Abstract GS3-01: GS3-01 EMERALD phase 3 trial of elacestrant versus standard of care endocrine therapy in patients with ER+/HER2- metastatic breast cancer: Updated results by duration of prior CDK4/6i in metastatic setting
Authors: Bardia Aditya , Bidard Francois-Clement , Neven Patrick , Streich Guillermo , Montero Alberto J. , Forget Frederic , Mouret-Reynier Marie-Ange , Sohn Joo Hyuk , Taylor Donatienne , Harnden Kathleen K. , Khong Hung , Kocsis Judit , Dalenc Florence , Dillon Patrick , Babu Sunil , Waters Simon , Deleu Ines , García-Sáenz Jose Angel , Bria Emilio , Cazzaniga Marina Elena , Aftimos Philippe , Cortés Javier , Tonini Giulia , Sahmoud Tarek , Habboubi Nassir , Grzegorzewski Krzysztof , Kaklamani Virginia 
Published: March 2023

Abstract
Background: In patients (pts) with ER+/HER2− metastatic breast cancer (MBC) following progression on prior endocrine and CDK4/6i therapy, the EMERALD trial demonstrated significantly prolonged progression-free survival (PFS) and a manageable safety profile for elacestrant versus standard of care endocrine therapy (SoC). Benefit was observed in all pts and in pts with ESR1 mutant MBC (ESR1-mut). EMERALD is the only oral SERD monotherapy pivotal trial where all pts were pretreated with CDK4/6 inhibitor (CDK 4/6i). Here, we examine the impact of duration of prior CDK4/6i on PFS.
Methods: EMERALD (NCT03778931) is a randomized, open-label, phase 3 trial that enrolled pts with ER+/HER2- MBC who previously had 1-2 lines of endocrine therapy, mandatory CDK4/6i, and ≤1 chemotherapy; prior treatment with fulvestrant was allowed. Patients were randomized 1:1 to elacestrant (400 mg orally daily) or SoC (investigator’s choice of aromatase inhibitor or fulvestrant). If randomized to the control arm, patients who received prior fulvestrant were to receive an aromatase inhibitor, and vice versa. If two CDK4/6i were used in the metastatic setting (n=40), the cumulative duration was calculated.
Results: A total of 478 pts were randomized (228 with ESR1-mut) between Feb 2019 – Oct 2020 (n=239, elacestrant; n=239, SoC). Overall survival was not yet mature, as of September 2nd 2022. Updated PFS results show statistically significant results in favor of elacestrant, both in all pts and in pts with ESR1-mut. The duration of prior CDK4/6i in the metastatic setting was positively associated with PFS, the longer the duration of prior CDK4/6i in the metastatic setting (n=465), the longer the PFS on elacestrant versus SoC (Table 1).
Updated safety data were consistent with previously reported results. Most of the adverse events (AEs), including nausea, were grade 1 and 2, and only 3.4% and 0.9% of the pts discontinued trial therapy because of an AE on elacestrant and SoC, respectively. A low percentage of pts received an antiemetic; 8.0%, 3.7%, and 10.3%, on elacestrant, fulvestrant, and AI, respectively. No hematological safety signal was observed and none of the patients in either of the two treatment arms had sinus bradycardia.
Conclusions: EMERALD is the first phase 3 trial to demonstrate a significant PFS improvement versus SoC in all pts and in the subgroup with ESR1 mutations in pts with ER-positive/HER2-negative MBC with 1-2 prior lines of endocrine treatment ± one line of chemotherapy. Elacestrant demonstrated longer PFS versus SOC that was positively associated with the duration of prior treatment with CDK4/6i, which was more pronounced in pts with ESR1-mut MBC. In this 2nd and 3rd line setting, elacestrant was well tolerated with significantly longer PFS versus SoC, highlighting its potential role as a therapeutic option for pts with ER+/HER2- MBC.
Table 1: PFS estimates in the elacestrant and SoC arms based on different cut-off points for the duration of prior CDK4/6i.
Citation Format: Aditya Bardia, Francois-Clement Bidard, Patrick Neven, Guillermo Streich, Alberto J. Montero, Frederic Forget, Marie-Ange Mouret-Reynier, Joo Hyuk Sohn, Donatienne Taylor, Kathleen K. Harnden, Hung Khong, Judit Kocsis, Florence Dalenc, Patrick Dillon, Sunil Babu, Simon Waters, Ines Deleu, Jose Angel García-Sáenz, Emilio Bria, Marina Elena Cazzaniga, Philippe Aftimos, Javier Cortés, Giulia Tonini, Tarek Sahmoud, Nassir Habboubi, Krzysztof Grzegorzewski, Virginia Kaklamani. GS3-01 EMERALD phase 3 trial of elacestrant versus standard of care endocrine therapy in patients with ER+/HER2- metastatic breast cancer: Updated results by duration of prior CDK4/6i in metastatic setting [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS3-01.