Endocrine therapy is the foundation of first-line therapy in most patients with hormone receptor–positive, HER2-negative metastatic breast cancer. Many of these patients respond to endocrine therapy but eventually become resistant to it through both intrinsic and acquired resistance mechanisms. This resistance has led to the use of targeted agents and combination strategies in later lines of therapy.1
Melissa McShane, MD
Lori J. Goldstein, MD, FASCO
Therapeutic Options After Standard Endocrine Therapy
Identifying therapies that are effective in tumors resistant to standard endocrine therapy is a challenge. Endocrine resistance is most often driven by ligand-independent estrogen receptor reactivation,2 such as estrogen receptor 1 (ESR1) mutations, which most often occur in hotspot regions in the ligand binding domain of estrogen receptor.3 Selective estrogen receptor degraders (SERDs) bind the estrogen receptor and induce degradation. SERDs have the potential to block both endocrine-dependent and endocrine-independent estrogen receptor signaling through ablation of the estrogen receptor, overcoming many potential causes of resistance.4
The SERD fulvestrant has been shown to be effective in the presence of an ESR1 mutation, although not as effective when compared with wild-type ESR1.3 Evaluation of the genetic landscape and clonal evolution of breast cancer resistance in the PALOMA-3 trial revealed that resistance to fulvestrant is a major driver of resistance to the combination of palbociclib plus fulvestrant.5 Acquired ESR1 mutations after fulvestrant use could be the result of poor bioavailability and incomplete estrogen receptor blockade by the required route of intramuscular administration.5
Novel oral SERDs, including elacestrant, are attractive therapeutic options for several reasons. These agents are oral, and therefore their dosing is not limited by intramuscular administration, as compared with fulvestrant.
Elacestrant is a nonsteroidal SERD that degrades the estrogen receptor alpha in a dose-dependent manner, inhibits estradiol-dependent estrogen receptor–directed gene transcription and tumor growth, and has good oral bioavailability.6 Elacestrant demonstrated single-agent activity in a phase I study of heavily pretreated women with estrogen receptor–positive, HER2-negative metastatic breast cancer.7
“Identifying therapies that are effective in tumors resistant to standard endocrine therapy is a challenge.— Melissa McShane, MD, and Lori J. Goldstein, MD, FASCO
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EMERALD Trial Results
As summarized in this issue of The ASCO Post, the EMERALD trial, reported by Bidard et al, is a phase III randomized, open-label, active-controlled trial evaluating elacestrant as second- or third-line monotherapy in estrogen receptor–positive, HER2-negative advanced or metastatic breast cancer.8 This study enrolled men and postmenopausal women who had experienced disease progression or relapse on or after one or two lines of endocrine therapy for advanced disease, one of which had to be given in combination with a cyclin-dependent kinase 4/6 inhibitor. Patients could not have received more than one line of chemotherapy for advanced disease. Patients were randomly assigned 1:1 to receive 400 mg of elacestrant daily or standard-of-care therapy, which included fulvestrant or an aromatase inhibitor (anastrozole, letrozole, or exemestane).
The primary endpoints were progression-free survival in all patients and in those with detectable ESR1 mutation, assessed by blinded independent central review. Secondary endpoints included overall survival, objective response rate, and duration of response.
Median progression-free survival in the intention-to-treat population was 2.8 months with elacestrant vs 1.9 months with the standard of care (hazard ratio [HR] = 0.70, 95% confidence interval [CI] = 0.55–0.88. P = .002). In the ESR1-mutant arm, median progression-free survival was 3.8 months with elacestrant vs 1.9 months with the standard of care (HR = 0.55, 95% CI = 0.39–0.77, P = .0005). Elacestrant was reported to be well tolerated, with the most common adverse event being nausea. Adverse events leading to treatment discontinuation were infrequent, occurring in 6.3% of patients in the elacestrant arm vs 4.4% in the standard-of-care arm.
The investigators noted an initial drop in the progression-free survival curves for both arms, which they noted could represent endocrine resistance in the second/third-line setting but clear separation favoring elacestrant afterward in the endocrine-sensitive setting. They did a nonprespecified landmark analysis at 6 and 12 months. The progression-free survival rate at 6 months was 34.3% vs 20.4% with elacestrant vs the standard of care in all patients. In those with ESR1 mutations, the 6-month rate was 40.8% vs 19.1%. The rates of progression-free survival at 12 months were 22.3% vs 9.4% in all patients and 26.8% vs 8.2% among those with ESR1 mutation. The interim analysis of overall survival showed hazard ratios favoring elacestrant of 0.75 in all patients and 0.59 in those with ESR1 mutation, although neither hazard ratio was statistically significant.
The trial does show that oral SERDs can be a safe and effective alternative, especially in a particular population for whom intramuscular fulvestrant is difficult.— Melissa McShane, MD, and Lori J. Goldstein, MD, FASCO
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Overall, the EMERALD trial showed statistically significant improvement in progression-free survival both in the total population and the ESR1-mutant subgroup. Many patients in this trial, however, did not receive much benefit, given the median progression-free survival of about 2 to 3 months in both arms. The progression-free survival differences seen in the landmark analysis at 6 and 12 months may highlight elacestrant’s effectiveness in an endocrine-sensitive subgroup, but these results should be interpreted with caution, given this was not a predefined primary endpoint. This difference highlights the need to better determine which patients may benefit from elacestrant and to identify markers for continued endocrine sensitivity.
The trial does show that oral SERDs can be a safe and effective alternative, especially in a particular population for whom intramuscular fulvestrant is difficult. This trial is not practice-changing but supports the need for further research utilizing oral SERDs in combination trials in metastatic breast cancer and in the adjuvant setting as well.
Dr. McShane is Assistant Professor in the Department of Hematology Oncology, and Associate Program Director of the Hematology Oncology Fellowship Program at Fox Chase Cancer Center. Dr. Goldstein is Professor of Medicine in the Department of Hematology Oncology; Director of the Phil and Naomi Lippincott Breast Evaluation Center; and Associate Director Clinical Research at Fox Chase Cancer Center, Philadelphia.
DISCLOSURE: Dr. McShane reported no conficts of interest. Dr. Goldstein has received honoraria from Daiichi Sankyo, Genomic Health, Roche/Genentech, and Teva; has served as a consultant or advisor to Aduro Biotech, Amgen, Eisai, Genentech, Genomic Health, Immunomedics, Merck, Mylan, Myriad Genetics, NanoString Technologies, Puma Biotechnology, and Syndax; has received institutional research funding from Genentech/Roche and Merck; and has held other relationships with Daiichi Sankyo.
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3. Fribbens C, O’Leary B, Kilburn L, et al: Plasma ESR1 mutations and the treatment of estrogen receptor-positive advanced breast cancer. J Clin Oncol 34:2961-2968, 2016.
4. Xiong R, Zhao J, Gutgesell LM, et al: Novel selective estrogen receptor down-regulators (SERDs) developed against treatment-resistant breast cancer. J Med Chem 60:1325-1342, 2017.
5. O’Leary B, Cutts RJ, Liu Y, et al: The genetic landscape and clonal evolution of breast cancer resistance to palbociclib plus fulvestrant in the PALOMA-3 trial. Cancer Discov 8:1390-1403, 2018.
6. Garner F, Shomali M, Paquin D, et al: RAD1901: A novel, orally bioavailable selective estrogen receptor degrader that demonstrates antitumor activity in breast cancer xenograft models. Anticancer Drugs 26:948-956, 2015.
7. Bardia A, Kaklamani V, Wilks S, et al: Phase I study of elacestrant (RAD1901), a novel selective estrogen receptor degrader, in ER-positive, HER2-negative advanced breast cancer. J Clin Oncol 39:1360-1370, 2021.
8. Bidard FC, Kaklamani VG, Neven P, et al: Elacestrant (oral selective estrogen receptor degrader) versus standard endocrine therapy for estrogen receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: Results from the randomized phase III EMERALD trial. J Clin Oncol. May 18, 2022 (early release online).
As reported in the Journal of Clinical Oncology by François-Clément Bidard, MD, PhD, of the Institut Curie, Paris and Saint Cloud, and colleagues, the phase III EMERALD trial has shown prolonged progression-free survival with the oral selective estrogen receptor degrader elacestrant vs standard...