PS5-09-15: ERADICATE: A phase Ib/II study of elacestrant plus trastuzumab deruxtecan in patients with CDK4/6 inhibitor and endocrine-resistant HR+/HER2-low or HER2-ultralow metastatic breast cancer

Abstract Background: The oral selective estrogen receptor degrader (SERD) elacestrant is FDA-approved for patients with hormone receptor-positive/HER2-negative metastatic breast cancer (HR+/HER2- MBC) with an ESR1 mutation and disease progression on first-line endocrine therapy (ET) with a CDK4/6 inhibitor. Furthermore, most patients with HR+/HER2- MBC have HER2-low or HER2-ultralow disease, which makes them eligible for treatment with trastuzumab deruxtecan (T-DXd). We recently generated preclinical data showing that the SERD fulvestrant produces synergistic activity with the chemotherapeutic agents fluorouracil and capecitabine in ESR1-mutant HR+ breast cancer cell lines.1 We also showed that in ER+/HER2- tumors, higher HER2 expression is associated with higher ER signaling.2 The phase Ib/II ERADICATE trial will evaluate the safety and efficacy of elacestrant plus T-DXd in patients with endocrine-resistant, HER2-low or HER2-ultralow HR+/HER2- MBC. Methods: Eligible patients include women or men age ≥ 18 years with HR+/HER2-low or HER2-ultralow (by local pathology review) unresectable locally advanced or metastatic breast cancer. HR+ is defined as estrogen receptor ≥ 10% (with any progesterone receptor expression). HER2-low is defined as HER2 IHC 1+ or IHC 2+ and ISH non-amplified. HER2-ultralow is defined as HER2 IHC 0 with any membranous staining on any prior primary or metastatic sample. The study population will be enriched for patients with ESR1 mutations (approximately 50%). Participants must have had disease progression on or within 12 months of adjuvant ET with a CDK4/6 inhibitor, or 1-2 lines of ET and CDK4/6 inhibitor in the MBC setting. Patients with stable or untreated, asymptomatic central nervous system (CNS) metastases are eligible. Participants must have measurable disease per RECIST 1.1 criteria and must not have received any prior chemotherapy or ADC in the metastatic setting. All participants will receive elacestrant 345 mg orally on days 1-21 and T-DXd 5.4 mg/kg IV on day 1 of each 21-day cycle. Treatment will continue until disease progression or unacceptable toxicity. The co-primary endpoints are DLT rates/determination of the RP2D (phase 1b) and objective response rate (ORR, phase II) in the overall study population. There will be a safety lead-in among the first 12 patients to determine the RP2D. Analysis of ORR will follow a Simon’s 2-stage design to distinguish between null and alternative ORRs of 50% and 65%, respectively, with 85% power at a one-sided type I error of 10%. Twenty-eight patients will be enrolled in stage 1, and if there are ≥ 15 responses, an additional 37 patients will be enrolled in stage 2. The combination will be considered worthy of further study if ≥ 38 objective responses are observed among the total 65 patients. Secondary endpoints include ORR in the ESR1-mutant population, as well as clinical benefit rate, duration of response, progression-free survival, and overall survival in both the overall study population and the ESR1-mutant population. Research biopsies will be performed at baseline (before initiation of study therapy) and at cycle 2, with an optional research biopsy at progression/end of treatment. Serial research blood samples will be collected for circulating tumor DNA (ctDNA) analyses. ERADICATE is currently pending the start of accrual. Research Sponsor: Stemline Therapeutics. References 1. Grinshpun A, Russo D, Ma W, et al: Pure estrogen receptor antagonists potentiate capecitabine activity in ESR1-mutant breast cancer. NPJ Breast Cancer 10:42, 2024 2. Qiu X, Tarantino P, Li R, et al: Molecular characterization of HER2-negative breast cancers reveals a distinct patient subgroup with 17q12 deletion and heterozygous loss of ERBB2. ESMO Open 10:104111, 2025 Citation Format: S. Sammons, S. Tolaney, N. Lin, L. Anderson, E. Mayer, N. Sinclair, J. Stoeckle, P. Sanz-Altamira, N. Graham, R. Jeselsohn. ERADICATE: A phase Ib/II study of elacestrant plus trastuzumab deruxtecan in patients with CDK4/6 inhibitor and endocrine-resistant HR+/HER2-low or HER2-ultralow metastatic breast cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS5-09-15.