Neoadjuvant chemotherapy followed by radical cystectomy is the standard treatment for cisplatin-eligible patients with muscle-invasive bladder cancer. Adding perioperative immunotherapy may improve outcomes.
In this phase 3, open-label, randomized trial, we 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). Event-free survival was one of two primary end points. Overall survival was the key secondary end point.
In total, 533 patients were assigned to the durvalumab group and 530 to the comparison group. The estimated event-free survival 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 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). The estimated overall survival 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 (hazard ratio 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.
Perioperative durvalumab plus neoadjuvant chemotherapy led to significant improvements in event-free survival and overall survival as compared with neoadjuvant chemotherapy alone. (Funded by AstraZeneca; NIAGARA ClinicalTrials.gov number, NCT03732677; EudraCT number, 2018-001811-59.)
Neoadjuvant chemotherapy followed by radical cystectomy has been the standard of care for cisplatin-eligible patients with muscle-invasive bladder cancer. In the metastatic setting, results from the Checkmate 901 have recently demonstrated that the combination therapy with nivolumab plus gemcitabine-cisplatin resulted in significantly better outcomes in patients with previously untreated advanced urothelial carcinoma than gemcitabine-cisplatin alone. The NIAGARA study explored the potential of perioperative immunotherapy added to chemotherapy to improve outcomes in the neoadjuvant setting.
The NIAGARA trial is a phase 3, open-label, randomised study. Patients with muscle-invasive bladder cancer who were eligible for cisplatin treatment were assigned in a 1:1 ratio to one of two groups: the first group received neoadjuvant durvalumab plus gemcitabine–cisplatin every three weeks for four cycles, followed by radical cystectomy and adjuvant durvalumab every four weeks for eight cycles. The second group (control group) received only neoadjuvant gemcitabine–cisplatin followed by radical cystectomy. The primary outcome measure was event-free survival, with overall survival as a key secondary outcome.
A total of 533 patients were assigned to the durvalumab group, while 530 were allocated to the control group. After 24 months, event-free survival was 67.8% (95% CI, 63.6 to 71.7) in the durvalumab group, compared to 59.8% (95% CI, 55.4 to 64.0) in the control group (hazard ratio for progression, recurrence, failure to undergo surgery, or death: 0.68; 95% CI, 0.56 to 0.82; P<0.001). Overall survival at 24 months was 82.2% (95% CI, 78.7 to 85.2) in the durvalumab group versus 75.2% (95% CI, 71.3 to 78.8) in the control group (hazard ratio for death: 0.75; 95% CI, 0.59 to 0.93; P=0.01).
Regarding toxicity, grade 3 or 4 treatment-related adverse events occurred in 41% of patients in the durvalumab group and 41% in the control group, with treatment-related deaths reported at 0.6% in both groups. Radical cystectomy was performed in 88.0% of patients in the durvalumab group and 83.2% in the control group.
Overall, in cisplatin-eligible patients with muscle-invasive bladder cancer, perioperative durvalumab in addition to neoadjuvant chemotherapy with radical cystectomy significantly improved both event-free survival and overall survival compared to neoadjuvant chemotherapy with radical cystectomy alone. This event-free survival benefit was consistent across prespecified subgroups. Additionally, the percentage of patients who underwent surgery was similar between the groups, indicating that the addition of neoadjuvant durvalumab did not reduce surgical rates.
Although pathological complete response rates were not significantly different between groups, the authors suggest that durvalumab enhances efficacy already in the neoadjuvant phase. However, the trial did not distinguish between the effects in the neoadjuvant and adjuvant phases, leaving open the question of whether patients could be selectively identified for adjuvant therapy based on individual responses. It is important to note that these findings apply only to patients eligible for cisplatin-based chemotherapy and do not offer a solution for the significant subgroup that is not suitable for cisplatin.
A key question moving forward is how this combination therapy will compare to emerging neoadjuvant immunotherapy regimens (with or without chemotherapy), as well as to novel agents. Nevertheless, the current results from the NIAGARA study indicate a potential shift in clinical practice, presenting a new option for the treatment of patients with muscle-invasive bladder cancer.