Neoadjuvant, adjuvant, and perioperative systemic therapy in urothelial cancers: Evolving paradigms and future directions

Radical surgery is the cornerstone of management for localized muscle-invasive urothelial carcinoma (MIUC), yet surgery alone cures only a proportion of patients because occult micrometastatic disease is common at diagnosis. Over the last two decades, perioperative systemic treatment has evolved from a cisplatin-based chemotherapy paradigm to a more complex framework incorporating immune checkpoint inhibitors, antibody-drug conjugates, biomarker-enriched strategies, and risk-adapted postoperative approaches. Cisplatin-based neoadjuvant chemotherapy remains a foundational standard in cisplatin-eligible muscle-invasive bladder cancer (MIBC), supported by randomized trials and meta-analyses demonstrating improved pathologic downstaging and overall survival. However, real-world delivery is limited by renal dysfunction, frailty, hearing loss, neuropathy, and physician or patient reluctance to delay definitive surgery. Adjuvant chemotherapy has been more difficult to establish in bladder cancer because of postoperative attrition and underpowered trials, although the EORTC 30994 study and the upper tract POUT trial support postoperative platinum-based treatment in selected high-risk settings. Single-agent neoadjuvant immunotherapy produced encouraging pathologic complete response (pCR) rates in phase II studies such as PURE-01 and ABACUS, laying the groundwork for modern perioperative immunotherapy.

The perioperative field has changed substantially with positive phase III studies. NIAGARA established perioperative Durvalumab plus neoadjuvant Gemcitabine-cisplatin followed by adjuvant Durvalumab as a new standard for cisplatin-eligible MIBC, improving event-free survival and overall survival. AMBASSADOR showed that adjuvant Pembrolizumab improves disease-free survival after radical surgery in high-risk MIUC, broadening postoperative immune checkpoint inhibition beyond Nivolumab. Most recently, KEYNOTE-905/EV-303 demonstrated that perioperative Enfortumab vedotin plus Pembrolizumab improves event-free survival, overall survival, and pCR versus surgery alone in cisplatin-ineligible or cisplatin-declining MIBC, filling one of the most important historical gaps in perioperative treatment.

This review summarizes the biological rationale, evidence base, current standards, unresolved controversies, and future directions for neoadjuvant, adjuvant, and perioperative systemic therapy in urothelial cancers, including bladder and upper tract disease. Particular emphasis is placed on patient selection, regimen choice, endpoints, biomarker development, and integration of the latest phase III data into clinical practice.