Abstract CT073: Efficacy of novel oral SERD elacestrant in fulvestrant-refractory hormone receptor-positive (HR+) breast cancer: a translational investigation

Abstract Purpose: Metastatic HR+ breast cancer initially responds to serial courses of endocrine therapy but ultimately becomes refractory Elacestrant, a new generation oral selective estrogen receptor degrader (SERD) and antagonist, has demonstrated efficacy in a subset of women with advanced HR+ breast cancer (Bidard FC, et al J Clin Oncol 2022;40:3246-3256), but there are few patient-derived models to characterize its effect in advanced cancers with diverse treatment histories and acquired mutations In this translational study, we tested the efficacy of elacestrant on ex vivo circulating tumor cells (CTCs) and patient-derived xenograft (PDX) mouse models with serial exposures to fulvestrant and conducted a reanalysis of the EMERALD trial to evaluate the efficacy of elacestrant vs standard endocrine therapy among patients who had received prior fulvestrant. Methods: Using PDX models and cultured CTCs isolated from metastatic breast cancer patients, we analyzed sensitivity to elacestrant, compared with the currently approved SERD, fulvestrant We further analyzed clinical responses to elacestrant, compared with endocrine therapy, among women who had previously been treated with a fulvestrant-containing regimen from the recent phase 3 EMERALD Study (NCT03778931), Results: In a patient-derived HR+ breast cancer PDX model, we demonstrate that elacestrant, at a clinically relevant dose, is highly effective in tumors extensively pretreated with fulvestrant In cultured CTCs isolated from HR+ breast cancer patients who had received multiple prior treatments, including fulvestrant, elacestrant is active, independent of mutations in the estrogen receptor (ESR1) or Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Alpha (PIK3CA) genes In these cells, elacestrant suppresses estrogen-receptor (ER) signaling at concentrations below those required for protein degradation Post-hoc analysis of the EMERALD clinical trial confirms that elacestrant is effective in patient populations previously treated with fulvestrant-containing regimens, irrespective of ESR1 mutation status. Conclusion: In the EMERALD study, elacestrant showed significantly prolonged PFS compared with SOC (including fulvestrant) Using a PDX model and CTCs isolated from patients with MBC from the EMERALD study, this translational investigation demonstrates that elacestrant retains efficacy in breast cancer cells that have acquired resistance to currently available ER-targeting therapies Elacestrant may be an option for patients with HR+/HER2- breast cancer whose disease progressed while receiving fulvestrant in the metastatic setting. Citation Format: Taronish D. Dubash, Aditya Bardia, Brian Chirn, Brittany A. Reeves, Joseph A. LiCausi, Risa Burr, Ben S. Wittner, Sumit Rai, Hitisha Patel, Teeru Bihani, Heike Arlt, Francois-Clement Bidard, Virginia G. Kaklamani, Philippe Aftimos, Javier Cortés, Simona Scartoni, Monica Binaschi, Nassir Habboubi, A. John Iafrate, Mehmet Toner, Daniel A. Haber, Shyamala Maheswaran. Efficacy of novel oral SERD elacestrant in fulvestrant-refractory hormone receptor-positive (HR+) breast cancer: a translational investigation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT073.