Abstract
Around 80% of breast cancers in women aged 45 years and older are estrogen receptor–positive (ER+). Despite advances in endocrine therapy, resistance driven by ESR1 mutations remains a major clinical challenge. These mutations cause constitutive receptor activation even in estrogen-deprived environments, limiting the efficacy of aromatase inhibitors and fulvestrant. Imlunestrant (Inluriyo™) is the first FDA-approved oral selective estrogen receptor degrader (SERD) designed to overcome ESR1-mediated resistance. As a potent, brain-penetrant agent, it blocks coactivator binding and promotes proteasomal degradation of both wild-type and mutant receptors, including the resistant Y537S variant. The phase 3 EMBER-3 trial demonstrated improved progression-free survival and favorable tolerability compared with standard endocrine therapy. Imlunestrant’s oral formulation, safety profile, and ability to target ESR1 mutations mark a pivotal step toward personalized care for ER-positive, HER2-negative breast cancer. Its approval highlights the evolving landscape of precision oncology, emphasizing mutation-guided treatment selection and the potential of next-generation SERDs to reshape hormone-driven cancer management.