Sequential Use of Trastuzumab Deruxtecan and Sacituzumab Govitecan in Patients with Breast Cancer: A Pharmacological Approach to Support the Clinical Rationale.

Antibody-drug conjugates (ADCs) represent a major advance in breast cancer therapy, with trastuzumab deruxtecan and sacituzumab govitecan emerging as leading agents targeting distinct tumor antigens and employing different linker-payload designs. Trastuzumab deruxtecan is a second-generation HER2-directed ADC composed of trastuzumab linked via a cleavable tetrapeptide linker to the camptothecin derivative exatecan, a highly potent topoisomerase I inhibitor. Its high drug-to-antibody ratio (DAR 8:1), membrane-permeable payload, and efficient lysosomal release confer strong antitumor activity, including a robust bystander effect in HER2-low tumors. By contrast, sacituzumab govitecan is a TROP-2-targeted ADC conjugated through a hydrolysable CL2A linker to SN-38, the active metabolite of irinotecan. Sacituzumab govitecan features a high DAR (7.6:1) and allows extracellular as well as intracellular release of SN-38, enhancing bystander killing in tumors with heterogeneous TROP-2 expression, while maintaining a favorable toxicity profile due to the lower intrinsic potency of SN-38 relative to exatecan. Since both these ADCs are conjugated to topoisomerase I inhibitors, concerns about potential cross-resistance regarding their sequencing in clinical practice are being raised, and currently there is a lack of predictive biomarkers providing a rational basis for their sequential administration. Resistance mechanisms exhibit significant heterogeneity: resistance to trastuzumab deruxtecan has been associated with mutations in TOPO I and SLX4, impaired lysosomal function, and efflux via ABC transporters. In contrast, resistance to sacituzumab govitecan is linked to overexpression of multidrug resistance proteins, particularly BCRP-mediated efflux. Clinically, trastuzumab deruxtecan has shown substantial efficacy in both HER2-positive and HER2-low breast cancer, whereas sacituzumab govitecan has demonstrated efficacy across triple-negative and hormone receptor-positive/HER2-negative breast cancers. Collectively, these agents highlight how variations in target antigen, linker chemistry, and payload potency impact ADC activity, therapeutic index, and potential strategies for sequential treatment in advanced breast cancer.