SERD Wars: Clinical Integration of Emerging Endocrine-Directed and Precision Therapies in Breast Cancer

Despite therapeutic advances, breast tumors treated with definitive intent can recur, and metastatic breast cancer (MBC) remains incurable. Hormone receptor-positive, HER2-negative (HR+/HER2-) breast cancer is driven by estrogen receptor (ER) signaling, and endocrine therapy (ET), frequently combined with CDK4/6 inhibition, is a key treatment of endocrine-sensitive disease. Endocrine resistance inevitably develops in the metastatic setting, often mediated by acquired ESR1 mutations that promote ligand-independent ER activation and reduce sensitivity to standard antiestrogens. Multiple next-generation ER-directed therapies are being developed to overcome resistance and improve outcomes, several of which are entering practice. This review examines clinical and translational evidence supporting emerging ER-targeted monotherapies and combination strategies across the metastatic and curative-intent settings. Pivotal trials demonstrate that oral selective estrogen receptor degraders (SERDs) and other novel ER-directed agents enhance anticancer activity, particularly for ESR1-mutant disease. Multidrug regimens pairing oral SERDs with CDK4/6 inhibitors, or with agents targeting the PI3K/AKT pathway, have shown encouraging efficacy in endocrine-refractory MBC, and these advances are reshaping management paradigms. Trial results and regulatory approvals are contextualized by outstanding questions surrounding the adoption of newer endocrine therapies. Their optimal integration and sequencing in practice remain uncertain, and for tumors harboring dual ESR1 and PIK3CA mutations, with multiple biomarker-guided options available, the best treatment strategies are unclear. Furthermore, dynamic monitoring of circulating tumor DNA for acquired ESR1 mutations could enable early therapeutic switching to a more active agent, but limitations remain for the broader adoption of this approach. With several oral SERDs emerging contemporaneously, data are needed to assess their relative efficacy, safety, and potential interchangeability. As the ET landscape grows increasingly complex, integrating clinical-genomic biomarkers with evidence from trials and real-world experience will be critical to optimize personalized care.