The 2025 paradigm shift in urothelial carcinoma pharmacotherapy: from chemotherapy to ADCs and ICIs

The pharmacotherapy of urothelial carcinoma (UC) has undergone a paradigm shift from conventional chemotherapy and BCG to novel agent-based strategies, including immune checkpoint inhibitors (ICIs) and antibody-drug conjugates (ADCs), moving from later-line to frontline, monotherapy to combination, and systemic to locoregional-systemic synergy. In non-muscle-invasive bladder cancer, ICI-BCG combinations and ADC-BCG regimens improve treatment responses and patient outcomes, while the intravesical delivery system TAR-200 also shows therapeutic potential. For muscle-invasive bladder cancer, ADC/ICI-based perioperative strategies alongside biomarker-guided approaches have shown significantly improved survival. In upper tract urothelial carcinoma, ADC/ICI-based combinations show promise in neoadjuvant, kidney-sparing, and adjuvant settings. For advanced or metastatic UC, first-line enfortumab vedotin plus pembrolizumab demonstrates superior survival over chemotherapy, and various clinical trials of novel agent-based strategies are ongoing. Challenges include optimizing patient selection, determining ideal treatment duration, managing treatment-related adverse events, and preserving organ function. Future directions emphasize precision-oriented, function-preserving, and biomarker-driven individualized management.