Revisiting Neoadjuvant Chemotherapy in Cisplatin-eligible Muscle-invasive Bladder Cancer

BACKGROUND AND OBJECTIVE: Management of muscle-invasive bladder cancer (MIBC) is evolving rapidly due to advances in systemic therapies and molecular understanding. Neoadjuvant cisplatin-based chemotherapy remains the cornerstone of cisplatin-eligible patients, supported by strong evidence of improved overall survival and pathological complete response. Phase 3 trials such as VESPER and NIAGARA have refined the standard of care by demonstrating the benefits of dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin combination and chemoimmunotherapy, respectively. This review aims to summarize current and emerging neoadjuvant strategies and outline future directions toward a more individualized approach. METHODS: We reviewed the recent literature and pivotal clinical trial data evaluating neoadjuvant therapies for MIBC, with a focus on systemic chemotherapy, immunotherapy, combination regimens, novel agents, and biomarker-driven approaches. Emerging bladder-preserving strategies were also examined. KEY FINDINGS AND LIMITATIONS: Neoadjuvant cisplatin-based chemotherapy remains the established benchmark; however, the NIAGARA trial has provided the first phase 3 evidence supporting neoadj chemo and perioperative IO as a new therapeutic option. The addition of durvalumab to cisplatin-based chemotherapy resulted in a significant improvement in survival and response endpoints. Antibody-drug conjugates and biomarkers such as circulating tumor DNA and DNA damage response mutations are shaping a more personalized treatment paradigm. However, optimal regimen selection, sequencing of therapies, and robust methods for response assessment remain unresolved. CONCLUSIONS AND CLINICAL IMPLICATIONS: Recent therapeutic advances, particularly the integration of immunotherapy, novel agents, and biomarker-driven strategies, are redefining the neoadjuvant landscape in MIBC. Neoadjuvant treatment for MIBC is moving toward a biomarker-informed risk-adapted approach, integrating novel agents and multidisciplinary decision-making. Refinement of patient selection and treatment sequencing will be critical to improving outcomes and advancing personalized, precision-based care.