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

The management of muscle-invasive bladder cancer (MIBC) continues to evolve rapidly as advances in systemic therapy, immunotherapy, and molecular profiling reshape treatment paradigms. In this review, we comprehensively revisit the role of neoadjuvant chemotherapy (NAC) in cisplatin-eligible patients, integrating data from pivotal phase 3 trials such as VESPER and NIAGARA, revisiting molecular classification in MIBC, and exploring new strategies and future directions in MIBC.^1-3

Cisplatin-based NAC remains the benchmark for improving overall survival and pathological complete response (pCR) in eligible patients. The VESPER trial reaffirmed the efficacy of dose-dense MVAC (ddMVAC) compared to gemcitabine/cisplatin (GC), supporting ddMVAC’s potential superiority in the neoadjuvant setting. More importantly, the NIAGARA trial introduced perioperative chemoimmunotherapy (durvalumab + GC) as a new standard, demonstrating significant improvements in event-free and overall survival without compromising surgical feasibility.^2-3 These results support the integration of PD-L1 blockade into curative-intent regimens, leading to FDA and European Commission approvals of durvalumab for perioperative use in 2025. The KEYNOTE-866 and ENERGIZE trials may provide further clarity on sequencing and optimal integration of chemoimmunotherapy.¹

Nowadays, the importance of patient selection—cisplatin eligibility, renal function, and comorbidities, along with the possibility of access to neoadjuvant treatment, remains a key determinant of therapeutic success. However, the current absence of validated predictive biomarkers limits precision in clinical decision-making. Molecular subtyping (as per the Kamoun consensus) identifies luminal, basal/squamous, and neuroendocrine-like tumors with distinct therapeutic sensitivities. For instance, basal tumors exhibit higher chemosensitivity, whereas luminal subtypes—especially FGFR3-driven luminal papillary tumors—may benefit from targeted or immunomodulatory approaches. DNA damage response (DDR) mutations—notably ERCC2, ATM, and RB1—also correlate with increased sensitivity to both cisplatin and checkpoint inhibition, supporting combined molecular and immune profiling as a clinical compass.^1,4

Moreover, circulating tumor DNA (ctDNA) is the most promising emerging real-time biomarker of minimal residual disease. Trials such as IMvigor010 and ABACUS show that ctDNA clearance predicts pCR and relapse-free survival, suggesting a future where therapy intensity could be escalated or de-escalated based on ctDNA dynamics. Positive IMvigor011 results were communicated, with full presentation awaited in ESMO 2025.^1,5

Future trials have to harmonize endpoints (such as pCR, ctDNA clearance, and molecular subtype response) to allow more meaningful cross-comparisons.

Next-generation agents may further refine perioperative therapy. Antibody-drug conjugates (ADCs) such as enfortumab vedotin are moving from metastatic to localized settings, with early data suggesting remarkable response rates even in cisplatin-ineligible patients. Phase III trials, such as VOLGA or positive communicated data from EV 303, are fully awaited.⁶ Additionally, bladder-preserving strategies combining systemic therapy, radiotherapy, and immunotherapy are redefining curative approaches for selected responders.

The next frontier in MIBC treatment will depend on the integration of biomarker-informed, multidisciplinary, and adaptive strategies. Real-time ctDNA monitoring, radiomics, and artificial intelligence (AI)–driven models may soon guide individualized decisions—determining not only who benefits from therapy but also when surgery can safely be deferred. This evolution toward precision-based, bladder-preserving, and patient-centered care represents a paradigm shift for urothelial oncology.^1,7

Written by: Javier Molina-Cerrillo, MD, PhD, Department of Medical Oncology, Hospital Universitario Ramón y Cajal, Madrid, Spain

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