Neoadjuvant Therapy in Cisplatin-Ineligible Muscle-Invasive Bladder Cancer: Recent Progress, Challenges, and Future Directions in the Era of TAR-200 and Enfortumab Vedotin Plus Pembrolizumab

Cisplatin-based neoadjuvant chemotherapy (NAC) followed by radical cystectomy remains the standard of care for patients with nonmetastatic muscle-invasive bladder cancer (MIBC) who are eligible for cisplatin. However, many patients cannot receive cisplatin because of renal dysfunction, frailty, neuropathy, ototoxicity, or comorbidities, leaving an unmet need for effective cisplatin-free perioperative options. Single-arm phase 2 studies of neoadjuvant immune checkpoint inhibitors (ICIs) have shown encouraging pathologic complete response (pCR) rates in patients who are ineligible for cisplatin or who decline it, and randomized survival evidence has only recently begun to mature. Two conceptually distinct cisplatin-free paradigms are now shaping the field: (1) systemic intensification with perioperative enfortumab vedotin plus pembrolizumab, an antibody-drug conjugate (ADC) plus programmed death 1 (PD-1) inhibitor regimen supported by phase 3 data; and (2) bladder-centered intensification with TAR-200 (intravesical sustained-release gemcitabine) combined with systemic PD-1 blockade, which has demonstrated promising pathologic activity in early-phase studies but remains investigational in MIBC. This narrative review summarizes the evolving perioperative evidence base across traditional NAC, neoadjuvant ICI monotherapy, ADC-ICI combinations, and locoregional drug delivery approaches; highlights key interpretive challenges including heterogeneous trial populations and endpoints and the limitations of cross-trial comparisons; and discusses future directions such as response-adapted escalation and de-escalation strategies using circulating tumor DNA and urinary tumor DNA. We present a conceptual framework for future prospective trials evaluating how systemic and bladder-centered strategies might be selected and sequenced, rather than definitive guidance for routine clinical practice.