<p>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.</p>