Decoding Clinical Trials in Metastatic Breast Cancer: Practical Insights for Optimal Therapy Sequencing.

The art of sequencing therapy in the management of breast cancer is a multifaceted challenge that demands the careful integration of clinical trial data, real-world evidence, and individualized patient factors to guide treatment decisions. As the therapeutic landscape evolves rapidly with new agents and combinations, clinicians are confronted with critical decisions on how best to order treatments to maximize benefit, minimize toxicity, and preserve future options. For patients with estrogen receptor-positive (ER+) disease, this review discusses how emerging resistance patterns after cyclin-dependent kinase 4 and 6 inhibitors require careful re-evaluation of subsequent endocrine and targeted therapies, as well as chemotherapy, emphasizing the need for evidence-based strategies and ethical crossover designs in clinical trials. In addition, for both ER+ and ER- metastatic breast cancer (MBC) with nonoverexpressed human epidermal growth factor receptor 2 (HER2), this review highlights pivotal trials investigating antibody-drug conjugates (ADCs)-including trastuzumab deruxtecan, sacituzumab govitecan, and datopotamab deruxtecan-and the challenges related to control arm selection and crossover that may affect outcome interpretation. Finally, for patients with HER2-positive disease, the review explores first-line and maintenance strategies-including insights from landmark trials like CLEOPATRA and PATINA-and addresses the impact of brain metastases on sequencing decisions. By critically appraising current data and identifying gaps in biomarker-guided and sequencing-specific strategies, this review provides practical insights to inform clinical practice and optimize personalized treatment plans for patients with MBC.