Abstract GS2-02: Elacestrant, an oral selective estrogen receptor degrader (SERD), vs investigator’s choice of endocrine monotherapy for ER+/HER2- advanced/metastatic breast cancer (mBC) following progression on prior endocrine and CDK4/6 inhibitor therapy: Results of EMERALD phase 3 trial

Abstract

Background: Endocrine therapy(ET) plus CDK4/6 inhibitor (i) is the mainstay for the management of estrogenreceptor-positive (ER+)/HER2- mBC. However, most patients (pts) with ER+ mBCeventually experience disease progression, including development of ESR1mutations (mESR1). Elacestrant, an oral SERD, demonstrated preclinical activity,and clinical activity in a phase 1 trial in ER+ mBC, including responses in ptswith prior fulvestrant, CDK4/6i, and mESR1tumors (Bardia JCO 2021).. Methods: EMERALD(NCT03778931), a multicenter, international, randomized, open-label, controlledphase 3 trial, enrolled postmenopausal pts with ER+/HER2- mBC who had received 1-2prior lines of ET and ≤1 line of chemotherapy in the mBC setting and had prior progressionon a ET plus CDK4/6i. Pts were randomized 1:1 to elacestrant (400 mg orallydaily) or standard of care (SOC; investigator’s choice of fulvestrant or anaromatase inhibitor). Stratification factors included mESR1 status (by central lab), priorfulvestrant exposure, and presence of visceral disease. The study had 2 primary endpoints of progression-free survival (PFS), by blindedindependent review committee, in pts withtumors harboring mESR1 and in all pts (mESR1 or mESR1 notdetected). Secondary endpoints included: overall survival (OS), safety, tolerability,and quality of life. An alpha-value of 0.0475 was used to determine statisticalsignificance (2-sided using the truncated Hochberg procedure).. Results: EMERALD enrolled 477 pts(228 with mESR1) between Feb 2019 - Oct 2020, with 239 pts randomized toreceive elacestrant vs 238 pts to SOC. Demographics and disease characteristicswere well-balanced across treatment arms [median age: 63 yrs vs 63.5 yrs; 2prior lines: 46% vs 40.8%; prior CDK4/6i: 100% in both arms]. The study met bothprimary endpoints. There was a 30% reduction in the risk of progression ordeath in the elacestrant arm in all pts (HR=0.697 [95% CI: 0.552, 0.88]; P=0.0018),and a 45% (HR=0.546 [95% CI: 0.387, 0.768]; P=0.0005) reduction in therisk of progression or death in pts with mESR1.For both endpoints, results in key prespecified subgroups, including visceral metastases,number of prior lines of therapy, pretreatment with fulvestrant, and geographicalregion, were consistent with the overall outcome. The PFS rate at 12 months was 22.32% (95% CI: 15.24%, 29.40%)with elacestrant vs 9.42% (95% CI: 4.02%, 14.81%) with SOC in all pts, and26.76% (95% CI: 16.17%, 37.36%) vs 8.19% (95% CI: 1.26%, 15.12%) in the mESR1 subgroup. The prespecified interim OS analysis plannedat the time of the final PFS analysis (allocated2-sided alpha level of 0.0001) demonstrated a trend in favor of elacestrant inall pts (HR=0.751 [95% CI: 0.542, 1.038]; P=0.0821) and in pts with mESR1(HR=0.592 [95% CI: 0.361, 0.958]; P=0.0325). The final OS analysisis expected next year. Common (>10%) treatment-related adverse events (AEs) withelacestrant vs SOC included: nausea (25.3% vs 8.7%), vomiting (11% vs 2.6%), and fatigue (11% vs 7.9%), mostlygrade 1/2. Treatment-emergent AEs leading to discontinuation of elacestrant orSOC were infrequent in both arms (6.3% and 4.4%). Grade ≥3 treatment-relatedAEs in the elacestrant arm vs SOC were 7.2% vs 3.1%, mainly driven by nausea(2.1% vs 0.9%). There were no treatment-related deaths in either group.. Conclusions:Elacestrant is the first oral SERD to demonstrate a statistically significantand clinically meaningful improvement of PFS vs SOC in a randomized phase 3study in pts with ER+/HER2- mBC in the 2nd/3rd-linesetting, including those whose tumors harbor mESR1. Elacestrant was well tolerated and hasthe potential to become the new standard of care for pts with ER+/HER2- mBC. Citation Format: Aditya Bardia, Patrick Neven, Guillermo Streich, Alberto J. Montero, Frédéric Forget, Marie-Ange Mouret-Reynier, Joo Hyuk Sohn, Peter Vuylsteke, Kathleen K. Harnden, Hung Khong, Judit Kocsis, Florence Dalenc, Virginia Kaklamani, Patrick Dillon, Sunil Babu, Simon Waters, Ines Deleu, José García-Sáenz, Emilio Bria, Marina Cazzaniga, Janice Lu, Philippe Aftimos, Javier Cortes, Shubin Liu, Dirk Laurent, Maureen G. Conlan, Francois-Clement Bidard. Elacestrant, an oral selective estrogen receptor degrader (SERD), vs investigator’s choice of endocrine monotherapy for ER+/HER2- advanced/metastatic breast cancer (mBC) following progression on prior endocrine and CDK4/6 inhibitor therapy: Results of EMERALD phase 3 trial [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr GS2-02.

How to Treat HR+/HER2- Metastatic Breast Cancer Patients after CDK4/6 Inhibitors: An Unfinished Story

“…To date, as suggested by clinical guidelines, after a first-line therapy with CDK4/6i and ET, treatment based on endocrine agents still represents an important possibility. Probably, single-agent ET is not enough efficacious in terms of disease control, as shown for the control arm in EMERALD and VERONICA trials; this could be particularly true in patients with bulky disease, or in those with a short response duration of first-line strategy [ 54 , 70 ].…”

“…Elacestrant showed a statistically significant improvement in PFS versus standard ET, with 30% reduction in the risk of progression or death in all patients (HR = 0.697 [95% CI: 0.55, 0.88]; p = 0.0018) and 45% reduction in the risk of progression or death in patients with ESR1 mutation (HR = 0.55 [95% CI: 0.39, 0.77]; p = 0.0005). The PFS rate at 12 months was 22.32% [ 54 ]. Other trials, analyzing elacestrant in association with CDK4/6i or mTOR inhibitors, are already ongoing or planned, in the same subgroup of patients, in earlier lines.…”

Update Breast Cancer 2022 Part 2 – Advanced Stage Breast Cancer

“…In der Gruppe von Patientinnen mit einer ESR1-Mutation in der ctDNA wurde das mediane PFS von im Median 1,9 Monaten auf 3,8 Monate verbessert (HR = 0,546; 95 %-KI: 0,387-0,768). Vergleicht man Patientinnen, die mit Elacestrant behandelt wurden, mit Patientinnen unter Fulvestranttherapie, betrug die HR in der Gesamtgruppe 0,684 (95 %-KI: 0,521-0,897) und in der Gruppe mit ESR1-Mutation 0,504 (95 %-KI: 0,341-0,741) [8]. Somit konnte gezeigt werden, dass in dieser stark vorbehandelten Population der orale SERD Elacestrant wirksamer war als Fulvestrant oder eine Behandlung mit Aromatasehemmern.…”

Virginia G. Kaklamani, MD, highlights important news from SABCS

“…“The EMERALD trial tested a novel oral antiestrogen called elacestrant, showing that it was superior to the standard‐of‐care antiestrogens in improving outcomes in patients with metastatic ERpositive disease. The FDA will look at this drug for potential approval,” says Dr. Kaklamani 9 . “It’s the first drug of its class with a large, randomized phase 3 trial looking at outcomes, and it was positive.”…”