Elacestrant

Publication Details

OVERVIEW

Introduction

Elacestrant is an estrogen receptor antagonist which is used for treatment of specific forms of refractory, advanced or metastatic breast cancer in postmenopausal women or adult men. Elacestrant has not been linked to elevations in serum aminotransferase levels during therapy or to cases of clinically apparent liver injury.

Background

Elacestrant (el” a ses’ trant) is a small molecule, estrogen receptor (ER) degrader that is used to treat postmenopausal women or adult men with advanced or metastatic breast cancer that is positive for ER and negative for human epidermal growth factor 2 (HER2). Elacestrant was the first orally available estrogen receptor degrader, a previous similarly active drug was fulvestrant which requires intramuscular injections every 2 to 4 weeks. Elacestrant binds to the estrogen receptor alpha and leads to its degradation, making cells resistant to estrogen-stimulated cell proliferation. In registration trials, elacestrant improved progression-free survival in women with advanced or metastatic, ER-positive, and HER2-negative breast cancer after failure of conventional antiestrogen therapy. Post hoc analyses showed that the benefit from elacestrant was largely in women who harbored an ESR1 mutation and when it was approved for use in the United States in 2023, the formal indications were limited to women with cancers and this specific mutation who have had disease progression following endocrine therapy. Elacestrant is available in tablets of 86 and 345 mg under the brand name Orserdu. The recommended dose is 345 mg daily to be continued until disease progression or unacceptable toxicity occurs. The dose can be decreased for adverse events or for preexisting moderate degrees of hepatic dysfunction. Common side effects include musculoskeletal pain, nausea, vomiting, diarrhea, abdominal pain, headache, and hot flushes. Laboratory abnormalities during elacestrant therapy can include increases in cholesterol and triglyceride, creatinine, and aminotransferase levels and decreases in hemoglobin and sodium. Less common but potentially severe adverse events include severe dyslipidemia and embryo-fetal toxicity.

Hepatotoxicity

In the major registration trial of elacestrant as therapy of breast cancer, serum ALT elevations arose in similar proportions of those on elacestrant as of the controls receiving “standard of care” (9% vs 10%) and were above 5 times the upper limit of normal in 2.1% vs 0.9% of controls. The elevations were transient and without symptoms or jaundice. No patient developed clinically apparent liver injury. Since its approval and more widespread use, there have been no published reports of hepatotoxicity attributed to elacestrant therapy.

Likelihood score: E (unlikely cause of clinically apparent liver injury).

Mechanism of Injury

The mechanism by which elacestrant might cause liver injury is not known. Elacestrant is a complex small molecule (a tetrahydronaphthalene) and is metabolized in the liver, predominantly by CYP 3A4. Elacestrant is susceptible to drug-drug interactions; moderate inhibitors of CYP 3A4 can cause increases in plasma levels to potentially toxic levels, and moderate inducers of CYP 3A4 can cause decreases in plasma levels to potentially subtherapeutic levels.

Outcome and Management

There is no evidence that elacestrant therapy can cause severe elevations in serum enzymes or lead to clinically apparent liver injury.

Drug Class: Antineoplastic Agents, Antiestrogens

Other Selective Estrogen Receptor Degraders: Fulvestrant

Other Selective Estrogen Receptor Modulators: Raloxifene, Tamoxifen, Toremifene

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Elacestrant – Orserdu®

DRUG CLASS

Antineoplastic Agents, Antiestrogens

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULA AND STRUCTURE

ANNOTATED BIBLIOGRAPHY

References updated: 25 February 2025

Abbreviations: ER, estrogen receptor; HER2, human epithelial growth factor 2.

  • Zimmerman HJ. Hepatotoxic effects of oncotherapeutic and immunosuppressive agents. In, Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999, pp. 699.
    (Expert review of hepatotoxicity published in 1999, before the availability of elacestrant and other estrogen receptor modulators and degraders).
  • Chitturi S, Farrell GC. Estrogen receptor antagonists. Adverse effects of hormones and hormone antagonists on the liver. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013, pp. 610-2.
    (Review of hepatotoxicity of estrogens and antiestrogens discusses tamoxifen but not elacestrant or fulvestrant).
  • Isaacs C, Wellstein A, Riegel AT. Hormones and related agents in the therapy of cancer. In, Brunton LL, Hilal-Dandan R, Knollman BC, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 13th ed. New York: McGraw-Hill, 2018, pp. 1237-1248.
    (Textbook of pharmacology and therapeutics).
  • FDA. 2023. Multi-Discipline Review. https://www​.accessdata​.fda.gov/drugsatfda_docs​/nda/2023/217639Orig1s000MultidisciplineR.pdf
    (FDA website with the product labels and integrated review of the data on efficacy and safety provided by the sponsor in support of approval of elacestrant as therapy of refractory and advanced, ER-positive breast cancer, mentions that ALT elevations were less frequent with elacestrant therapy than standard of care [17% vs 24%] including values greater than 5 times ULN [0.4% vs 1.3%], and there were no cases of clinically apparent liver injury).
  • Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, Reddy KR, et al.; United States Drug Induced Liver Injury Network. Features and outcomes of 899 patients with drug-induced liver injury: the DILIN Prospective Study. Gastroenterology 2015; 148: 1340-52.e7. [PMC free article: PMC4446235] [PubMed: 25754159]
    (Among 899 cases of drug induced liver injury enrolled in a US prospective study between 2004 and 2013, no cases were attributed to elacestrant).
  • Conlan MG, de Vries EFJ, Glaudemans A, Wang Y, Troy S. Pharmacokinetic and pharmacodynamic studies of elacestrant, a novel oral selective estrogen receptor degrader, in healthy post-menopausal women. Eur J Drug Metab Pharmacokinet. 2020; 45:675-689. [PMC free article: PMC7511284] [PubMed: 32661909]
    (In phase 1 trials in 140 healthy, postmenopausal women, elacestrant demonstrated robust occupancy of estrogen receptors and acceptable tolerance, the most frequent adverse events being nausea, dyspepsia, vomiting, abdominal pain, esophageal pain, salivary hypersecretion, and diarrhea; and “there were no clinically significant changes in laboratory tests”).
  • Jager A, de Vries EGE, der Houven van Oordt CWM, Neven P, Venema CM, Glaudemans AWJM, et al. A phase 1b study evaluating the effect of elacestrant treatment on estrogen receptor availability and estradiol binding to the estrogen receptor in metastatic breast cancer lesions using 18F-FES PET/CT imaging. Breast Cancer Res. 2020; 22:97. [PMC free article: PMC7488419] [PubMed: 32912274]
    (Among 16 patients with advanced ER-positive breast cancer treated with elacestrant [200 or 400 mg] once daily for 14 days followed by continuation at the higher dose, PET scanning at 14 days demonstrated a decrease in estrogen receptor activity, and continued treatment showed antitumor activity with acceptable toxicity; no mention of ALT elevations or hepatotoxicity).
  • Bardia A, Kaklamani V, Wilks S, Weise A, Richards D, Harb W, Osborne C, 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. 2021;39: 1360-1370. [PMC free article: PMC8078341] [PubMed: 33513026]
    (Among 57 postmenopausal, heavily pretreated women with advanced ER-positive, HER2-negative breast cancer treated with elacestrant [mostly with 400 mg daily], clinical responses occurred in 43% by 24 weeks, and adverse events were largely mild-to-moderate gastrointestinal complaints of nausea and vomiting, dyspepsia, abdominal pain, and fatigue, while ALT elevations arose in 18% and were above 5 times ULN in 4%, none were associated with jaundice or symptoms).
  • Bidard FC, Kaklamani VG, Neven P, Streich G, Montero AJ, Forget F, Mouret-Reynier MA, 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; 40:3246-3256. [PMC free article: PMC9553388] [PubMed: 35584336]
    (Among 477 patients with advanced and refractory ER-positive, HER2-negative breast cancer treated with oral elacestrant [400 mg daily] vs standard of care, median progression-free survival at 1 year was 22% vs 8%, while adverse event rates were 92% vs 86%, the most frequent events being nausea [35% vs 19%], fatigue [19% vs 19%], vomiting [19% vs 8%], decreased appetite [15% vs 9%], and arthralgia [14% vs 16%]; ALT elevations arising in 9% vs 10% and were above 5 times ULN in 2% vs 0.9% ).
  • Hoy SM. Elacestrant: first approval. Drugs. 2023;83:555-561. [PMC free article: PMC10667141] [PubMed: 37060385]
    (Review of the mechanism of action, history of development, pharmacology, clinical efficacy, and toxicity of elacestrant shortly after its approval for use in breast cancer in the US, mentions the common gastrointestinal adverse events but does not mention ALT elevations or hepatotoxicity).
  • Shah M, Lingam H, Gao X, Gittleman H, Fiero MH, Krol D, Biel N, et al. US Food and Drug Administration approval summary: elacestrant for estrogen receptor-positive, human epidermal growth factor receptor 2-negative, ESR1-mutated advanced or metastatic breast cancer. J Clin Oncol. 2024;42:1193-1201. [PMC free article: PMC11003513] [PubMed: 38381994]
    (Summary of the efficacy and safety data that supported the FDA decision to approve elacestrant as therapy of refractory, advanced or metastatic breast cancer, discusses the analysis of a safety cohort of 467 patients in whom there were no deaths, but discontinuations occurred in 6% of the treated vs 4.3% of standard of care controls; no mention of ALT elevations or hepatotoxicity).
  • Bardia A, Cortés J, Bidard FC, Neven P, Garcia-Sáenz J, Aftimos P, O'Shaughnessy J, et al. Elacestrant in ER+, HER2- metastatic breast cancer with ESR1-mutated tumors: subgroup analyses from the phase III EMERALD trial by prior duration of endocrine therapy plus CDK4/6 inhibitor and in clinical subgroups. Clin Cancer Res. 2024;30:4299-4309. [PMC free article: PMC11443208] [PubMed: 39087959]
    (Among 477 patients with advanced and refractory ER-positive, HER2-negative breast cancer treated with oral elacestrant [400 mg daily] vs standard of care [Bardia 2022], subgroup analyses demonstrated improvements in progression-free survival was improved regardless of presence of ER mutations or previous therapies, and adverse event rates in these subgroups were similar, ALT elevations arising in 5% vs 12% [elacestrant vs standard of care] and were above 5 times ULN in 1.0% vs <1.0% ).