Oral Selective Estrogen Receptor Degraders in HR-Positive/HER2- Negative Metastatic Breast Cancer: Clinical Insights on Sequencing, Biomarkers, and Emerging Combinations

KEY TAKEAWAYS

• ESR1 mutations emerge in 30%-40% of patients after aromatase inhibitor exposure, representing a key mechanism of acquired endocrine resistance that can be targeted with oral selective estrogen recept

• Two oral SERDs are now FDA-approved (elacestrant and imlunestrant), both demonstrating superior effi cacy in ESR1-mutated patients compared to standard endocrine therapy
• Treatment sequencing remains complex due to lack of head-to-head comparative data, requiring consideration of patient-specifi c factors including cost, access, biomarker testing, and practical considerations
• Future development focuses on combination strategies and earlier-line use to prevent resistance emergence, with promising results from trials showing the potential for ESR1-guided treatment switching