HR for death 0.75; 95% CI 0.59 to 0.93; p = 0.01 by stratified log-rank test).
Treatment-related adverse events of grade 3 or 4 in severity occurred in 40.6% of the patients in the durvalumab group and in 40.9% of those in the comparison group; treatment-related adverse events leading to death occurred in 0.6% in each group.
Radical cystectomy was performed in 88.0% of the patients in the durvalumab group and in 83.2% of those in the comparison group.
The authors commented that the study was performed before the widespread availability of adjuvant nivolumab for high-risk muscle invasive bladder cancer or enfortumab vedotin with pembrolizumab for advanced disease, and the potential effect of these treatment options on the observed survival benefit is unclear. Blinding of the sponsor during the trial limited the analysis of subsequent therapies in this interim analysis; unblinding and additional follow-up will allow greater understanding of subsequent therapies received by the patients in both groups.
The study was funded by AstraZeneca.
References
- Powles T, Catto JWF, Galsky MD, et al. for the NIAGARA Investigators. Perioperative Durvalumab with Neoadjuvant Chemotherapy in Operable Bladder Cancer. NEJM; Published online 15 September 2024. DOI: 10.1056/NEJMoa2408154
- LBA5 – Powles TB, van der Heijden MS, Galsky MD, et al. A randomized phase III trial of neoadjuvant durvalumab plus chemotherapy followed by radical cystectomy and adjuvant durvalumab in muscle-invasive bladder cancer (NIAGARA). Annals of Oncology 2024;35(Suppl 2):S1271.