Targeting HER2 in urothelial carcinoma: from pathway inhibition to antibody–drug conjugates

Urothelial carcinoma (UC) is a biologically and clinically heterogeneous malignancy with persistently poor outcomes in locally advanced or metastatic disease. Although platinum-based chemotherapy and immune checkpoint inhibitors have improved survival, durable disease control remains limited, and therapeutic resistance is common. Antibody–drug conjugates (ADCs) targeting Nectin-4 and Trop-2 have further expanded the therapeutic landscape, yet the need for additional biomarker-driven strategies remains pressing. Human epidermal growth factor receptor 2 (HER2), encoded by ERBB2 , has emerged as a therapeutically relevant target in a subset of UC. HER2 expression in UC is highly heterogeneous and varies across histological and molecular subtypes, with the highest expression rates reported in the micropapillary subtype. Early attempts to target HER2 in UC yielded disappointing results, largely due to biological heterogeneity, lack of standardized HER2 assessment and an incomplete understanding of HER2 pathway dependence in UC. Recent advances in molecular profiling and the development of HER2-directed ADCs have fundamentally reshaped the therapeutic relevance of HER2 in UC, enabling activity even in tumors with heterogeneous or low expression of HER2. This comprehensive narrative review synthesizes current knowledge on HER2 biology in UC, addresses challenges in biomarker assessment, critically appraises the evolving clinical trial landscape of HER2-directed ADCs, explores the interaction between HER2 and other oncogenic alterations and discusses mechanisms of resistance with future directions for HER2-targeted strategies in UC.