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Systemic Therapy Advances in Muscle-Invasive Bladder Cancer: A Critical Juncture for Cisplatin-Based Trials

In patients with muscle-invasive bladder cancer (MIBC) managed with radical cystectomy, the perioperative systemic therapy landscape is transforming rapidly. Historically, cisplatin-eligible patients have been offered neoadjuvant cisplatin-based chemotherapy followed by surgery, yet relapse rates remain high, and many patients are ineligible for cisplatin due to comorbidities. The NIAGARA trial, a randomized phase 3 trial, compared neoadjuvant gemcitabine/cisplatin plus the PD-L1 inhibitor durvalumab, followed by surgery and adjuvant durvalumab, versus neoadjuvant gemcitabine/cisplatin alone. The trial enrolled 1,063 patients with operable MIBC and demonstrated at 24 months an event-free survival (EFS) rate of 67.8% in the durvalumab arm versus 59.8% in chemotherapy alone, corresponding to a hazard ratio (HR) of 0.68 (95% CI 0.56–0.82; P < 0.001).

Overall survival (OS) at 24 months was 82.2% versus 75.2%, with HR 0.75 (95% CI 0.59–0.93; P = 0.01). Grade 3 or 4 treatment-related adverse events were similar between groups (~40%).1 These results led to U.S. FDA approval in March 2025 of durvalumab combined with gemcitabine/cisplatin as neoadjuvant therapy followed by adjuvant durvalumab for operable cisplatin-eligible MIBC, establishing a new standard of care.2

In contrast, cisplatin-ineligible patients, who comprise a substantial portion of MIBC cases, have had limited perioperative options. The KEYNOTE-905/EV-303 trial recently addressed this unmet need by evaluating enfortumab vedotin (EV), an antibody-drug conjugate targeting Nectin-4, plus pembrolizumab versus radical cystectomy (RC) alone. This randomized phase 3 study enrolled patients ineligible for cisplatin (per Galsky criteria) or who declined cisplatin, with clinical stage T2–T4a N0 M0 or T1–T4a N1 M0 disease and at least 50% urothelial histology. Patients in the investigational arm received three cycles of neoadjuvant EV (1.25 mg/kg days 1 and 8 every 21 days) plus pembrolizumab (200 mg every 3 weeks), followed by RC with pelvic lymph-node dissection (PLND), then adjuvant EV (six cycles) plus pembrolizumab (14 cycles). The primary endpoint was event-free survival (EFS), with key secondary endpoints of overall survival (OS) and pathologic complete response (pCR).

At a median follow-up of 25.6 months, the investigational arm demonstrated significantly superior outcomes. Median EFS was not reached (NR; 95% CI 37.3–NR) versus 15.7 months (95% CI 10.3–20.5) in the control arm (HR 0.40; 95% CI 0.28–0.57; p < 0.0001). Median OS was also NR in the EV plus pembrolizumab group versus 41.7 months in controls (HR 0.50; 95% CI 0.33–0.74; p = 0.0002). The pCR rate was 57.1% versus 8.6%.3 These benefits were consistent across subgroups, including age, performance status, and PD-L1 expression. Grade ≥3 adverse events occurred in 71.3% of treated patients versus 45.9% in controls, including skin reactions, neuropathy, hyperglycemia, and immune-related events.3

KEYNOTE-905/EV-303 represents the first robust evidence of survival benefit with perioperative systemic therapy in cisplatin-ineligible MIBC and sets the stage for a new treatment standard. In parallel, the KEYNOTE-B15/EV-304 trial in cisplatin-eligible patients is evaluating EV plus pembrolizumab administered perioperatively versus standard neoadjuvant gemcitabine/cisplatin.4 If this trial confirms superiority to EV plus pembrolizumab, it may further displace cisplatin-based chemotherapy, even in currently cisplatin-eligible patients.
This prospect raises an important and time-sensitive consideration: there are several ongoing cisplatin-based perioperative trials in cisplatin-eligible patients (see below) that are still actively enrolling. These trials may offer critical insights into optimization of cisplatin-based regimens or the integration of emerging biomarkers for both treatment intensification and deintensification. However, with a very reasonable likelihood that EV-304 will significantly alter the standard of care for cisplatin-eligible patients in the near future, this now represents a crucial window to complete accrual to these trials before equipoise is lost.

In summary, systemic treatment for MIBC is undergoing rapid redefinition. For cisplatin-eligible patients, NIAGARA has already shifted the standard to include immunotherapy, while KEYNOTE-905/EV-303 provides a long-awaited breakthrough for the cisplatin-ineligible population. With KEYNOTE-B15/EV-304 on the horizon and many active trials nearing completion, this is a pivotal moment in perioperative bladder cancer care: one in which the traditional reliance on cisplatin may soon give way to novel, more effective, and more inclusive treatment strategies.

Actively Accruing Neoadjuvant Trials for MIBC, including cisplatin-based combination regimens

  • NCT06537154 – NEO-BLAST evaluates potential for active surveillance after neoadjuvant cisplatin-based chemotherapy
  • NCT06960577 – NIAGARA-2 evaluating durvalumab with ddMVAC
  • NCT06571708 – NeoSTOP-IT evaluating gemcitabine/cisplatin plus cemiplimab with or without fianlimab
  • NCT05137262 – Neoadjuvant chemotherapy for node positive urothelial carcinoma
Written by: Evan Yu, MD, Section Head of Cancer Medicine in the Clinical Research Division at Fred Hutchinson Cancer Center. He also serves as the Medical Director of Clinical Research Support at the Fred Hutchinson Cancer Research Consortium and is a Professor of Medicine in the Division of Oncology and Department of Medicine at the University of Washington School of Medicine in Seattle, WA

References:

  1. 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.
  2. U.S. Food and Drug Administration. FDA Approves Durvalumab Combo for Muscle-Invasive Bladder Cancer. March 28, 2025. Available at: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-durvalumab-muscle-invasive-bladder-cancer
  3. Vulsteke C, Kaimakliotis HZ, Danchaivijitr P, et al. Perioperative enfortumab vedotin (EV) plus pembrolizumab in participants with muscle-invasive bladder cancer who are cisplatin-ineligible: Phase III KEYNOTE-905 study. ESMO Congress 2025, Abstract LBA2.
  4. https://www.clinicaltrials.gov/study/NCT04700124