Clinical and Genomic Factors Associated with Elacestrant Outcomes in ESR1-Mutant Metastatic Breast Cancer.

ESR1 mutations mediate resistance to antiestrogen therapy in hormone receptor-positive metastatic breast cancer (MBC). Elacestrant, an oral selective estrogen receptor degrader, improves progression-free survival over standard endocrine therapy in ESR1-mutant MBC. We assessed real-world elacestrant use and clinical-genomic factors associated with outcomes. This study used the GuardantINFORM database, linking >42,000 real-world breast cancer cases with sequencing and claims data. We included patients with activating ESR1 mutations detected <6 months before elacestrant initiation (January 2023-March 2024). Outcomes of time-to-treatment-discontinuation, time-to-next-treatment (TTNT), and overall survival were estimated with Kaplan-Meier and Cox regression analysis, adjusting for clinical variables. We identified 756 patients (76% with prior cyclin-dependent kinase-4/6 inhibitor and 38% with prior chemotherapy exposure), and 742 (98.2%) were evaluable for outcomes. The median TTNT was 6.4 months, and the time-to-treatment-discontinuation was 4.6 months. In those with ≤1 prior lines of metastatic therapy, the TTNT was 8.8 months, compared with 6.0 months in the third-line setting. Prior fulvestrant exposure trended toward shorter treatment duration (hazard ratio, 1.19; 95% confidence interval, 0.91-1.56). Higher ESR1 polyclonality (≥4 alterations; 11% of patients) correlated with a shorter TTNT of 5.2 months (hazard ratio, 1.44; 95% confidence interval, 1.01-2.06), but efficacy was consistent across ESR1 alleles (e.g., Y537S and D538G). Disease with dual ESR1 and PI3K pathway mutations (PIK3CA, AKT1, and PTEN) had a median TTNT of 5.2 months. In ESR1-mutant MBC, elacestrant treatment durations support the routine use of elacestrant monotherapy in appropriately selected patients. For patients with concurrent ESR1 and PI3K pathway mutations, single-agent activity was comparable with outcomes observed in phase III studies. See related article by Rugo et al., p. 179.