Trastuzumab deruxtecan and the evolving role of human epidermal growth factor receptor 2-targeted antibody-drug conjugates in breast and ovarian cancer.

PURPOSE OF REVIEW: Breast cancer remains a leading cause of cancer-related morbidity and mortality worldwide. One of the most significant advances in treatment has been the evolution of human epidermal growth factor receptor 2 (HER2)-targeted therapies. This review summarizes recent clinical progress in HER2-directed antibody-drug conjugates (ADCs), with specific focus on trastuzumab deruxtecan (T-DXd) in breast and ovarian cancer, and highlights emerging ADCs shaping the next generation of HER2-targeted therapy.

RECENT FINDINGS: T-DXd has demonstrated superior efficacy to trastuzumab emtansine (T-DM1) in breast cancer across the metastatic and adjuvant settings, and has also shown significant activity in HER2-low and ultralow disease. Mechanistic innovations, including a cleavable linker, a high drug-to-antibody ratio, and a membrane-permeable topoisomerase I inhibitor payload, enhance its potency. In ovarian cancer, T-DXd has shown promising early efficacy in heavily pretreated patients; however, additional real-world data are needed to better define its clinical benefit and optimize patient selection. Emerging HER2-directed ADCs such as disitamab vedotin aim to overcome resistance and broaden therapeutic options for patients.

SUMMARY: The efficacy of T-DXd represents a major advance in HER2-targeted therapy, expanding treatment beyond HER2-positive disease into a wider continuum of HER2 expression. Ongoing clinical development of next-generation ADCs aims to improve efficacy, safety, and access to precision-guided cytotoxic therapy across solid tumors.