Elacestrant 

(6R)-6-[2-[ethyl-[[4-[2-(ethylamino)ethyl]phenyl]methyl]amino]-4-methoxyphenyl]-5,6,7,8-tetrahydronaphthalen-2-ol

(6R)-6-{2-[ethyl({4-[2-(ethylamino)ethyl]phenyl}methyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-ol

FDA 1/27/2023, Orserdu

WeightAverage: 458.646
Monoisotopic: 458.293328472

Chemical FormulaC₃₀H₃₈N₂O₂

To treat estrogen receptor-positive, human epidermal growth factor receptor 2-negative, ESR1-mutated, advanced or metastatic breast cancer with disease progression following at least one line of endocrine therapy
Drug Trials Snapshot

• CAS 722533-56-4
• RAD-1901
• ER-306323
• FM6A2627A8
• WHO 10247

Elacestrant, sold under the brand name Orserdu, is a selective estrogen receptor degrader (SERD) used in the treatment of breast cancer.^[1][4] It is taken by mouth.^[1][4]

Elacestrant is an antiestrogen that acts as an antagonist of estrogen receptors, which are the biological targets of endogenous estrogens like estradiol.^[1] The most common side effects of elacestrant include body pain, nausea and vomiting, increased serum lipids, elevated liver enzymes, fatigue, decreased hemoglobin, raised creatinine, decreased appetite, diarrhea, headache, constipation, abdominal pain, and hot flashes.^[2]

Elacestrant was approved for medical use in the United States in January 2023,^[1][2][5][6] and in the European Union in September 2023.^[3][7]

PATENTS

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

• US10745343
• US10071066
• US8399520
• US10385008
• US7612114
• US10420734
• US11779552
• US11819480

Patent Number	Pediatric Extension	Approved	Expires (estimated)
US10071066	No	2018-09-11	2034-10-10
US10385008	No	2019-08-20	2038-01-05
US10420734	No	2019-09-24	2034-10-10
US10745343	No	2020-08-18	2038-01-05
US11779552	No	2023-10-10	2034-10-10
US11819480	No	2023-11-21	2036-11-29
US7612114	No	2009-11-03	2026-08-18
US8399520	No	2013-03-19	2023-12-25

PATENT

https://patents.google.com/patent/US10385008B2/en

Medical uses

Elacestrant is indicated for the treatment of postmenopausal women or adult men with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative, ESR1–mutated, advanced or metastatic breast cancer with disease progression following at least one other line of endocrine therapy.^[2][4]

Pharmacology

Pharmacodynamics

Elacestrant is an antiestrogen that acts as an antagonist of estrogen receptors, specifically targeting the estrogen receptor alpha (ERα), which is the biological target of endogenous estrogens like estradiol.^[1] Additionally, elacestrant is a selective estrogen receptor degrader (SERD), meaning it induces the degradation of ERα.^[1][8]

Pharmacokinetics

Elacestrant has an oral bioavailability of approximately 10%.^[1] Its plasma protein binding exceeds 99% and remains independent of concentration.^[1] Elacestrant is metabolized in the liver, primarily by the cytochrome P450 enzyme CYP3A4 and to a lesser extent by CYP2A6 and CYP2C9.^[1] The elimination half-life of elacestrant is 30 to 50 hours.^[1] It is excreted primarily in feces (82%) and to a lesser extent in urine (7.5%).^[1]

History

The efficacy of elacestrant was evaluated in the EMERALD trial, which was a randomized, open-label, active-controlled, multicenter study involving 478 postmenopausal women and men with ER-positive, HER2-negative advanced or metastatic breast cancer. Among them, 228 participants had ESR1 mutations. Eligible participants had experienced disease progression on one or two prior lines of endocrine therapy, including one line with a CDK4/6 inhibitor, and could have received up to one prior line of chemotherapy in the advanced or metastatic setting.^[2]

Participants were randomly assigned in a 1:1 ratio to receive either elacestrant 345 mg orally once daily or investigator’s choice of endocrine therapy. The choices for the control arm included fulvestrant, or an aromatase inhibitor. Randomization was stratified based on whether the ESR1 mutation was detected or not, prior treatment with fulvestrant, and presence of visceral metastasis.^[2]

The FDA granted the application for elacestrant priority review and fast track designations.^[2]

Research

It is a nonsteroidal combined selective estrogen receptor modulator (SERM) and selective estrogen receptor degrader (SERD) (described as a “SERM/SERD hybrid (SSH)”) that was discovered by Eisai and is under development by Radius Health and Takeda for the treatment estrogen receptor (ER)-positive advanced breast cancer.^[9] Elacestrant has dose-dependent, tissue-selective estrogenic and antiestrogenic activities, with biphasic weak partial agonist activity at the ER at low doses and antagonist activity at higher doses.^[10] It shows agonistic activity on bone and antagonistic activity on breast and uterine tissues.^[11] Unlike the SERD fulvestrant, elacestrant is able to readily cross the blood-brain-barrier into the central nervous system, where it can target breast cancer metastases in the brain,^[10][11] and is orally bioavailable and does not require intramuscular injection.^[10][11]

References

1. ^ Jump up to:^{a b c d e f g h i j k l m n o p q} “Orserdu- elacestrant tablet, film coated”. DailyMed. 8 February 2023. Archived from the original on 11 February 2023. Retrieved 11 February 2023.
2. ^ Jump up to:^{a b c d e f g} “FDA approves elacestrant for ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer”. U.S. Food and Drug Administration (FDA). 27 January 2023. Archived from the original on 2 February 2023. Retrieved 1 February 2023.  This article incorporates text from this source, which is in the public domain.
3. ^ Jump up to:^a b “Orserdu Product information”. Union Register of medicinal products. 18 September 2023. Retrieved 1 October 2023.
4. ^ Jump up to:^a b c d “Orserdu EPAR”. European Medicines Agency (EMA). 9 October 2023. Retrieved 9 October 2023.
5. ^ https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2023/217639Orig1s000ltr.pdf Archived 2023-02-02 at the Wayback Machine  This article incorporates text from this source, which is in the public domain.
6. ^ “Stemline Therapeutics Inc., a wholly owned subsidiary of Menarini Group, Receives Approval from U.S. FDA for Orserdu (elacestrant) as the First and Only Treatment Specifically Indicated for Patients with ESR1 Mutations in ER+, HER2- Advanced or Metastatic Breast Cancer”. Radius (Press release). 31 January 2023. Archived from the original on 2 February 2023. Retrieved 1 February 2023.
7. ^ “EC approves Menarini Group’s Orserdu for advanced or metastatic breast cancer”. PMLive. 21 September 2023. Retrieved 22 September 2023.
8. ^ Lloyd MR, Wander SA, Hamilton E, Razavi P, Bardia A (2022). “Next-generation selective estrogen receptor degraders and other novel endocrine therapies for management of metastatic hormone receptor-positive breast cancer: current and emerging role”. Therapeutic Advances in Medical Oncology. 14: 17588359221113694. doi:10.1177/17588359221113694. PMC 9340905. PMID 35923930.
9. ^ Clinical trial number NCT03778931 for “Phase 3 Trial of Elacestrant vs. Standard of Care for the Treatment of Patients With ER+/HER2- Advanced Breast Cancer” at ClinicalTrials.gov
10. ^ Jump up to:^a b c Wardell SE, Nelson ER, Chao CA, Alley HM, McDonnell DP (October 2015). “Evaluation of the pharmacological activities of RAD1901, a selective estrogen receptor degrader”. Endocrine-Related Cancer. 22 (5): 713–724. doi:10.1530/ERC-15-0287. PMC 4545300. PMID 26162914.
11. ^ Jump up to:^a b c Garner F, Shomali M, Paquin D, Lyttle CR, Hattersley G (October 2015). “RAD1901: a novel, orally bioavailable selective estrogen receptor degrader that demonstrates antitumor activity in breast cancer xenograft models”. Anti-Cancer Drugs. 26 (9): 948–956. doi:10.1097/CAD.0000000000000271. PMC 4560273. PMID 26164151.

Clinical data
Pronunciation	/ˌɛləˈsɛstrənt/ EL-ə-SES-trənt
Trade names	Orserdu
Other names	RAD-1901; ER-306323
License data	US DailyMed: Elacestrant
Routes of administration	By mouth
ATC code	L02BA04 (WHO)
Legal status
Legal status	US: ℞-only[1][2]EU: Rx-only[3][4]
Pharmacokinetic data
Bioavailability	~10%[1]
Protein binding	>99%[1]
Metabolism	Liver (major: CYP3A4, minor: CYP2A6, CYP2C9)[1]
Elimination half-life	30–50 hours[1]
Excretion	Feces (82%), urine (7.5%)[1]
Identifiers
showIUPAC name
CAS Number	722533-56-4
PubChem CID	23642301
DrugBank	DB06374
ChemSpider	57583807
UNII	FM6A2627A8
KEGG	D11671
ChEMBL	ChEMBL4297509
PDB ligand	I0V (PDBe, RCSB PDB)
CompTox Dashboard (EPA)	DTXSID901045846
ECHA InfoCard	100.312.890
Chemical and physical data
Formula	C30H38N2O2
Molar mass	458.646 g·mol−1
3D model (JSmol)	Interactive image
showSMILES
showInChI

/////////Elacestrant, Orserdu, FDA 2023, APPROVALS 2023, FM6A2627A8, WHO 10247, ER 306323, RAD 1901, RAD1901