SUMMARY: The American Cancer Society estimates that in the United States for 2025, about 84,870 new cases of bladder cancer will be diagnosed and approximately 17,420 patients will die of the disease. Bladder cancer is the fourth most common cancer in men, but it is less common in women. Bladder cancer accounts for 90% of urothelial cancers, and urothelial cancer can also be found in the renal pelvis, ureter and urethra. Approximately 12% of urothelial cancer cases at diagnosis are locally advanced or metastatic.
The standard treatment for Cisplatin-eligible patients with Muscle-Invasive Bladder Cancer (MIBC) is neoadjuvant chemotherapy followed by radical cystectomy. However, the high relapse rate and risk of death despite this treatment has prompted further research into optimizing outcomes. Perioperative immunotherapy, particularly with immune checkpoint inhibitors, has shown promise in improving these outcomes. Immune checkpoints are cell surface inhibitory proteins/receptors that are expressed on activated T cells. They harness the immune system and prevent uncontrolled immune reactions. By inhibiting checkpoint proteins and their ligands, T cells are unleashed, resulting in T cell proliferation, activation and a therapeutic response. It has been noted that PD-L1 is widely expressed in tumor and immune cells of patients with Urothelial Carcinoma. This in turn helps cancer cells to evade detection from the immune system by binding to the PD-1 receptor on cytotoxic T lymphocytes.
Durvalumab (IMFINZI®) is a selective, high-affinity human IgG1 monoclonal antibody directed against PD-L1 and blocks the interaction of PD-L1 with PD-1 and CD80. A preceding single-group, Phase 2 trial indicated that perioperative Durvalumab, combined with neoadjuvant Gemcitabine plus Cisplatin chemotherapy followed by radical surgery, was both safe and effective. Building on these findings, the Phase 3 NIAGARA trial aimed to evaluate the efficacy and safety of perioperative Durvalumab combined with neoadjuvant chemotherapy (Gemcitabine plus Cisplatin), followed by radical cystectomy, compared with neoadjuvant chemotherapy alone followed by radical cystectomy, in Cisplatin-eligible MIBC patients.
The NIAGARA trial was an open-label, randomized, multicenter, Phase 3 study, enrolling 1,063 (N=1063) Cisplatin-eligible patients with Muscle Invasive Bladder Cancer (clinical stage cT2–T4aN0/1M0). Patients were randomized in a 1:1 ratio to receive one of two treatment regimens. The experimental arm (Durvalumab group) included neoadjuvant Durvalumab 1500 mg IV alongside Gemcitabine plus Cisplatin every 3 weeks for 4 cycles, followed by radical cystectomy and adjuvant Durvalumab monotherapy 1500 mg IV every 4 weeks for up to 8 cycles (N=533). The comparison arm consisted of neoadjuvant Gemcitabine plus Cisplatin followed by radical cystectomy alone, without the addition of Durvalumab (N=530). Patients were stratified by clinical tumor stage (cT2N0 vs more than cT2N0), renal function (CrCl 60 mL/min or more vs 40 or more to less than 60 mL/min), and PD-L1 status (high vs low/negative). The dual Primary endpoints of the trial were Event-Free Survival (EFS) and pathological Complete Response (pCR), with Overall Survival (OS) as a key Secondary endpoint, as well as Metastasis Free Survival and Disease-Specific Survival. Event-Free Survival was defined as the time from randomization until progression that precluded surgery, failure to undergo surgery, recurrence after cystectomy, or death from any cause.
In the pre-planned interim analysis, the results demonstrated a significant improvement in both EFS and OS in the Durvalumab group compared to the chemotherapy-alone group. At 24 months, the estimated EFS was 67.8% in the Durvalumab group, compared to 59.8% in the comparison group (HR=0.68; P<0.001). Furthermore, the estimated OS at 24 months was 82.2% in the Durvalumab group versus 75.2% in the comparison group (HR for death=0.75; P=0.01). A pathological Complete Response (pCR) as assessed by central pathology review was noted in 37.3% of the patients in the Durvalumab group and in 27.5% of those in the comparison group. Notably, the percentage of patients who underwent radical cystectomy was similar between the two groups, with 88% in the Durvalumab group and 83% in the comparison group, indicating that the addition of Durvalumab did not reduce surgical completion rates.
An exploratory post hoc analysis of EFS and OS in patients with pCR versus those without pCR was also performed in the intent-to-treat population. The researchers herein reported additional outcomes and exploratory analysis results from NIAGARA study.
Patients in the Durvalumab group had a 33% reduction in risk of developing distant metastases or death (HR=0.67; P<0.001), and 31% reduction in risk of death from bladder cancer (HR=0.69; P=0.008) versus patients in the comparator group. More patients in the Durvalumab group achieved a pCR at the time of surgery versus the comparator (37% versus 28%) and patients who achieved a pCR had better EFS and OS, compared to those who did not. Patients in the Durvalumab group derived greater EFS and OS benefit versus the comparator group in both pCR group (EFS HR=0.58; OS HR=0.72), reducing the risk of disease progression or death by 42% and the risk of death by 28%, as well as non-pCR group (EFS HR=0.77; OS HR=0.84), reducing the risk of disease progression or death by 23% and risk of death by 16%. The most common immune-related adverse events included hypothyroidism in 10% of patients treated with Durvalumab compared to 1% in the comparator group, and hyperthyroidism in 3% versus 0.8% respectively. All immune mediated adverse events resolved in 41% of affected patients in the Durvalumab group and 44% in the comparator group.
It was concluded that the addition of perioperative Durvalumab to neoadjuvant chemotherapy significantly improved EFS and OS in both pCR and non-pCR groups, compared to chemotherapy alone, without compromising the ability to perform radical cystectomy. Further, perioperative Durvalumab combined with neoadjuvant chemotherapy reduced the risk of developing metastases and death from bladder cancer. These results are practice-changing, marking a major advancement in the treatment of MIBC. The findings support the hypothesis that perioperative immune checkpoint inhibitors, by priming the immune system before surgery and targeting residual micrometastatic disease post-surgery, improve long-term clinical outcomes. Biomarkers like circulating tumor DNA (ctDNA) could be pivotal in guiding treatment decisions, as emerging data suggests that negative ctDNA status post-neoadjuvant therapy correlates with reduced relapse risk.
Additional efficacy and safety outcomes and an exploratory analysis of the impact of pathological complete response (pCR) on long-term outcomes from NIAGARA. Galsky M, Van Der Heijden M, Catto J, et al. J Clin Oncol 43, 2025 (suppl 5; abstr 659). DOI 10.1200/JCO.2025.43.5_suppl.659
