Advancing Bladder Cancer Management: The Role of Neoadjuvant and Adjuvant Therapies and Biomarkers in Muscle Invasive Bladder Cancer.

Abstract

Opinion statement: The management of muscle-invasive bladder cancer (MIBC) is evolving rapidly, with the integration of neoadjuvant and adjuvant therapies and biomarker-driven patient selection now essential to refining treatment decisions. While cisplatin-based neoadjuvant chemotherapy has been the standard of care, its underutilization due to toxicity and patient ineligibility underscores the need for alternative strategies. Immune checkpoint inhibitors and targeted therapies, particularly fibroblast growth factor receptor (FGFR) inhibitors and antibody-drug conjugates (ADCs) like enfortumab vedotin (Nectin-4-directed) and disitamab vedotin (human epidermal growth factor receptor 2 [HER2]-directed), have transformed the management of metastatic urothelial carcinoma and are now being investigated in MIBC. The next challenge is to deploy these agents rationally by using robust biomarkers. FGFR3 alterations are predictive of response to FGFR inhibitors, whereas HER2 over-expression is chiefly prognostic but may also predict benefit from HER2-targeted ADCs. Circulating tumor DNA (ctDNA) is both prognostic and predictive, guiding dynamic therapy escalation when positive and potential de-escalation when negative in ongoing perioperative trials. In the adjuvant setting, immune-checkpoint blockade has begun to change practice: nivolumab in CheckMate 274 and pembrolizumab in the Alliance AMBASSADOR study each produced a statistically significant improvement in disease-free survival for high-risk patients after radical cystectomy, with overall survival (OS) data still Maturing. More recently, the phase 3 NIAGARA trial showed that adding perioperative durvalumab to neoadjuvant gemcitabine/cisplatin, followed by surgery and adjuvant durvalumab, conferred significant gains in both event-free survival and OS compared with chemotherapy alone. ctDNA's role as a marker of minimal residual disease is especially compelling. Trials, such as IMvigor010, have laid the foundation for ctDNA's utility as an MRD Marker, while the IMvigor 011 and VOLGA trials are utilizing ctDNA-driven treatment escalation or de-escalation to enable appropriate patient selection. Moving forward, the integration of multi-omics technologies, liquid biopsies, and adaptive trial designs will be crucial in optimizing treatment strategies. Challenges remain in standardizing biomarker assays, validating their predictive value, and translating findings into routine clinical practice. Collaborative efforts and large-scale prospective studies are necessary to bridge existing gaps and advance precision medicine tailored for MIBC.