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EMERALD: updated results on the impact of duration of prior CDK4/6i  and FDA priority review

The U.S. Food and Drug Administration (FDA) has granted priority review for elacestrant, a selective estrogen receptor degrader (SERD), based on findings from the Phase III EMERALD trial (NCT03778931).1 

Endocrine therapy has become the backbone of treatment for the >70% of breast cancers that are endocrine receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-).2,3 Yet despite endocrine therapies dramatically improving outcomes for patients with ER+/ HER2- breast cancers, the emergence of resistance– particularly through the acquisition of mutations in the estrogen receptor 1 gene (ESR1) – has become a clinical challenge.3–5 The second-generation oral SERD elacestrant has demonstrated activity against wild-type and mutant ESR1 breast cancer cell lines and patient-derived xenograft models.6 These models were also resistant to CDK4/6 inhibitors (CDK4/6i),6 which are commonly combined with endocrine therapies.7 

The randomized, open-label, active-controlled EMERALD trial is evaluating elacestrant as second- or third-line monotherapy in ER+, HER2- metastatic breast cancer (MBC) patients who had received prior treatment with one or two lines of endocrine therapy, including a CDK4/6i. The primary endpoints of the study were progression-free survival (PFS) in the overall patient population and in those with ESR1 mutations. MBC patients (n = 478), including 228 with ESR1 mutations, were randomized to receive either elacestrant (n = 239) or standard of care (SOC) with the investigator’s choice of aromatase inhibitor (AI) or fulvestrant (n = 239). 

Updated results on the impact of duration of prior CDK4/6i on PFS were presented by Virginia Kaklamani, MD, of UT Health San Antonio, San Antonio, TX, at the San Antonio Breast Cancer Symposium 2022.  Elacestrant demonstrated a significantly longer median PFS (mPFS) versus SOC in all patients (hazard ratio (HR) [95% confidence interval] = 0.70 [0.55-0.88]; P = 0.002) and in those with ESR1 mutations (HR = 0.55 [0.39-0.77]; P = 0.0005).8 This PFS advantage was positively associated with the duration of prior treatment with CDK4/6i, with longer duration of prior CDK4/6i correlating with longer mPFS on elacestrant, and more pronounced in patients with ESR1 mutant disease (≥six months of prior CDK4/6i: mPFS in all patients = 2.8 months on elacestrant versus 1.9 months on SOC, HR = 0.69 [0.54-0.88], mPFS in ESR1 mutant = 4.1 versus 1.9 months, respectively, HR 0.52 [0.36-0.74]; ≥12 months of prior CDK4/6i: mPFS all = 3.8 versus 1.9 months, respectively, HR = 0.61 [0.45-0.83], mPFS ESR1 mutant = 8.6 versus 1.9 months, respectively, HR = 0.41 [0.26-0.63]; ≥18 months of prior CDK4/6i: mPFS all = 5.5 versus 3.3 months, respectively, HR = 0.70 [0.48-1.02], mPFS ESR1 mutant = 8.6 versus 2.1 months, respectively HR = 0.47 [0.20-0.79]). 

Elacestrant was well tolerated in this second- and third-line setting; most adverse events (AEs) were grade 1/2. Only 3.4% of elacestrant and 0.9% of SOC patients discontinued therapy because of an AE. A small percentage of patients on each therapy received an antiemetic; 8.0%, 3.7%, and 10.3%, on elacestrant, fulvestrant, and AI, respectively. No hematological safety signal was observed, and no patients had sinus bradycardia. These safety data were consistent with previously reported results. 

Secondary endpoints included overall survival (OS), objective response rate (ORR) and duration of response (DOR), for which the outcomes are still being assessed. 

Overall, EMERALD met its primary endpoint, suggesting elacestrant is a potential treatment option for ER+, HER2- MBC patients with endocrine therapy resistance, and particularly in those with ESR1 mutant disease and/or longer duration of prior treatment with CDK4/6i.  

Written by Hannah Balfour

References 

  1. Menarini Group’s Elacestrant Granted Priority Review by the U.S. FDA for Patients with ER+/HER2- Advanced or Metastatic Breast Cancer. News release. Cision PR Newswire. Menarini Industrie Farmaceutiche Riunite. August 11, 2022. Accessed December 2, 2022.  Available from: https://www.prnewswire.com/news-releases/menarini-groups-elacestrant-granted-priority-review-by-the-us-fda-for-patients-with-erher2–advanced-or-metastatic-breast-cancer-301604240.html 
  1. Downton T, Zhou F, Segara D, et al. Oral selective estrogen receptor Degraders (SERDS) in breast cancer: Advances, challenges, and current status. Drug Design, Development and Therapy. 2022Sep2;Volume 16:2933–48.  
  1. Howlader N, Altekruse SF, Li CI, et al. US incidence of breast cancer subtypes defined by joint hormone receptor and HER2 status. JNCI: Journal of the National Cancer Institute. 2014Apr28;106(5).  
  1. Spoerke JM, Gendreau S, Walter K, et al. Heterogeneity and clinical significance of ESR1 mutations in ER-positive metastatic breast cancer patients receiving fulvestrant. Nature Communications. 2016May13;7(1).  
  1. Toy W, Shen Y, Won H, et al. ESR1 ligand-binding domain mutations in hormone-resistant breast cancer. Nature Genetics. 2013Nov3;45(12):1439–45.  
  1. Patel HK, Tao N, Lee K-M, et al. Elacestrant (RAD1901) exhibits anti-tumor activity in multiple ER+ breast cancer models resistant to CDK4/6 inhibitors. Breast Cancer Research. 2019Sep16;21(1).  
  1. Hu Q, Kang W, Wang Q, Luo T. Role of CDK4/6 inhibitors in patients with hormone receptor (hr)-positive, human epidermal receptor-2 negative (HER-2) metastatic breast cancer study protocol for a systematic review, network meta-analysis and cost-effectiveness analysis. BMJ Open. 2022May30;12(5). 
  1. Bidard F-C, 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. Journal of Clinical Oncology. 2022Oct1;40(28):3246–56.