Abstract
Brain metastases (BM) represent a significant unmet need in ER+/HER2– mBC. Although endocrine therapy (ET) plus CDK4/6i is the 1L systemic treatment, most agents have limited BBB penetration, and tumors eventually develop resistance to ET, leading to disease progression. Elacestrant is the only single-agent oral SERD to significantly improve PFS versus standard-of-care ET in the EMERALD trial in both the overall population (HR = 0.70; 95% CI:0.55-0.88; P = 0.0018) and in patients with ESR1-mutant tumors (HR = 0.55; 95% CI:0.39-0.77; P = 0.0005), with a manageable safety profile (Bidard, 2022). Preclinical data demonstrate both elacestrant and abemaciclib cross the BBB (Conlan, 2020; Tolaney, 2020), providing a rationale for evaluating this combination in patients with BM. ELECTRA (NCT05386108) is an open-label, multicenter, phase 1b/2 study evaluating elacestrant plus abemaciclib in patients with BM from ER+/HER2– breast cancer. Eligibility includes locally advanced/mBC with ≥1 active, measurable BM (RECISTv1.1), prior therapy in the metastatic setting including ≥1 ET, ≤2 chemotherapy regimens, and 0-2 prior CDK4/6i (excluding abemaciclib). Phase 1b established the RP2D. Phase 2 primary endpoint is ORR (RECISTv1.1). Secondary endpoints include iORR, DoR, CBR, PFS, OS, PK, and QoL. Exploratory endpoints include CSF PK of elacestrant plus abemaciclib. This analysis reports phase 2 CSF PK results. In evaluable patients (n = 7), elacestrant achieved clinically meaningful CSF concentrations, with levels exceeding the target engagement threshold in 50% of patients. Abemaciclib attained CSF levels sufficient for CDK4/6 inhibition. These findings confirm that the combination achieves pharmacologically relevant drug exposure in the CNS. Updated safety, and clinical efficacy data, including intracranial-response assessments, will be presented (n = 33). Both elacestrant and abemaciclib successfully penetrated the BBB, achieving clinically meaningful CSF concentrations in most patients. These PK data support the continued evaluation of this all-oral BBB-penetrant combination for patients with ER+/HER2– mBC and BM. The phase 2 portion of ELECTRA is actively enrolling worldwide.