Positioning oral selective estrogen receptor degraders in patients with metastatic breast cancer.

Approximately 40 % of patients with estrogen receptor (ER)-positive, HER2-negative metastatic breast cancer (mBC) who receive first-line treatment with CDK4/6 inhibitors (CDK4/6i) and aromatase inhibitors (AIs) develop acquired ESR1 mutations, leading to ligand-independent ER activation and resistance to AIs. Fulvestrant, the first selective estrogen receptor degrader (SERD) approved for clinical use, was developed to address this resistance and has remained the standard second-line endocrine therapy. However, its clinical use is limited by intramuscular administration and low bioavailability. To overcome these limitations, oral SERDs have been developed and have demonstrated superiority over fulvestrant in patients with ESR1-mutant tumors following progression on CDK4/6i plus AI therapy. The positioning of oral SERDs in the treatment sequence is evolving. They are being evaluated not only in the post-CDK4/6i setting but also as first-line therapy in combination with CDK4/6i, and as an early switch strategy guided by detection of emerging ESR1 mutations in circulating tumor DNA (ctDNA). The SERENA-6 trial demonstrated that early switching to the oral SERD camizestrant in patients with ESR1 mutation detected on ctDNA, prior to radiographic progression, significantly improved progression-free survival and patient-reported outcomes. However, whether molecular progression should routinely trigger treatment change remains an open question, requiring validation through long-term clinical endpoints. In conclusion, the integration of oral SERDs into current therapeutic algorithms poses clinical challenges, and ongoing trials will clarify their role across the disease continuum.