Advances in Antibody–Drug Conjugate Therapy for Breast Cancer: Clinical and Mechanistic Insights into Trastuzumab Deruxtecan and Datopotamab Deruxtecan

Antibody–drug conjugates (ADCs) have emerged as a transformative class of targeted therapies, offering new hope in the management of advanced breast cancer and other solid tumors. Among the most impactful developments are fam-trastuzumab deruxtecan-nxki (T-DXd) and datopotamab deruxtecan (Dato-DXd, also known as Datroway), both of which integrate precise tumor targeting with potent cytotoxic activity. T-DXd, a HER2-directed ADC, has significantly advanced the treatment paradigm for HER2-positive and HER2-low metastatic breast cancer. Results from the DESTINY-Breast01, DESTINY-Breast03, and DESTINY-Breast04 trials demonstrated exceptional objective response rates (ORR) and substantial improvements in progression-free survival (PFS). The molecule’s design—featuring a high drug-to-antibody ratio and a cleavable linker that allows for a bystander effect—enables it to effectively eliminate heterogeneous tumor populations and overcome resistance to prior HER2-targeted therapies. These findings have positioned T-DXd as a breakthrough option that extends the benefits of HER2-directed treatment beyond traditional HER2-positive disease categories. Similarly, Dato-DXd, a novel ADC targeting TROP2, has shown considerable promise in hormone receptor (HR)-positive, HER2-negative breast cancer and non–small cell lung cancer (NSCLC). In the TROPION-Breast01 trial, Dato-DXd achieved a 37% reduction in the risk of disease progression, establishing its clinical potential as a new therapeutic standard. Like T-DXd, it employs a topoisomerase I inhibitor (DXd) payload, which, combined with its bystander killing capacity, ensures strong activity even in tumors with heterogeneous or low antigen expression. Despite their remarkable efficacy, both agents face challenges that require careful management. The most significant among these are interstitial lung disease (ILD), a potentially serious adverse event, as well as the issues of acquired resistance and treatment cost. Ongoing research efforts are focused on improving patient selection criteria, developing combination strategies with other targeted or immune-based therapies, and enhancing safety monitoring to mitigate toxicity.