Datopotamab deruxtecan for endocrine-resistant HR-positive/HER2-negative breast cancer: biological rationale and...

Hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR-positive/HER2-negative) breast cancer is primarily managed with endocrine-based therapies; however, resistance to endocrine therapy and CDK4/6 inhibitors commonly develops in advanced disease. Following treatment failure, therapeutic options are largely limited to sequential chemotherapy, which provides modest clinical benefit and is associated with cumulative toxicity. Antibody-drug conjugates (ADCs) targeting trophoblast cell surface antigen 2 (TROP-2) have emerged as a promising strategy for delivering cytotoxic agents selectively to tumor cells in endocrine-refractory disease. This narrative review summarizes current evidence on the biological rationale, pharmacologic characteristics, and clinical development of datopotamab deruxtecan (Dato-DXd), with emphasis on findings from the phase III TROPION-Breast01 trial and relevant translational studies. Datopotamab deruxtecan is a TROP-2-directed ADC that enables targeted delivery of a potent topoisomerase I inhibitor payload to tumor cells. In the TROPION-Breast01 trial, Dato-DXd demonstrated a statistically significant improvement in progression-free survival compared with investigator's choice chemotherapy in patients with endocrine-refractory HR-positive/HER2-negative metastatic breast cancer. Clinical activity was observed across heterogeneous TROP-2 expression, including in heavily pretreated patients and those with visceral disease. Hematologic toxicity was relatively limited, although interstitial lung disease remains an important safety consideration requiring proactive monitoring. Datopotamab deruxtecan represents a clinically meaningful therapeutic option based on the targeted delivery of cytotoxic chemotherapy for patients with endocrine-resistant HR-positive/HER2-negative breast cancer. Ongoing studies are required to define optimal treatment sequencing, combination strategies, and long-term safety outcomes.