Trastuzumab deruxtecan in HER2-expressing urothelial carcinoma: current evidence, biomarker challenges, and future therapeutic strategies

Urothelial carcinoma (UC) has become a prototype for antibody–drug conjugate (ADC)-based therapy, but relapse after first-line enfortumab vedotin plus pembrolizumab remains common. HER2 protein expression, ERBB2 amplification and activating mutations identify overlapping but distinct populations; this review focuses on HER2-expressing disease and separately examines genomic alterations. We examine HER2 testing, trastuzumab deruxtecan (T-DXd) pharmacology, clinical evidence, safety, and treatment sequencing. PubMed/MEDLINE was searched from database inception through 20 August 2026 for urothelial/bladder cancer, HER2/ERBB2, T-DXd, other ADCs, biomarkers, heterogeneity, and interstitial lung disease (ILD). T-DXd is a promising later-line option for selected patients, with the strongest evidence in HER2-positive (immunohistochemistry [IHC] 3+) UC; amplification or mutation alone does not establish equivalent treatment eligibility. Standardized UC-specific testing, reassessment of HER2 at progression, and prospective biomarker-rich studies after enfortumab vedotin are needed to define its optimal use.