NAV

Elacestrant

Identification

Summary

Elacestrant is an estrogen receptor antagonist used to treat ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer with disease progression following at least one line of endocrine therapy.

Brand Names
Orserdu
Generic Name
Elacestrant
DrugBank Accession Number
DB06374
Background

Elacestrant is a non-steroidal small molecule and an estrogen receptor (ER) antagonist.3,8 In January 2023, it was approved by the FDA for the treatment of ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer.8,9 Elacestrant binds to estrogen receptor-alpha (ERα) and acts as a selective estrogen receptor degrader (SERD) thanks to its ability to block the transcriptional activity of the ER and promote its degradation.1,6,9 Other types of endocrine therapy, such as selective estrogen receptor modulators (SERMs) and aromatase inhibitors (AIs), may lead to drug resistance over time; therefore, the use of a SERD represents a therapeutic approach for the treatment of endocrine-resistant breast cancers.7 Unlike fulvestrant, another FDA-approved SERD, elacestrant is orally bioavailable.2

Type
Small Molecule
Groups
Approved, Investigational
Structure
3D
Similar Structures
Weight
Average: 458.646
Monoisotopic: 458.293328472
Chemical Formula
C30H38N2O2
Synonyms
  • (2R)-2-(2-(ethyl-((4-(2-(ethylamino)ethyl)phenyl)methyl)amino)-4-methoxy-phenyl)tetralin-6-ol
  • (6R)-6-(2-(ethyl((4-(2- (ethylamino)ethyl)phenyl)methyl)amino)-4-methoxyphenyl)- 5,6,7,8-tetrahydronaphthalen-2-ol
  • 2-naphthalenol, 6-(2-(ethyl((4-(2-(ethylamino)ethyl)phenyl)methyl)amino)-4-methoxyphenyl)-5,6,7,8-tetrahydro-, (6R)-
  • Elacestrant
External IDs
  • ER-306323
  • RAD-1901
  • RAD1901

Pharmacology

Indication

Elacestrant is indicated for the treatment of postmenopausal women or adult men with ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer with disease progression following at least one line of endocrine therapy.8

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Associated Conditions
Contraindications & Blackbox Warnings
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Pharmacodynamics

The exposure-response relationships and pharmacodynamics time course of elacestrant have not been fully characterized. At the approved recommended dose, the use of elacestrant does not lead to QTc interval increases higher than 20 msec. Hypercholesterolemia and hypertriglyceridemia have occurred in patients taking elacestrant, and administering this drug to pregnant women may cause fetal harm.8 Unlike other selective estrogen receptor modulators and degraders, elacestrant is capable of crossing the blood-brain barrier.6

Mechanism of action

Elacestrant is an oral selective estrogen receptor degrader (SERD) that binds to estrogen receptor-alpha (ERα).2,3,8 Breast tumors that express ERα depend on estrogen-mediated growth signaling; therefore, endocrine therapies that target the estrogen receptor (ER) are commonly used in the treatment of this type of cancer. SERDs are a type of endocrine therapy that antagonizes the transcriptional activity of the ER and promotes its degradation.1

In ER-positive (ER+) HER2-negative (HER2-) breast cancer cells, elacestrant inhibits 17β-estradiol-mediated cell proliferation and induces ERα degradation through the proteasomal pathway.8 Elacestrant also slows ER nuclear translocation and promotes ER turnover, disrupting downstream signaling.1 Elacestrant has in vitro and in vivo anti-tumor activity in ER+ HER2- breast cancer models resistant to fulvestrant and cyclin-dependent kinase 4/6 inhibitors, as well as cancer models with estrogen receptor 1 gene (ESR1) mutations.4,5,8

TargetActionsOrganism
UEstrogen receptor alpha
antagonist
Humans
Absorption

With the recommended dosage of 345 mg once daily, elacestrant has a steady-state Cmax of 119 ng/mL and an AUC0-24h of 2440 ng⋅h/mL. The Cmax and AUC of elacestrant increase more than dose-proportional between 43 mg and 862 mg once daily (0.125 to 2.5 times the approved recommended dosage). By day 6, elacestrant reaches steady-state and has a 2-fold mean accumulation ratio based on AUC0-24h. The tmax of elacestrant goes from 1 to 4 hr, and its oral bioavailability is approximately 10%. Compared to a fasted state, the Cmax and AUC of elacestrant (345 mg) were 42% and 22% higher, respectively, when administered with a high-fat meal (800 to 1000 calories, 50% fat).8

Volume of distribution

Elacestrant has an apparent volume of distribution of 5800 L.8

Protein binding

Elacestrant has a protein plasma binding higher than 99% and independent of concentration.8

Metabolism

Elacestrant is metabolized in the liver, mainly by CYP3A4 and, to a lesser extent, by CYP2A6 and CYP2C9.8

Route of elimination

Elacestrant is mainly eliminated through feces and urine. Approximately 82% was recovered in feces (34% unchanged), and 7.5% was recovered in urine (< 1% unchanged) following a single radiolabeled oral dose of 345 mg.8

Half-life

The elimination half-life of elacestrant is 30 to 50 hours.8

Clearance

Elacestrant has an estimated clearance of 186 L/hr and a renal clearance of ≤ 0.14 L/hr.8

Adverse Effects
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Toxicity

Toxicity information regarding elacestrant is not readily available. Patients experiencing an overdose are at an increased risk of severe adverse effects such as dyslipidemia and gastrointestinal disorders.8 Symptomatic and supportive measures are recommended. The carcinogenicity of elacestrant has not been evaluated. Elacestrant did not show mutagenicity in the in vitro Ames assay and was negative for clastogenicity in in vitro chromosome aberration assays and the in vivo rat bone marrow micronucleus assay.8

Fertility studies with elacestrant in animals have not been performed. Rats and cynomolgus monkeys presented adverse reactions in female reproductive organs including atrophy of the vagina, cervix, and uterus and follicular cysts in the ovary after receiving repeated doses of elacestrant. Male rats presented decreased cellularity of Leydig cells and degeneration/atrophy of the seminiferous epithelium in the testis.8

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
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interactions in your software
AbametapirThe serum concentration of Elacestrant can be increased when it is combined with Abametapir.
AbemaciclibThe serum concentration of Abemaciclib can be increased when it is combined with Elacestrant.
AfatinibThe serum concentration of Afatinib can be increased when it is combined with Elacestrant.
AllopurinolThe serum concentration of Allopurinol can be increased when it is combined with Elacestrant.
AlpelisibThe serum concentration of Alpelisib can be increased when it is combined with Elacestrant.
AmbrisentanThe serum concentration of Ambrisentan can be increased when it is combined with Elacestrant.
AmbroxolThe risk or severity of methemoglobinemia can be increased when Elacestrant is combined with Ambroxol.
AmiodaroneThe serum concentration of Elacestrant can be increased when it is combined with Amiodarone.
AmprenavirThe serum concentration of Elacestrant can be increased when it is combined with Amprenavir.
ApalutamideThe serum concentration of Elacestrant can be decreased when it is combined with Apalutamide.
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Food Interactions
  • Take with food. Take with food to reduce nausea and vomiting.

Products

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International/Other Brands
Orserdu (Stemline Therapeutics)
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
OrserduTablet, film coated345 mg/1OralStemline Therapeutics, Inc.2023-01-27Not applicableUS flag
OrserduTablet, film coated86 mg/1OralStemline Therapeutics, Inc.2023-01-27Not applicableUS flag

Categories

Drug Categories
Classification
Not classified
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
FM6A2627A8
CAS number
722533-56-4
InChI Key
SIFNOOUKXBRGGB-AREMUKBSSA-N
InChI
InChI=1S/C30H38N2O2/c1-4-31-17-16-22-6-8-23(9-7-22)21-32(5-2)30-20-28(34-3)14-15-29(30)26-11-10-25-19-27(33)13-12-24(25)18-26/h6-9,12-15,19-20,26,31,33H,4-5,10-11,16-18,21H2,1-3H3/t26-/m1/s1
IUPAC Name
(6R)-6-{2-[ethyl({4-[2-(ethylamino)ethyl]phenyl}methyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-ol
SMILES
CCNCCC1=CC=C(CN(CC)C2=C(C=CC(OC)=C2)[C@@H]2CCC3=CC(O)=CC=C3C2)C=C1

References

Synthesis Reference

Cruskie MP, et al. (2019). Polymorphic forms of RAD1901-2HCl (U.S. Patent No. 10,385,008 B2). U.S. Patent and Trademark Office. https://patentimages.storage.googleapis.com/42/82/b6/e9fcbbbd08054e/US10385008.pdf

General References
  1. Lloyd MR, Wander SA, Hamilton E, Razavi P, Bardia A: Next-generation selective estrogen receptor degraders and other novel endocrine therapies for management of metastatic hormone receptor-positive breast cancer: current and emerging role. Ther Adv Med Oncol. 2022 Jul 30;14:17588359221113694. doi: 10.1177/17588359221113694. eCollection 2022. [Article]
  2. Garner F, Shomali M, Paquin D, Lyttle CR, Hattersley G: RAD1901: a novel, orally bioavailable selective estrogen receptor degrader that demonstrates antitumor activity in breast cancer xenograft models. Anticancer Drugs. 2015 Oct;26(9):948-56. doi: 10.1097/CAD.0000000000000271. [Article]
  3. Bihani T, Patel HK, Arlt H, Tao N, Jiang H, Brown JL, Purandare DM, Hattersley G, Garner F: Elacestrant (RAD1901), a Selective Estrogen Receptor Degrader (SERD), Has Antitumor Activity in Multiple ER(+) Breast Cancer Patient-derived Xenograft Models. Clin Cancer Res. 2017 Aug 15;23(16):4793-4804. doi: 10.1158/1078-0432.CCR-16-2561. Epub 2017 May 4. [Article]
  4. Patel HK, Tao N, Lee KM, Huerta M, Arlt H, Mullarkey T, Troy S, Arteaga CL, Bihani T: Elacestrant (RAD1901) exhibits anti-tumor activity in multiple ER+ breast cancer models resistant to CDK4/6 inhibitors. Breast Cancer Res. 2019 Dec 18;21(1):146. doi: 10.1186/s13058-019-1230-0. [Article]
  5. Bidard FC, Kaklamani VG, Neven P, Streich G, Montero AJ, Forget F, Mouret-Reynier MA, Sohn JH, Taylor D, Harnden KK, Khong H, Kocsis J, Dalenc F, Dillon PM, Babu S, Waters S, Deleu I, Garcia Saenz JA, Bria E, Cazzaniga M, Lu J, Aftimos P, Cortes J, Liu S, Tonini G, Laurent D, Habboubi N, Conlan MG, Bardia A: 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 Oct 1;40(28):3246-3256. doi: 10.1200/JCO.22.00338. Epub 2022 May 18. [Article]
  6. Chinnasamy K, Saravanan M, Poomani K: Investigation of binding mechanism and downregulation of elacestrant for wild and L536S mutant estrogen receptor-alpha through molecular dynamics simulation and binding free energy analysis. J Comput Chem. 2020 Jan 15;41(2):97-109. doi: 10.1002/jcc.26076. Epub 2019 Oct 10. [Article]
  7. Lu Y, Liu W: Selective Estrogen Receptor Degraders (SERDs): A Promising Strategy for Estrogen Receptor Positive Endocrine-Resistant Breast Cancer. J Med Chem. 2020 Dec 24;63(24):15094-15114. doi: 10.1021/acs.jmedchem.0c00913. Epub 2020 Nov 2. [Article]
  8. FDA Approved Drug Products: ORSERDU (elacestrant) tablets for oral use [Link]
  9. BioSpace: Stemline Therapeutics Receives U.S. FDA Approval for ORSERDUTM (elacestrant) as the First and Only Treatment Specifically Indicated for Patients with ESR1 Mutations in ER+, HER2- Advanced or Metastatic Breast Cancer [Link]
ChemSpider
57583807
BindingDB
349630
RxNav
2628469
ChEMBL
CHEMBL4297509
PDBe Ligand
I0V
Wikipedia
Elacestrant
PDB Entries
7te7

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3Active Not RecruitingTreatmentBreast Cancer1
3Not Yet RecruitingTreatmentBreast Cancer, Stage III / Estrogen Receptor Positive Breast Cancer / Human Epidermal Growth Factor 2 Negative Carcinoma of Breast / Stage IIB Breast Cancer1
2CompletedTreatmentHot Flashes1
2Not Yet RecruitingTreatmentMetastatic Breast Cancer1
2TerminatedTreatmentHot Flashes / Vasomotor Symptoms Associated With Menopause1
1CompletedTreatmentAdvanced ER+, HER2-Negative Breast Cancer1
1CompletedTreatmentMetastatic Breast Cancer1
1, 2Active Not RecruitingTreatmentBreast Cancer1
1, 2RecruitingTreatmentBrain Disorders / Brain Neoplasm / Breast Diseases / Breast Neoplasms / Central Nervous System Disorder / Central Nervous System Neoplasm / Neoplasm / Neoplasms by Site1
1, 2RecruitingTreatmentBreast Cancer1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Tablet, film coatedOral345 mg/1
Tablet, film coatedOral86 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US10745343No2018-01-052038-01-05US flag
US10071066No2014-10-102034-10-10US flag
US8399520No2003-12-252023-12-25US flag
US10385008No2018-01-052038-01-05US flag
US7612114No2006-08-182026-08-18US flag
US10420734No2014-10-102034-10-10US flag

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.00035 mg/mLALOGPS
logP6.54ALOGPS
logP6.23Chemaxon
logS-6.1ALOGPS
pKa (Strongest Acidic)10.58Chemaxon
pKa (Strongest Basic)9.96Chemaxon
Physiological Charge1Chemaxon
Hydrogen Acceptor Count4Chemaxon
Hydrogen Donor Count2Chemaxon
Polar Surface Area44.73 Å2Chemaxon
Rotatable Bond Count10Chemaxon
Refractivity143.17 m3·mol-1Chemaxon
Polarizability55.16 Å3Chemaxon
Number of Rings4Chemaxon
Bioavailability1Chemaxon
Rule of FiveNoChemaxon
Ghose FilterNoChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleYesChemaxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available

Targets

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insights and accelerate drug research.
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Use our structured and evidence-based datasets to unlock new insights and accelerate drug research.
Learn more
Details1. Estrogen receptor alpha
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Antagonist
General Function
Zinc ion binding
Specific Function
Nuclear hormone receptor. The steroid hormones and their receptors are involved in the regulation of eukaryotic gene expression and affect cellular proliferation and differentiation in target tissu...
Gene Name
ESR1
Uniprot ID
P03372
Uniprot Name
Estrogen receptor
Molecular Weight
66215.45 Da
References
  1. Garner F, Shomali M, Paquin D, Lyttle CR, Hattersley G: RAD1901: a novel, orally bioavailable selective estrogen receptor degrader that demonstrates antitumor activity in breast cancer xenograft models. Anticancer Drugs. 2015 Oct;26(9):948-56. doi: 10.1097/CAD.0000000000000271. [Article]
  2. Chinnasamy K, Saravanan M, Poomani K: Investigation of binding mechanism and downregulation of elacestrant for wild and L536S mutant estrogen receptor-alpha through molecular dynamics simulation and binding free energy analysis. J Comput Chem. 2020 Jan 15;41(2):97-109. doi: 10.1002/jcc.26076. Epub 2019 Oct 10. [Article]
  3. FDA Approved Drug Products: ORSERDU (elacestrant) tablets for oral use [Link]

Enzymes

Details1. Cytochrome P450 3A4
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. FDA Approved Drug Products: ORSERDU (elacestrant) tablets for oral use [Link]
Details2. Cytochrome P450 2A6
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Exhibits a high coumarin 7-hydroxylase activity. Can act in the hydroxylation of the anti-cancer drugs cyclophosphamide and ifosphamide. Competent in the metabolic activation of aflatoxin B1. Const...
Gene Name
CYP2A6
Uniprot ID
P11509
Uniprot Name
Cytochrome P450 2A6
Molecular Weight
56501.005 Da
References
  1. FDA Approved Drug Products: ORSERDU (elacestrant) tablets for oral use [Link]
Details3. Cytochrome P450 2C9
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2C9
Uniprot ID
P11712
Uniprot Name
Cytochrome P450 2C9
Molecular Weight
55627.365 Da
References
  1. FDA Approved Drug Products: ORSERDU (elacestrant) tablets for oral use [Link]

Transporters

Details1. Solute carrier organic anion transporter family member 2B1
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Mediates the Na(+)-independent transport of organic anions such as taurocholate, the prostaglandins PGD2, PGE1, PGE2, leukotriene C4, thromboxane B2 and iloprost.
Gene Name
SLCO2B1
Uniprot ID
O94956
Uniprot Name
Solute carrier organic anion transporter family member 2B1
Molecular Weight
76709.98 Da
References
  1. FDA Approved Drug Products: ORSERDU (elacestrant) tablets for oral use [Link]
Details2. P-glycoprotein 1
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Xenobiotic-transporting atpase activity
Specific Function
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
Multidrug resistance protein 1
Molecular Weight
141477.255 Da
References
  1. FDA Approved Drug Products: ORSERDU (elacestrant) tablets for oral use [Link]
Details3. ATP-binding cassette sub-family G member 2
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Xenobiotic-transporting atpase activity
Specific Function
High-capacity urate exporter functioning in both renal and extrarenal urate excretion. Plays a role in porphyrin homeostasis as it is able to mediates the export of protoporhyrin IX (PPIX) both fro...
Gene Name
ABCG2
Uniprot ID
Q9UNQ0
Uniprot Name
ATP-binding cassette sub-family G member 2
Molecular Weight
72313.47 Da
References
  1. FDA Approved Drug Products: ORSERDU (elacestrant) tablets for oral use [Link]

Drug created at March 19, 2008 16:28 / Updated at February 15, 2023 07:39