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Despite recent developments in the landscape of urothelial carcinoma (UC) treatment, platinum combination chemotherapy still remains a milestone. Recently immunotherapeutic agents have gained ever-growing attractivity, particularly in the metastatic setting. Novel chemotherapeutic strategies and agents, such as antibody-drug conjugates (ADCs), and powerful combination regimens have been developed to overcome the resistance of most UC to current therapies. Herein, we review the current standard-of-care chemotherapy, the development of ADCs, the rationale for combining therapy regimens with chemotherapy in current trials, and future directions in UC management. Immunotherapy has prompted a revolution in the treatment paradigm of UC. However, only a few patients experience a long-term response when treated with single-agent immunotherapies. Combination treatments are necessary to bypass resistance mechanisms and broaden the clinical utility of current options. Current evidence supports the intensification of standard-of-care chemotherapy with maintenance immunotherapy. However, the optimal sequence, combination, and duration must be determined to achieve individual longevity with acceptable health-related quality of life. In that regard, ADCs appear as a promising alternative for single and combination strategies in UC, as they specifically target the tumor cells, thereby, theoretically improving treatment efficacy and avoiding extensive off-target toxicities.

Perspectives on the future of urothelial carcinoma therapy: chemotherapy and beyond