Expanding horizons to cure muscle-invasive bladder cancer: A novel treatment algorithm

SUMMARY NIAGARA,[1] a phase 3, open-label randomized trial that evaluated the efficacy of neoadjuvant durvalumab in cisplatin-eligible muscle-invasive bladder cancer (MIBC: cT2-TaN0/1M0), including those with divergent differentiation or histologic subtypes where 1:1 randomization was done in two groups. In the durvalumab arm, patients received durvalumab 1500 mg intravenous (IV) Q3W (every 3 weeks) with gemcitabine + cisplatin (GC) for 4 cycles, followed by radical cystectomy (RC) and adjuvant durvalumab 1500 mg IV Q4W (every 4 weeks) for up to 8 cycles. In the comparator arm, patients received GC followed by RC and no adjuvant treatment. The dual primary endpoints were pathological complete response (pCR) rate and event-free survival (EFS), defined as progressive disease precluding RC, recurrence post-RC, failure to undergo RC on schedule, or death from any cause, with overall survival (OS) as the secondary endpoint. Notable findings from the NIAGARA trial (n = 1063) showed a higher pCR rate in the durvalumab arm versus the comparator arm (37.3% vs. 27.5%; hazard ratio [HR] = 1.60; 95% confidence interval [CI]: 1.23–2.08; P = 0.0005). At a median follow-up of 42.3 months, the 2-year estimated EFS favored durvalumab (67.8% vs. 59.8%; HR = 0.68; 95% CI: 0.56–0.82; P < 0.001), showing consistent benefits across most subgroups, including baseline histological type, no previous (Bacillus Calmette-Guerin) BCG exposure, >T2 tumor stage, creatinine clearance, and programmed death-ligand 1 (PD-L1) expression, except for N1 disease (HR = 0.75; 95% CI: 0.22–1.64; n = 58), likely due to small sample size. At 24 months, OS was 82.2% in the durvalumab arm versus 75.2% in the comparator arm (HR = 0.75; 95% CI: 0.59–0.93; P = 0.016). Grade 3/4 treatment-related adverse events were comparable (69.4% vs. 67.5%). COMMENTS Neoadjuvant cisplatin-based chemotherapy followed by RC improves OS in MIBC by targeting micrometastasis and remains the standard of care. The role of immune checkpoint inhibitors (ICIs) in the perioperative period has recently gained increasing prominence. The CheckMate 274[2] and AMBASSADOR Alliance A031501[3] trials demonstrated significantly improved disease-free survival with adjuvant nivolumab and pembrolizumab, respectively, following RC in high-risk MIBC, opening avenues for further exploration of ICIs in this setting. Neoadjuvant ICIs enhance anti-tumor activity by targeting the primary tumor and lymph nodes, boosting T-cell responses to eradicate micrometastases, establishing immune memory, and improving cure rates. The phase 2 PURE-01[4] and ABACUS trials demonstrated significant pCR rates with pembrolizumab (200 mg every 3 weeks) and two cycles of atezolizumab administered before RC, respectively. Perioperative durvalumab was shown to be safe and efficacious in a Phase II Trial SAKK 06/17.[5] NIAGARA, the first randomized phase 3 trial, positions perioperative durvalumab, PD-L1 inhibitor, combined with chemotherapy as a potential new standard of care; however, few points warrant further discussion. The NIAGARA trial was not structured to determine the individual contributions of neoadjuvant and adjuvant durvalumab, which would have been particularly valuable for evaluating patients with a pCR. Furthermore, while all patients received adjuvant therapy, its necessity in responders remains uncertain, as the addition of 8 months of treatment increases financial burden, toxicity, and diminished quality of life. pCR is generally insufficient for phase 3 trials due to their limited reliability as surrogates for EFS or OS, a stance supported by regulatory agencies. While EFS is a strong endpoint, this trial should have prioritized OS as the primary measure, particularly given the availability of salvage treatments at relapse, as it provides the strongest rationale for exposing patients to potentially toxic and costly therapies. Like ongoing phase 3 trials such as KEYNOTE-B15/EV-304, initiating immunotherapy earlier in the treatment pathway raises key questions about sequencing at recurrence, particularly the feasibility of reusing immunotherapy after disease progression. The comparison group in this trial lacked adjuvant therapy, unlike current guidelines recommending 1 year of adjuvant nivolumab for ypT2–ypT4a or ypN + residual disease, making real-world alignment more relevant. In addition, biomarkers such as ctDNA, a prognostic factor following RC, play a crucial role in monitoring recurrence and identifying patients most likely to benefit from adjuvant immunotherapy, as demonstrated in the IMvigor011 and MODERN trials. The rise of bladder-preserving approaches in the MIBC cohort underscores the potential of integrating ICIs with trimodal therapy to widen patient eligibility, improve clinical outcomes, and enhance quality of life. To conclude, NIAGARA represents a significant advancement in managing NMIBC, providing the first evidence of a survival benefit over neoadjuvant chemotherapy, and offering the potential to redefine the standard of care. Whether this signifies a true milestone toward a “new dawn” is yet to be determined, but the future is promising with advancements in novel therapies and predictive biomarkers, paving the way for precision medicine that matches the right treatment to the right patient consistently. Financial support and sponsorship: Nil. Conflicts of interest: There are no conflicts of interest.