Pharmacist's Application to Practice

Elacestrant for Hormone Receptor (HR) Positive, Human Epidermal Growth Factor Receptor 2 (HER2) negative metastatic breast cancer.

Corresponding FDA Drug Update:

Elacestrant for ER-positive, HER2-negative, ESR1-mutated breast cancer

What is the potential role for elacestrant in the treatment of metastatic breast cancer?

  • Elacestrant is a novel selective estrogen receptor degrader (SERD) approved for the treatment of postmenopausal women or adult men, with estrogen receptor (ER) positive, human epidermal growth factor receptor 2 (HER2) negative, estrogen receptor 1 (ESR1) mutated advanced or metastatic breast cancer with disease progression following at least one line of endocrine therapy.1
  • ESR1 mutations are found in approximately 40% of HR+/HER2- metastatic breast cancer patients and result in the estrogen receptor remaining in an active conformation, allowing estrogen-independent ER activation and resistance to estrogen blockade therapy by aromatase inhibitors. ESR1 mutations have also been associated with partial resistance to tamoxifen and fulvestrant.1,2
  • ESR1 mutations are associated with worse progression free survival (PFS) and overall survival (OS).3
  • Elacestrant is a first-in-class, non-steroidal, oral selective estrogen receptor degrader. The last endocrine therapy to be approved for breast cancer was fulvestrant in 2002.1,2
  • Elacestrant’s mechanism varies in a dose dependent manner. At low doses, it acts as a selective estrogen receptor modulator (SERM) while at high doses it acts as a SERD.2
  • While fulvestrant is given as an intramuscular injection, elacestrant offers a more convenient method via the oral route.2
  • Study Design4:
    • EMERALD is an international, multicenter, randomized, open-label, phase III clinical study.
    • Patient population:
      • Post-menopausal women or men aged 18 years or older
      • Histologically or cytologically proven ER+/HER2- breast adenocarcinoma and either locoregionally recurrent or metastatic disease, including wildtype and ESR1-mutated patients.
      • Disease progression after 1-2 lines of endocrine therapy for advanced/metastatic disease. Patients must have been on previous CDK4/6 inhibitor treatment in combination with fulvestrant or an aromatase inhibitor.
      • Patients could only have one prior line of chemotherapy for advanced disease
      • Patients with symptomatic metastatic visceral disease or certain cardiovascular events were excluded.
  • Patients were randomized 1:1 to elacestrant or standard of care (SOC) therapy, which consisted of investigator’s choice of fulvestrant, anastrozole, letrozole, or exemestane, based on previous lines of therapy.
    • Randomization was stratified by ESR1 mutation status, prior treatment with fulvestrant, and visceral metastasis.
  • Results:
    • 477 patients were randomized to elacestrant 400 mg daily (239 patients) or standard of care (238 patients).
    • 115 patients had an ESR1 mutation in the elacestrant arm and 113 patients had an ESR1 mutation in the SOC arm (total 228 patients).
    • Most patients had 1 prior line of endocrine therapy.
      • 54% of patients in the elacestrant arm had 1 prior line of endocrine therapy versus 59.2% of patients in the SOC arm.
      • 46% of patients in the elacestrant arm had 2 prior lines of therapy versus 40.8% of patients in the SOC arm.
    • Very few patients had previous mTOR inhibitor or PI3K inhibitor exposure.
      • 4.2% of patients had a previous mTOR inhibitor and 1.3% of patients had a previous PI3K inhibitor in the elacestrant arm.
      • 2.5% of patients had a previous mTOR inhibitor and 0.4% had a previous PI3K inhibitor in the SOC arm.
    • Most patients had visceral metastases: 68.2% of patients in the elacestrant arm versus 71% of patients in the SOC arm. Visceral metastases included brain, lung, liver, pleural, and peritoneal involvement.
  • Primary Endpoint:
    • The primary endpoint was PFS in all patients and in patients with ESR1 mutations assessed by blinded independent central review (BICR).
    • PFS rate:
      • The 6-month PFS rate was 34.3% in all patients with elacestrant versus 20.4% with SOC.
      • The 6-month PFS rate was 40.8% in ESR1 mutated patients with elacestrant versus 19.1% in ESR1 mutated patients on SOC.
      • The 12-month PFS rate was 22.3% in all patients with elacestrant versus 9.4% on SOC.
      • The 12-month PFS rate was 26.8% in ESR1 mutated patients with elacestrant versus 8.2% in ESR1 mutated patients on SOC.
  • PFS Hazard Ratio
    • The hazard ratio for PFS in all patients was 0.70 (95% confidence interval [CI], 0.55–0.88, p = 0.002).
    • The hazard ratio for PFS in ESR1 mutated patients was 0.55 (95% CI, 0.39 – 0.77, p = 0.0005).
    • An exploratory analysis of PFS in the subgroup of patients without ESR1 mutations showed a HR of 0.86 (95% CI, 0.63 - 1.19), indicating that the PFS benefit in the overall population was primarily driven by the ESR1 mutated population.
  • Median PFS estimates were 2.8 months for all patients in the elacestrant arm vs. 1.9 months for all patients in the SOC arm.
  • Median PFS estimates were 3.8 months for ESR1 mutated patients in the elacestrant arm vs. 1.9 months for all patients in theSOC arm.
  • Fulvestrant comparison
    • The PFS HR of elacestrant versus fulvestrant was 0.68 (95% CI, 0.52 – 0.90, p=0.0049).
    • Elacestrant demonstrated improved PFS compared to fulvestrant in all patients with a 6-month PFS rate of 34.3% versus 22.9% and a 12-month PFS rate of 22.3% vs. 10.1%.
  • Secondary Endpoints:
    • Secondary endpoints included investigator-assessed PFS, OS in patients with ESR1 mutations, objective response rate, and duration of response.
      • Interim OS analysis demonstrated a HR of 0.75 (95% CI, 0.54 – 1.04, p=0.08) in all patients and HR of 0.59 (95% CI 0.36 – 0.96, p=0.03) in ESR1 mutated patients.
      • The HR for OS in ESR1 mutated patients was not statistically significant. Mature OS data will be published at a later date.
  • Subgroup analyses favored elacestrant in ESR1 wild-type and mutated patients, 1 or 2 of lines of prior endocrine therapy, no prior chemotherapy, presence of visceral metastases, and measurable disease at baseline.
    • The HR for patients with 2 prior lines of endocrine therapy was 0.59 (95% CI 0.42 – 0.84) versus 0.70 (95% CI 0.51 – 0.95) in patients with 1 prior line of endocrine therapy.
    • The differences in HR may be secondary to more endocrine resistance in the second and later line setting as opposed to retained endocrine sensitivity in the first-line setting.
    • The number of patients by involved visceral metastatic site and individual HR for PFS/OS for associated metastatic site were not available.
  • Safety:
    • Elacestrant was well tolerated with primarily grade 1-2 adverse events (AEs).
    • The most common AEs across all grades were nausea (35%), fatigue (19%), vomiting (19%), decreased appetite (14.8%), and arthralgia (14.3%).
    • Most common all grade lab abnormalities included hypercholesterolemia (30%), hypertriglyceridemia (27%), AST elevation (13.1%) and AST elevation (9.3%).

What role can the pharmacist play in the management of patients on elacestrant?

  • Elacestrant is available as 345 mg (equivalent to 400 mg elacestrant dihydrochloride) and 86 mg (equivalent to 100 mg elacestrant dihydrochloride) tablets.1
  • Coadministration with food is recommended to reduce nausea and vomiting and to improve elacestrant’s low oral bioavailability of ~10%.5
    • Elacestrant administration with a high fat meal (800-1000 calories, 50% fat) increased Cmax by 42% and AUC by 22% compared to fasted administration.
    • An example of a high fat breakfast includes fried eggs in butter, bacon strips, hash brown potatoes, and a glass of whole milk.6
  • Dosage modifications are indicated for hepatic impairment.1
    • Mild liver dysfunction (Child Pugh A) increases elacestrant AUC 1.28-fold and moderate liver dysfunction (Child Pugh B) increases AUC 1.83-fold.
    • PBPK model simulations predict an AUC increase by 3-fold in patients with severe liver dysfunction (Child Pugh C). An FDA required post-marketing pharmacokinetic trial in patients with severe liver dysfunction is ongoing.
    • Dose reduction to 258 mg daily is required for moderate liver dysfunction. Elacestrant should be avoided in patients with severe liver dysfunction.
  • Elacestrant is metabolized primarily via CYP3A4, and to a lesser extent by CYP2A6 and CYP2C9. Significant drug interactions with concomitant CYP3A4 inhibitors and inducers may occur, and concomitant use should be avoided if possible. Pharmacists can play a key role in reviewing medication lists for significant drug-drug interactions.5
    • Coadministration of elacestrant 172 mg once daily dose with strong CYP3A4 inhibitors resulted in 5.3x increase in AUC.
    • Coadministration of elacestrant 345 mg once daily dose with moderate CYP3A4 inhibitors resulted in 2.3x increase in AUC.
    • There are no recommendations for dose reductions for concomitant use with a CYP3A4 inhibitor or inducer.
  • Elacestrant is a weak P-glycoprotein (P-gp) inhibitor and weak breast cancer resistance protein (BCRP) inhibitor.5
  • Hypercholesterolemia and hypertriglyceridemia may develop with treatment.5
    • Lipid profile monitoring is recommended prior to initiation and periodically thereafter.

Clinical Pearls

  • Although the clinical trial evaluated elacestrant in ESR1-wildtype and ESR1-mutated patients, the FDA labeled indication is only for ESR1 mutated patients.1
  • Guardant360 CDx is the FDA approved companion diagnostic test for detection of ESR1 mutations.1
    • Guardant360 is a liquid biopsy test that detects ESR1 missense mutations between codons 310 and 547 on circulating tumor DNA.
  • The American Society of Clinical Oncology (ASCO) recommends ESR1 testing at recurrence or progression on endocrine therapy for patients with metastatic HR+ breast cancer. Patients who retain ESR1 wild type may be retested at each subsequent progression for detection of ESR1 mutation emergence.7
  • The phase I randomized, double-blind, placebo-controlled, multiple-ascending dose study of elacestrant in healthy post-menopausal women evaluated elacestrant capsules of 200 mg to 1000 mg daily for 7 days. Minimal levels of elacestrant were detected in the cerebrospinal fluid indicating low penetration of the blood-brain barrier.4
  • There is an ongoing study assessing the efficacy for elacestrant and abemaciclib in brain metastases from HR+/HER2- breast cancer (ELECTRA) (NCT05386108).8
  • Elacestrant is only filled by Onco360 or Biologics Specialty Pharmacy by McKesson.9
  • Orserdu® Access Programs offer financial assistance for eligible patients via a co-pay program, patient assistance program, and rapid start program.10
    • A social security number is not required for enrollment in the patient assistance program.
    • Patients enrolled on the Rapid Start Program will receive 15 days of free drug while awaiting completion of a prior authorization or medical necessity approval.


1.Orserdu (elacestrant) [package insert]. Stemline Therapeutics Inc: New York, NY; 2023.

2.Bardia A, Aftimos P, Bihani T, et al. Emerald: Phase III trial of elacestrant (RAD1901) vs endocrine therapy for previously treated ER+ advanced breast cancer. Future Oncol. 2019;15(28):3209-3218. doi:10.2217/fon-2019-0370.

3.Chandarlapaty S, Chen D, He W, et al. Prevalence of ESR1 mutations in cell-free DNA and outcomes in metastatic breast cancer. JAMA Oncology. 2016;2(10):1310. doi:10.1001/jamaoncol.2016.1279.

4.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. J Clin Oncol. 2022;40(28):3246-3256. doi:10.1200/jco.22.00338.

5.Beumer JH, Foldi J. Pharmacology and pharmacokinetics of elacestrant. Cancer Chemother Pharmacol. Published online June 14, 2023. doi:10.1007/s00280-023-04550-7.

6.U.S. Food & Drug Administration. Assessing the effects of food on drugs in INDs and NDAs — clinical pharmacology considerations guidance for industry. Updated June 23, 2022. Accessed June 20, 2023.

7.Burstein HJ, DeMichele A, Somerfield MR, Henry NL. Testing for ESR1 mutations to guide therapy for hormone receptor–positive, human epidermal growth factor receptor 2–negative metastatic breast cancer: ASCO guideline rapid recommendation update. J Clin Oncol. 2023;41(18):3423-3425. doi:10.1200/jco.23.00638.

8.Stemline Therapeutics, Inc. Study of Abemaciclib and Elacestrant in Patients With Brain Metastasis Due to HR+/HER2- Breast Cancer (ELECTRA). NCT05386108. Updated April 14, 2023. Accessed July 1, 2023.

9.ORSERDU Ordering and Distribution. Accessed July 1. 2023.

10.ORSERDU Savings and Support. Accessed July 1, 2023.

Monica Chintapenta

PharmD, BCOP

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