A large, international phase 3 clinical trial has found that adding the immunotherapy drug durvalumab to standard chemotherapy before and after surgery significantly improves outcomes for patients with muscle-invasive bladder cancer. The study, known as the NIAGARA trial, was published on November 14, 2024 in The New England Journal of Medicine.
This randomized, open-label trial enrolled 1,063 patients with operable muscle-invasive bladder cancer from 22 countries. Patients were randomly assigned to receive either standard neoadjuvant chemotherapy (gemcitabine plus cisplatin) followed by surgery, or the same chemotherapy regimen plus durvalumab before surgery, followed by additional durvalumab after surgery.
The study was funded by AstraZeneca, the manufacturer of durvalumab. Its primary aim was to determine if adding durvalumab to standard treatment could improve event-free survival and pathological complete response rates.
To be eligible, patients had to have histologically confirmed muscle-invasive bladder cancer (clinical stage T2-T4a, N0-N1, M0), be eligible for cisplatin-based chemotherapy, and be medically fit for radical cystectomy. The study population was representative of muscle-invasive bladder cancer patients in Europe, Asia, North America, Australia, and South America, though Black patients were underrepresented.
The results showed that patients who received durvalumab had significantly better outcomes. After a median follow-up of 42.3 months, the estimated 24-month event-free survival rate was 67.8% in the durvalumab group compared to 59.8% in the standard treatment group. This translated to a 32% lower risk of disease progression, recurrence, death, or failure to undergo cystectomy in the durvalumab group.
Overall survival at 24 months was also improved with durvalumab, at 82.2% versus 75.2% in the control group. This represents a 25% reduction in the risk of death. These survival benefits were generally consistent across pre-specified subgroups.
Interestingly, while there was a numerical increase in the pathological complete response rate with durvalumab (37.3% vs 27.5%), this did not reach the pre-specified threshold for statistical significance. However, the early separation of event-free survival curves suggests durvalumab provides benefit in the neoadjuvant phase.
Importantly, the addition of durvalumab did not appear to compromise patients' ability to undergo surgery. Similar proportions in both groups proceeded to radical cystectomy (88.0% with durvalumab vs 83.2% in the control group).
The safety profile of adding durvalumab was consistent with known side effects of the individual drugs. Rates of grade 3-4 treatment-related adverse events were similar between groups (40.6% with durvalumab vs 40.9% with chemotherapy alone). Immune-related adverse events were more common with durvalumab (20.9% vs 3.0%) but were generally manageable.
The study had some limitations, including its open-label design. However, this was mitigated to some extent by blinded independent review of efficacy outcomes. Additionally, the trial was not designed to isolate the relative contributions of neoadjuvant versus adjuvant durvalumab to the observed benefits.
The authors concluded that perioperative durvalumab combined with neoadjuvant chemotherapy significantly improves both event-free and overall survival compared to neoadjuvant chemotherapy alone in patients with muscle-invasive bladder cancer. They suggest this approach could become a new standard of care for cisplatin-eligible patients.
The potential clinical impact of these findings is substantial. Muscle-invasive bladder cancer has a high risk of recurrence and death even with current standard treatments. This study demonstrates a clinically meaningful improvement in outcomes with the addition of immunotherapy. If widely adopted, this approach could significantly reduce relapse rates and improve survival for many bladder cancer patients.
However, several factors will likely influence the broader implementation of this treatment strategy. These include the cost and availability of durvalumab, the ability to manage immune-related side effects, and how these results compare to other emerging approaches in bladder cancer treatment. Ongoing and future studies may help refine patient selection and optimize the timing and duration of immunotherapy in this setting.
In conclusion, the NIAGARA trial represents an important advance in the treatment of muscle-invasive bladder cancer. By demonstrating the benefit of combining immunotherapy with standard chemotherapy in the perioperative setting, it opens new avenues for improving outcomes in this challenging disease. As with any major advance, these results will need to be balanced against costs, side effects, and alternative approaches as clinicians and patients make treatment decisions.
References
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
