Evolving ADC Strategies in HER2– mBC: TROPION-Breast01 and Real-World Data From ASCO 2025

Trastuzumab Deruxtecan Historical Context and Current Role

The TROPiCS-02 trial established sacituzumab govitecan as an important treatment option for hormone receptor–positive, HER2-negative metastatic breast cancer in the heavily pretreated setting. This phase 3 study enrolled patients who had received 2 to 4 prior chemotherapy regimens and demonstrated median progression-free survival of 5.5 months compared with 4 months with standard chemotherapy. Updated analysis confirmed overall survival benefit, establishing sacituzumab govitecan as a standard option in this treatment setting.

Trastuzumab deruxtecan’s role in hormone receptor–positive disease must be considered within the context of the Destiny-Breast04 and Destiny-Breast06 trials, which established efficacy in HER2-low and -ultralow populations, representing 85% of patients with hormone receptor–positive disease. Clinical implementation varies based on patient factors, with some clinicians using ADCs in the frontline post–CDK4/6 inhibitor setting for aggressive disease and others reserving these agents for later lines after exhausting endocrine options.

The sequential use of different ADCs requires careful consideration, as real-world analyses demonstrate diminished efficacy when using topoisomerase I inhibitor–containing ADCs sequentially. Neither TROPiCS-02 nor the DESTINY Breast trials allowed prior exposure to the alternative ADC, creating uncertainty about optimal sequencing. Clinical practice increasingly focuses on using trastuzumab deruxtecan first in the HER2-low/ultralow population, with sacituzumab govitecan reserved for later lines or specific clinical scenarios.