The phase III NIAGARA trial has revealed that perioperative treatment with durvalumab, a PD-L1 inhibitor, combined with neoadjuvant chemotherapy, significantly improves event-free survival (EFS) and overall survival (OS) in patients with muscle-invasive bladder cancer (MIBC). This marks a significant advancement in the treatment landscape for this aggressive disease, where nearly half of patients experience recurrence after standard treatment with neoadjuvant chemotherapy and cystectomy.
The NIAGARA trial, a global effort involving 1,000 patients across 200 sites, explored the addition of durvalumab to standard neoadjuvant chemotherapy (gemcitabine/cisplatin) followed by radical cystectomy and adjuvant durvalumab monotherapy. Patients with T2 to T4a, N1 MIBC who were fit for cystectomy were included in the study. The results, presented at the European Society for Medical Oncology (ESMO) Congress 2024, demonstrated a 32% reduction in the risk of disease progression, recurrence, or death (HR = 0.68; 95% CI = 0.56–0.82; P < .0001). The estimated median event-free survival was not reached in the durvalumab arm, compared to 46.1 months in the chemotherapy-alone arm. At 2 years, 67.8% of patients in the durvalumab arm were event-free, compared to 59.8% in the comparator arm.
Overall Survival Benefit
The study also met its key secondary endpoint of overall survival, with the durvalumab regimen reducing the risk of death by 25% (HR = 0.75; 95% CI = 0.59–0.93; P = .0106). Median survival was not yet reached for either arm, but the 2-year overall survival rate was 82.2% for the durvalumab arm versus 75.2% for the chemotherapy-alone arm.
Pathological Complete Response
An improvement in pathological complete response (pCR) rates was observed, increasing from 27% with chemotherapy alone to 37% with the addition of durvalumab. According to Dr. Thomas Powles, Director of Barts Cancer Centre and principal investigator of the NIAGARA trial, this pCR rate establishes a new benchmark. He cautioned against cross-trial comparisons of pCR rates due to inconsistencies in staging and reporting across different studies.
Safety and Tolerability
Durvalumab was generally well-tolerated, with no new safety signals observed in the neoadjuvant and adjuvant settings. Grade 3 or 4 adverse events occurred in 69% of patients treated with durvalumab and 68% of patients treated with neoadjuvant chemotherapy. The addition of durvalumab did not compromise patients' ability to complete surgery.
Clinical Implications
The NIAGARA trial suggests that early administration of immunotherapy in the perioperative setting may be more effective than reserving it for later lines of treatment. Dr. Powles emphasized the importance of giving the best drugs upfront, especially in aggressive cancers like urothelial carcinoma. The trial's inclusive design, which included patients with variant histology subtypes and creatinine clearance as low as 40 mL, suggests that a broader range of patients may benefit from this treatment approach.
While PD-L1 expression has been a topic of debate in bladder cancer, the NIAGARA trial results suggest that durvalumab can provide significant benefits regardless of PD-L1 status. This study is poised to change clinical practice, offering a new standard of care for patients with muscle-invasive bladder cancer and potentially improving cure rates.
