Elacestrant (Orserdu): A Comprehensive Monograph on the First-in-Class Oral SERD for ESR1-Mutated, ER+/HER2- Metastatic Breast Cancer

Abstract

Elacestrant, marketed under the brand name Orserdu, represents a significant advancement in the treatment of hormone receptor-positive breast cancer. As the first-in-class orally bioavailable Selective Estrogen Receptor Degrader (SERD), it addresses key limitations of previous endocrine therapies. This report provides a comprehensive analysis of Elacestrant, covering its physicochemical properties, pharmacology, clinical evidence, and regulatory status. Its mechanism of action is dual in nature, involving both competitive antagonism of the estrogen receptor alpha (ERα) and induction of its degradation through the proteasomal pathway. This dual action is particularly effective against tumors that have developed resistance to aromatase inhibitors via acquired mutations in the estrogen receptor 1 gene (ESR1). The pivotal Phase III EMERALD trial demonstrated Elacestrant's superiority over standard-of-care endocrine monotherapy in patients with estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2−), advanced or metastatic breast cancer who had progressed on prior endocrine therapy, including a CDK4/6 inhibitor. The clinical benefit was most pronounced in the subgroup of patients with activating ESR1 mutations, leading to a statistically significant improvement in Progression-Free Survival (PFS) (Hazard Ratio 0.55; P=0.0005).[1] This finding established Elacestrant as a new standard of care for this specific patient population and led to its approval by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA). The safety profile of Elacestrant is well-characterized and manageable, with the most common adverse events being gastrointestinal effects (nausea, vomiting) and dyslipidemia (increased cholesterol and triglycerides), which are typically low-grade. Elacestrant's approval, coupled with a companion diagnostic for

ESR1 mutation testing, marks a critical step forward in the era of precision oncology for breast cancer, offering a targeted, oral therapeutic option for a defined molecular subtype of endocrine-resistant disease. Ongoing research is further exploring its potential in combination therapies and in earlier stages of breast cancer.

Drug Profile and Physicochemical Properties

Introduction to Elacestrant

Elacestrant, sold under the brand name Orserdu, is a novel, non-steroidal, small molecule antineoplastic agent developed for the treatment of specific subtypes of breast cancer.[2] It is a member of the tetralin class of compounds and functions as a potent antiestrogen.[3] Its development and subsequent approval represent a landmark achievement in endocrine therapy, as it is the first orally bioavailable Selective Estrogen Receptor Degrader (SERD) to receive regulatory approval for clinical use.[2] This oral formulation provides a significant advantage in convenience and patient adherence over the first-approved SERD, fulvestrant, which requires intramuscular injection.[4] Elacestrant was discovered by Eisai and subsequently developed by Radius Health, Takeda, and later Stemline Therapeutics, a subsidiary of the Menarini Group.[5]

Chemical Identity

Elacestrant is chemically defined as a substituted 1,2,3,4-tetrahydronaphthalene.[3] Its structure features a hydroxy group at position 2 and a complex 2-(ethyl{4-[2-(ethylamino)ethyl]benzyl}amino)-4-methoxyphenyl group at the 6R position.[3] This specific stereochemistry and molecular architecture are critical for its high-affinity binding to the estrogen receptor.

The International Union of Pure and Applied Chemistry (IUPAC) name for the compound is (6R)-6-{2-[Ethyl({4-[2-(ethylamino)ethyl]phenyl}methyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-ol.[5] It has a molecular formula of

C30​H38​N2​O2​ and a molar mass of approximately 458.65 g·mol⁻¹.[5] In its solid form, it is typically a white to off-white powder.[9]

Key Identifiers

For precise identification in scientific, clinical, and regulatory contexts, Elacestrant is associated with a range of unique identifiers. These are consolidated in Table 1 to provide a comprehensive reference profile for the molecule.

Table 1: Key Drug Identifiers and Physicochemical Properties of Elacestrant

Property	Value	Source Snippet(s)
Generic Name	Elacestrant	2
Brand Name	Orserdu	2
DrugBank ID	DB06374	2
CAS Number	722533-56-4	3
Type/Modality	Small Molecule	2
Chemical Formula	C30​H38​N2​O2​	2
Molecular Weight (Average)	458.646 g·mol⁻¹	2
Molecular Weight (Monoisotopic)	458.293328472	2
IUPAC Name	(6R)-6-{2-[Ethyl({4-[2-(ethylamino)ethyl]phenyl}methyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-ol	5
ATC Code	L02BA04	3
Other Names/Development Codes	RAD-1901; ER-306323	5
Physical Form	White to off-white solid	9

Pharmacology and Mechanism of Action

Classification as a SERD

Elacestrant belongs to the therapeutic class of Selective Estrogen Receptor Degraders (SERDs), also known as estrogen receptor antagonists (ERAs).[2] This class of drugs is designed specifically to target the estrogen receptor (ER), a key driver of tumor growth in the majority of breast cancers.[11] The mechanism of SERDs is distinct from other classes of endocrine therapy. Aromatase inhibitors (AIs), such as anastrozole and letrozole, function by blocking the peripheral conversion of androgens to estrogens, thereby reducing the circulating levels of estrogen available to stimulate the ER.[2] Selective Estrogen Receptor Modulators (SERMs), like tamoxifen, act as competitive antagonists at the ER in breast tissue but can have partial agonist (estrogen-like) effects in other tissues, such as the uterus and bone.[2] In contrast, SERDs like Elacestrant and fulvestrant are pure antagonists that not only block ER signaling but also actively promote the destruction of the receptor protein itself.[2]

Dual Mechanism of Action

Elacestrant exerts its potent antitumor effects through a dual mechanism that combines receptor antagonism with receptor degradation, providing a comprehensive blockade of the ER signaling pathway.[13]

Estrogen Receptor (ER) Antagonism

Elacestrant binds with high affinity and selectivity to the estrogen receptor, primarily the alpha isoform (ERα), which is the predominant form expressed in breast tumors.[2] By occupying the ligand-binding domain of the receptor, Elacestrant competitively prevents the endogenous ligand, 17β-estradiol, from binding and activating it.[2] This blockade prevents the receptor from undergoing the necessary conformational changes required for dimerization, nuclear translocation, and interaction with coactivator proteins. As a result, the transcription of estrogen-responsive genes that drive cell cycle progression, proliferation, and survival is inhibited.[2]

Estrogen Receptor Degradation

The defining characteristic of Elacestrant as a SERD is its ability to induce the degradation of the ERα protein.[1] Upon binding, Elacestrant forces the receptor into an unstable conformation. This altered structure is recognized by the cell's protein quality control machinery, specifically the ubiquitin-proteasome system.[2] Ubiquitin ligases are recruited to the destabilized Elacestrant-ER complex, tagging the receptor with a chain of ubiquitin molecules. This polyubiquitination serves as a signal for the proteasome, the cell's primary protein degradation complex, to recognize and destroy the receptor.[1] This process leads to a profound and sustained downregulation of total

ERα protein levels within the cancer cell, effectively eliminating the primary target of estrogen signaling and rendering the cell less responsive to hormonal growth signals.[13]

Overcoming Acquired Resistance

A significant challenge in the long-term management of ER+ metastatic breast cancer is the development of acquired resistance to endocrine therapies.[11] Elacestrant's mechanism of action is uniquely suited to address one of the most common drivers of this resistance.

Efficacy Against ESR1 Mutations

The gene encoding ERα, known as ESR1, can acquire mutations during the course of treatment, particularly under the selective pressure of AIs.[4] These mutations, which are detected in up to 40% of patients with metastatic disease after progression on endocrine therapy, typically occur in the ligand-binding domain of the receptor.[4] The resulting mutant

ERα protein is constitutively active, meaning it can signal for cell growth and proliferation even in the absence of estrogen.[16] This ligand-independent activity renders AIs, which work by depleting estrogen, completely ineffective.[19]

Elacestrant was specifically designed to be effective against both wild-type and mutated forms of the ER.[1] It demonstrates strong binding affinity for these mutated receptors, allowing it to exert its antagonistic and degradative effects.[18] While AIs fail because the mutated receptor no longer requires estrogen, Elacestrant succeeds because it targets the receptor protein itself. By inducing the degradation of the constitutively active mutant receptor, Elacestrant directly removes the engine of resistance-driven tumor growth.[12] This is not merely an alternative therapeutic strategy but a direct and logical countermeasure to the primary mechanism of AI resistance. This explains why its clinical efficacy, as demonstrated in the EMERALD trial, is so markedly superior in the

ESR1-mutated patient population.[1]

In Vitro and In Vivo Preclinical Evidence

The clinical development of Elacestrant was supported by robust preclinical data. In vitro studies using ER+ breast cancer cell lines, such as MCF-7, demonstrated that Elacestrant potently inhibits ERα expression in a dose-dependent manner, with a half-maximal effective concentration (EC50​) of 0.6 nM.[10] It also effectively antagonized estradiol-stimulated cell proliferation, with a half-maximal inhibitory concentration (

IC50​) of 4.2 nM.[10] Elacestrant showed high selectivity for ERα over ERβ, with

IC50​ values of 48 nM and 870 nM, respectively.[10] In vivo studies using patient-derived xenograft models confirmed its potent antitumor activity, including in models that were resistant to fulvestrant and CDK4/6 inhibitors, as well as those harboring

ESR1 mutations.[2]

Blood-Brain Barrier Penetration

A notable pharmacological feature that distinguishes Elacestrant from fulvestrant is its ability to cross the blood-brain barrier.[2] This property was demonstrated in preclinical models and has significant clinical implications, as the brain is a common site of metastasis for breast cancer.[22] The central nervous system penetration of Elacestrant suggests it may have therapeutic activity against existing brain metastases and could potentially play a role in preventing their formation, an area of active clinical investigation.[11]

Clinical Pharmacokinetics (ADME)

The pharmacokinetic profile of Elacestrant, which describes its absorption, distribution, metabolism, and excretion (ADME), has been well-characterized in clinical studies and supports its once-daily oral dosing regimen.

Absorption

Elacestrant is administered orally and exhibits low absolute bioavailability, estimated to be approximately 10%.[3] Following oral administration, the time to reach peak plasma concentration (

Tmax​) ranges from 1 to 4 hours.[3] The drug's exposure, measured by maximum concentration (

Cmax​) and area under the curve (AUC), increases in a more than dose-proportional manner, suggesting potential saturation of clearance mechanisms at higher doses.[3] At the recommended dose of 345 mg once daily, Elacestrant reaches steady-state concentrations by day 6, with a mean accumulation ratio of approximately 2-fold.[3]

A significant food effect has been observed. Administration with a high-fat meal (800 to 1000 calories, 50% fat) increases the Cmax​ by 42% and the AUC by 22% compared to administration in a fasted state.[3] This finding is clinically important, as it forms the basis for the recommendation to take Elacestrant with food to enhance its absorption and bioavailability, while also helping to mitigate gastrointestinal side effects like nausea.[26]

Distribution

Elacestrant is extensively distributed throughout the body tissues, as indicated by its large apparent volume of distribution (Vd​) of 5800 L.[3] It is highly bound to plasma proteins, with a binding fraction exceeding 99%, which is independent of the drug concentration.[2] This high degree of protein binding limits the amount of free, pharmacologically active drug in circulation but contributes to its long duration of action.

Metabolism

Elacestrant is primarily cleared via hepatic metabolism, mediated by the cytochrome P450 (CYP) enzyme system.[2] The major metabolic pathway involves the CYP3A4 isoenzyme.[5] To a lesser extent, CYP2A6 and CYP2C9 also contribute to its metabolism.[5] The drug undergoes N-dealkylation, N-demethylation, and various oxidations.[24] The heavy reliance on CYP3A4 for its clearance is the underlying reason for the clinically significant drug-drug interactions with strong inhibitors and inducers of this enzyme.

Excretion

The elimination of Elacestrant and its metabolites occurs predominantly through the feces. Following a single radiolabeled oral dose, approximately 82% of the dose was recovered in the feces (with 34% as unchanged drug), while only a small fraction (~7.5%) was recovered in the urine (with less than 1% as unchanged drug).[3] Elacestrant has a long terminal elimination half-life, ranging from 30 to 50 hours, which supports the convenience of a once-daily dosing schedule.[2]

Table 2: Summary of Pharmacokinetic Parameters of Elacestrant

Parameter	Value	Notes/Source Snippet(s)
Route of Administration	Oral	5
Bioavailability	~10%	3
Tmax​ (Time to Peak Concentration)	1–4 hours	3
Food Effect (High-Fat Meal)	↑ Cmax​ by 42%, ↑ AUC by 22%	3
Plasma Protein Binding	>99%	5
Apparent Volume of Distribution (Vd​)	5800 L	3
Primary Metabolism	Hepatic, CYP3A4 (major), CYP2A6/2C9 (minor)	5
Elimination Half-Life	30–50 hours	2
Route of Excretion	Feces (~82%), Urine (~7.5%)	3
Steady State	Achieved by Day 6	3

Pivotal Clinical Efficacy: The EMERALD Trial

The regulatory approvals of Elacestrant were based on the robust efficacy and safety data from the pivotal EMERALD trial (NCT03778931), a landmark study that established its role in the treatment of ER+/HER2- metastatic breast cancer.

Trial Design and Methodology

EMERALD was a Phase III, international, multicenter, randomized, open-label, active-controlled study designed to compare the efficacy and safety of Elacestrant with standard-of-care (SOC) endocrine monotherapy.[1]

Patient Population

The trial enrolled 477 postmenopausal women and adult men with ER+/HER2- advanced or metastatic breast cancer.[1] A critical inclusion criterion was disease progression after one or two prior lines of endocrine therapy for advanced disease. Furthermore, all patients were required to have received prior treatment with a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor in combination with either an AI or fulvestrant.[1] This ensured that the study population was representative of the modern, heavily pre-treated clinical setting where endocrine resistance is a major challenge. Baseline characteristics were well-balanced between the two arms, with a median age of 63 years, a high rate of visceral metastases (~70%), and nearly half of the patients (47.8%) having detectable

ESR1 mutations in their circulating tumor DNA (ctDNA) at baseline.[31]

Randomization and Treatment

Patients were randomized in a 1:1 ratio to receive either Elacestrant at a dose of 345 mg orally once daily or investigator's choice of SOC endocrine monotherapy.[29] The SOC arm consisted of fulvestrant or an AI (anastrozole, letrozole, or exemestane), reflecting real-world treatment options after progression on a CDK4/6 inhibitor.[30] Randomization was stratified based on three key factors:

ESR1 mutational status (detected vs. not detected), prior treatment with fulvestrant (yes vs. no), and the presence of visceral metastases (yes vs. no).[29]

Primary Endpoints

The EMERALD trial was designed with two co-primary endpoints to assess efficacy in both a broad and a targeted population:

1. Progression-Free Survival (PFS), as assessed by a blinded independent central review, in the overall intent-to-treat (ITT) population.
2. PFS in the pre-specified subgroup of patients whose tumors harbored a detectable ESR1 mutation.[1]

Key Efficacy Results

The trial successfully met both of its primary endpoints, demonstrating the superiority of Elacestrant over SOC endocrine therapy.

Intent-to-Treat (ITT) Population

In the overall population of 477 patients, treatment with Elacestrant resulted in a statistically significant improvement in PFS. Elacestrant reduced the risk of disease progression or death by 30% compared to the SOC arm (Hazard Ratio 0.70; 95% Confidence Interval [CI], 0.55 to 0.88; P=0.002).[16] The median PFS was 2.8 months for patients receiving Elacestrant versus 1.9 months for those receiving SOC.[35]

ESR1-Mutated Subgroup

The clinical benefit of Elacestrant was substantially more pronounced in the subgroup of 228 patients with detectable ESR1 mutations. In this biomarker-defined population, Elacestrant reduced the risk of progression or death by an impressive 45% (HR 0.55; 95% CI, 0.39 to 0.77; P=0.0005).[1] The median PFS was doubled, reaching 3.8 months with Elacestrant compared to 1.9 months with SOC.[1]

Landmark analyses further underscored the durable benefit for a subset of these patients. At 12 months, the rate of PFS was more than three times higher in the Elacestrant arm, with 26.8% of patients remaining progression-free compared to only 8.2% in the SOC arm.[35] Regulatory agencies, including the FDA, concluded that the overall benefit observed in the ITT population was primarily driven by these strong results in the

ESR1-mutated subgroup, which ultimately led to the specific, biomarker-guided indication for the drug.[1]

Table 3: Baseline Characteristics of the EMERALD Phase III Trial Population

Characteristic	Elacestrant (n=239)	Standard of Care (n=238)
Median Age, years (range)	63 (33-89)	63 (24-89)
ESR1 Mutation Status, n (%)	115 (48.1)	113 (47.5)
Visceral Metastases, n (%)	163 (68.2)	169 (71.0)
Prior Lines of Endocrine Therapy, n (%)
1 line	135 (56.5)	135 (56.7)
2 lines	103 (43.1)	104 (43.7)
Prior Chemotherapy for Advanced Disease, n (%)	50 (20.9)	56 (23.5)
Source Data: 31

Table 4: Key Efficacy Outcomes from the EMERALD Trial

Endpoint	Subgroup	Elacestrant	Standard of Care	Hazard Ratio (95% CI)	P-value
Median PFS (months)	ITT Population (n=477)	2.8	1.9	0.70 (0.55–0.88)	0.002
Median PFS (months)	ESR1-Mutated (n=228)	3.8	1.9	0.55 (0.39–0.77)	0.0005
12-Month PFS Rate (%)	ITT Population	22.3	9.4	N/A	N/A
12-Month PFS Rate (%)	ESR1-Mutated	26.8	8.2	N/A	N/A
Source Data: 1

Subgroup Analyses and Predictors of Response

Further analyses of the EMERALD trial data provided deeper understanding into which patients derive the most substantial benefit from Elacestrant, reinforcing its role in a precision medicine framework.

Impact of Prior CDK4/6 Inhibitor Duration

One of the most clinically significant findings from a post-hoc analysis of the EMERALD trial was the strong correlation between the duration of prior treatment with a CDK4/6 inhibitor and the magnitude of benefit from Elacestrant.[4] This observation suggests that the length of time a patient's cancer was controlled by a prior endocrine-based therapy serves as a powerful clinical indicator of underlying endocrine sensitivity.

The logic follows that patients who experience a prolonged benefit from a CDK4/6 inhibitor combined with an AI or fulvestrant have tumors that are fundamentally dependent on, or "addicted to," the estrogen receptor signaling pathway for their growth and survival. Even after developing an ESR1 mutation that confers resistance to the initial therapy, their cancer's core biology remains ER-driven. Conversely, patients who progress very quickly on a first-line CDK4/6 inhibitor regimen may have tumors with primary endocrine resistance, driven by alternative signaling pathways.

For these endocrine-sensitive tumors, a potent and next-generation ER-targeting agent like Elacestrant is exceptionally effective. The data from EMERALD strongly supports this. In the subgroup of patients with ESR1 mutations who had been treated with a prior CDK4/6 inhibitor for 12 months or longer, the efficacy of Elacestrant was striking. The median PFS in this group reached 8.6 months, compared to only 1.9 months for those receiving SOC (HR 0.41; 95% CI, 0.26-0.63).[29] This finding refines patient selection beyond simply identifying an

ESR1 mutation; it suggests that the ideal candidate for Elacestrant is a patient with an ESR1 mutation who has also demonstrated a durable response to previous endocrine-based strategies.

This benefit was consistent across various clinical scenarios within this subgroup. For instance, among patients with bone metastases and a prior CDK4/6i duration of ≥12 months, median PFS was 9.1 months with Elacestrant versus 1.9 months with SOC. For those with more aggressive disease, such as three or more metastatic sites, the median PFS was 10.8 months versus 1.8 months, respectively.[29]

Comparative Efficacy vs. SOC Components

Post-hoc analyses also directly compared Elacestrant to the individual components of the SOC arm, primarily fulvestrant and AIs. Fulvestrant was the investigator's choice of therapy for 69% of patients in the control arm, making it the most relevant comparator.[30] In a head-to-head comparison within the

ESR1-mutated population, Elacestrant demonstrated clear superiority, reducing the risk of progression or death by 50% compared to fulvestrant (HR=0.504).[35] This result was particularly noteworthy, as it established Elacestrant as the first oral SERD to show superior efficacy over the injectable standard in a pivotal Phase III trial.[35] Similarly, Elacestrant demonstrated improved PFS compared to the AI subgroup as well.[30]

Safety, Tolerability, and Risk Management

The clinical utility of an effective anticancer agent is contingent upon a manageable safety profile that allows for sustained treatment. Elacestrant has demonstrated a predictable and generally well-tolerated safety profile, consistent with its mechanism as an endocrine therapy.

Overall Safety Profile

In the EMERALD trial, the majority of adverse events (AEs) associated with Elacestrant were Grade 1 or 2 in severity and were considered manageable with supportive care or dose modification.[15] Treatment-related Grade 3 or higher AEs were infrequent, occurring in 7.2% of patients receiving Elacestrant compared to 3.1% in the SOC arm.[33] Permanent discontinuation of treatment due to an adverse reaction was also low, at 6% for Elacestrant and 4% for SOC.[33]

Common Adverse Reactions

The most frequently reported AEs are primarily gastrointestinal and systemic in nature. Nausea was the most common AE, reported in 35% of patients on Elacestrant, though the vast majority of cases were Grade 1 or 2.[12] In clinical trials, most patients who experienced nausea were able to manage it without requiring anti-nausea medication.[4] Other common AEs (occurring in ≥10% of patients) included musculoskeletal pain, fatigue, vomiting, decreased appetite, diarrhea, headache, constipation, abdominal pain, and hot flushes.[5]

Clinically significant laboratory abnormalities were also observed, most notably dyslipidemia. Increased total cholesterol and increased triglycerides were common findings, along with elevations in liver transaminases (AST and ALT) and decreased hemoglobin.[15]

Table 5: Summary of Adverse Reactions (≥10% Incidence) from the EMERALD Trial

Adverse Reaction	Elacestrant (n=239) - All Grades (%)	Elacestrant - Grade 3/4 (%)	Standard of Care (n=238) - All Grades (%)	Standard of Care - Grade 3/4 (%)
Musculoskeletal pain	41	2.9	39	2.1
Nausea	35	2.5	19	0.4
Increased Cholesterol	30	0.9	17	0.4
Increased AST	29	2.9	34	4.3
Increased Triglycerides	27	2.2	16	1.3
Fatigue	26	1.7	27	2.1
Decreased Hemoglobin	26	2.1	22	2.1
Vomiting	19	0.8	9	0.4
Increased ALT	17	2.9	23	2.6
Decreased Appetite	15	0.4	10	0.4
Diarrhea	13	0	14	0.4
Headache	12	0.4	9	0
Constipation	12	0	7	0
Abdominal Pain	11	0.8	8	0.4
Hot Flush	11	0	8	0
Source Data: 5

Warnings and Precautions

The prescribing information for Elacestrant includes specific warnings and precautions that require clinical attention:

• Dyslipidemia: Hypercholesterolemia and hypertriglyceridemia were reported in 30% and 27% of patients, respectively.[18] While severe (Grade 3/4) events were uncommon, it is recommended to monitor the patient's lipid profile prior to starting treatment and periodically thereafter.[4]
• Embryo-Fetal Toxicity: Based on its antiestrogenic mechanism of action and findings from animal studies, Elacestrant can cause harm to a developing fetus.[2] It is contraindicated in pregnancy. Females of reproductive potential must be advised of this risk and should use effective contraception during treatment and for one week following the final dose. Male patients with female partners of reproductive potential should also use effective contraception during the same period.[18]

Dose Modifications for Adverse Reactions

A structured approach for managing AEs is outlined in the prescribing information. For Grade 1 toxicity, treatment can continue at the current dose. For Grade 2, a temporary interruption may be considered. For Grade 3 or 4 toxicities, treatment should be interrupted until resolution, and then resumed at a reduced dose level.[38] The standard 345 mg daily dose can be reduced first to 258 mg (three 86-mg tablets) and then to 172 mg (two 86-mg tablets). If further dose reduction is required, the drug should be permanently discontinued.[38]

Drug-Drug Interactions

Elacestrant's metabolism via CYP3A4 makes it susceptible to significant drug-drug interactions.

• CYP3A4 Inhibitors and Inducers: Co-administration with strong or moderate CYP3A4 inhibitors (e.g., itraconazole, clarithromycin, fluconazole) can substantially increase Elacestrant plasma concentrations and the risk of toxicity. Conversely, co-administration with strong or moderate CYP3A4 inducers (e.g., rifampin, carbamazepine, St. John's Wort) can dramatically decrease Elacestrant concentrations, potentially compromising its efficacy. Concomitant use with these agents should be avoided.[18]
• P-gp and BCRP Substrates: Elacestrant is an inhibitor of the drug transporters P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP).[3] This can increase the plasma concentrations of co-administered drugs that are substrates of these transporters. Caution is advised, and dose reduction may be necessary for P-gp or BCRP substrates with a narrow therapeutic index, such as digoxin or rosuvastatin.[27]

Table 6: Clinically Significant Drug-Drug Interactions with Elacestrant

Interacting Agent Class	Example Drugs	Effect on Elacestrant/Other Drug	Clinical Recommendation
Strong/Moderate CYP3A4 Inhibitors	Itraconazole, Clarithromycin, Fluconazole, Ketoconazole	Increases Elacestrant exposure and risk of toxicity	Avoid concomitant use
Strong/Moderate CYP3A4 Inducers	Rifampin, Carbamazepine, Phenytoin, St. John's Wort	Decreases Elacestrant exposure and efficacy	Avoid concomitant use
P-gp/BCRP Substrates	Digoxin, Rosuvastatin, Dabigatran, Afatinib	Elacestrant increases exposure of the substrate drug	Use with caution; consider dose reduction of the substrate drug per its prescribing information
Source Data: 2

Regulatory History and Approved Indications

Elacestrant has received marketing authorization from major regulatory bodies in North America and Europe, solidifying its role as a new therapeutic option for a specific subset of breast cancer patients.

U.S. Food and Drug Administration (FDA)

Recognizing the significant unmet need and the positive results of the EMERALD trial, the FDA granted Elacestrant both Priority Review and Fast Track designations during its development.[17]

• Approval Date: The FDA approved Elacestrant on January 27, 2023.[1]
• Approved Indication: The approved indication is 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 line of endocrine therapy.[2]
• Companion Diagnostic: Concurrent with the drug's approval, the FDA also approved the Guardant360 CDx assay, a liquid biopsy test, as the companion diagnostic necessary to identify patients with activating ESR1 mutations in plasma specimens, thereby determining their eligibility for treatment with Elacestrant.[4]

European Medicines Agency (EMA)

Following a review of the EMERALD data, the EMA's Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion on July 20, 2023, recommending marketing authorisation.[40]

• Marketing Authorisation Granted: The European Commission officially granted marketing authorisation for Elacestrant on September 15, 2023.[2]
• Approved Indication: The indication in the European Union is for use as a monotherapy for the treatment of postmenopausal women, and men, with ER-positive, HER2-negative, locally advanced or metastatic breast cancer with an activating ESR1 mutation who have disease progression following at least one line of endocrine therapy including a CDK 4/6 inhibitor.[2]

The slight divergence in the wording of the FDA and EMA indications warrants consideration. The EMERALD trial, which served as the evidence base for both approvals, exclusively enrolled patients who had received prior therapy with a CDK4/6 inhibitor.[29] Therefore, there is no Phase III evidence supporting the use of Elacestrant in a CDK4/6 inhibitor-naïve population. The EMA's label is a more precise reflection of this evidence base, explicitly stating the requirement of prior CDK4/6 inhibitor therapy. The FDA's indication, while not technically incorrect (as a CDK4/6i regimen is a line of endocrine therapy), is broader and could be interpreted as supporting use in the rare clinical scenario of a patient progressing on an AI alone without ever having received a CDK4/6 inhibitor. This regulatory nuance underscores the importance for clinicians to base treatment decisions on the specific clinical trial data that underpins an approval, with the EMA's language providing a clearer guide to the proven clinical context for Elacestrant's use.

Clinical Application and Patient Management

The integration of Elacestrant into clinical practice requires careful patient selection, adherence to specific administration guidelines, and proactive monitoring for potential toxicities.

Patient Selection

The use of Elacestrant is highly specific and guided by both clinical and molecular criteria:

• Tumor Subtype: The patient must have ER-positive, HER2-negative advanced or metastatic breast cancer.[4]
• Molecular Biomarker: An activating ESR1 mutation must be confirmed via an FDA-approved test, such as the Guardant360 CDx assay, using a plasma specimen (liquid biopsy).[4] Testing for ESR1 mutations is recommended at the time of disease progression on a prior line of endocrine therapy.
• Treatment History: Patients should have experienced disease progression after at least one prior line of endocrine therapy for advanced disease. As per the EMERALD trial design and the EMA label, this prior therapy should include a CDK4/6 inhibitor.[1]
• Clinical Predictors of Benefit: The ideal candidate is a patient who has demonstrated a degree of endocrine sensitivity, as suggested by a more durable response (e.g., ≥12 months) to their prior CDK4/6 inhibitor-based regimen.[4]

Dosage and Administration

Proper administration is key to optimizing the efficacy and tolerability of Elacestrant:

• Recommended Dose: The standard dose is 345 mg taken orally once daily.[1]
• Administration with Food: Elacestrant must be taken with food. This enhances its absorption and helps to reduce the incidence and severity of nausea and vomiting.[4]
• Tablet Integrity: The tablets should be swallowed whole. They must not be chewed, crushed, or split, as this can alter the drug's release profile.[26] Damaged tablets should not be taken.
• Missed Dose or Vomiting: If a dose is missed by more than 6 hours, or if the patient vomits after taking the dose, that dose should be skipped entirely. The patient should resume the normal schedule the following day. An extra dose should not be taken to make up for the missed one.[25]

Management of Specific Populations

• Hepatic Impairment: Dose adjustments are necessary for patients with liver dysfunction. For patients with moderate hepatic impairment (Child-Pugh Class B), the dose should be reduced to 258 mg once daily. Elacestrant has not been studied in patients with severe hepatic impairment (Child-Pugh Class C) and its use should be avoided in this population.[38]
• Geriatric and Pediatric Use: No dose adjustment is required for elderly patients, as studies have not shown age-specific problems limiting its utility.[26] The safety and efficacy of Elacestrant have not been established in pediatric patients.[26]

Monitoring and Follow-up

Patients receiving Elacestrant require routine monitoring to manage potential side effects and assess treatment response:

• Lipid Profile: Given the risk of dyslipidemia, a baseline lipid panel (total cholesterol and triglycerides) should be obtained before starting treatment, with periodic monitoring during therapy.[4]
• Toxicity and Disease Progression: Patients should be monitored regularly for common AEs, particularly gastrointestinal symptoms, and for signs of disease progression through standard clinical and imaging assessments.

Future Perspectives and Ongoing Clinical Research

While Elacestrant has established a new standard of care in the second-line setting for ESR1-mutated metastatic breast cancer, its full potential is still being explored. The current research landscape is focused on two primary strategic directions: evaluating its role in combination therapies to enhance efficacy and delay resistance, and moving its use into earlier stages of the disease to prevent recurrence.

Combination Therapies

The future of metastatic breast cancer treatment lies in rational combination strategies. Several ongoing trials are investigating Elacestrant as a backbone endocrine therapy combined with other targeted agents.

• ELEVATE (NCT05563220): This is a large Phase 1b/2 umbrella study designed to assess the safety and efficacy of Elacestrant in combination with several key targeted drugs. The arms of the study are evaluating Elacestrant with the PI3K inhibitor alpelisib (for PIK3CA-mutated tumors), the mTOR inhibitor everolimus, various CDK4/6 inhibitors (palbociclib, abemaciclib, and ribociclib), and the AKT inhibitor capivasertib. This trial will provide critical data on potential synergistic combinations and help define future treatment paradigms.[6]
• ELECTRA (NCT05386108): This Phase 1b/2 study is specifically focused on the combination of Elacestrant with the CDK4/6 inhibitor abemaciclib. Notably, this trial includes cohorts of patients with brain metastases, leveraging Elacestrant's ability to cross the blood-brain barrier to address this significant unmet need.[6]
• ELONA (NCT05618613): This Phase 1b/2 trial is exploring a novel combination of Elacestrant with onapristone, a progesterone receptor (PR) antagonist. This study aims to determine if dual blockade of both the estrogen and progesterone receptor pathways can provide enhanced antitumor activity in patients with ER+/PR+ breast cancer.[6]

Expansion into Early-Stage Breast Cancer

The ultimate goal in breast cancer therapy is to prevent metastatic recurrence. Given its efficacy in the advanced setting, Elacestrant is now being evaluated as an adjuvant therapy for patients with early-stage disease.

• ELEGANT (NCT06492616): This is a pivotal, global Phase III study that will be crucial in defining the future role of Elacestrant. The trial is enrolling patients with high-risk, node-positive, ER+/HER2- early breast cancer who have already completed 2 to 5 years of standard adjuvant endocrine therapy. Patients will be randomized to either continue with standard ET or switch to Elacestrant for a total of 5 years. The primary endpoint is invasive breast cancer-free survival (IBCFS). If positive, this trial could establish Elacestrant as a new standard adjuvant option for high-risk patients.[55]
• ELIPSE (NCT04797728): This was a completed "window-of-opportunity" study conducted in the neoadjuvant (pre-operative) setting. It demonstrated that short-term treatment with Elacestrant had significant biological activity in primary tumors, such as reducing the proliferation marker Ki67. These findings provided the biological rationale and proof-of-concept for launching the larger ELEGANT adjuvant trial.[6]

Table 7: Summary of Key Ongoing Clinical Trials Investigating Elacestrant

Trial Name (Identifier)	Phase	Patient Population	Intervention(s)	Primary Endpoint(s)	Status (as of late 2024)
ELEVATE (NCT05563220)	1b/2	ER+/HER2- mBC	Elacestrant + Alpelisib, Everolimus, CDK4/6i, or Capivasertib	Recommended Phase 2 Dose (Ph 1b); Objective Response Rate (Ph 2)	Recruiting
ELECTRA (NCT05386108)	1b/2	ER+/HER2- mBC (including brain metastases)	Elacestrant + Abemaciclib	Recommended Phase 2 Dose (Ph 1b); PFS (Ph 2)	Recruiting
ELEGANT (NCT06492616)	3	High-Risk, Node-Positive ER+/HER2- Early BC (post 2-5 yrs adjuvant ET)	Elacestrant vs. Standard ET	Invasive Breast Cancer-Free Survival (IBCFS)	Recruiting
TREAT ctDNA (NCT05512364)	3	ER+/HER2- BC with ctDNA Relapse	Elacestrant vs. Standard ET	Invasive Disease-Free Survival	Not yet recruiting
ELONA (NCT05618613)	1/2	ER+/PR+/HER2- mBC with ESR1 mutation	Elacestrant + Onapristone	Safety, Tolerability, Recommended Phase 2 Dose	Recruiting
Source Data: 6

Conclusion

Elacestrant (Orserdu) represents a paradigm shift in the management of ER-positive, HER2-negative metastatic breast cancer. As the first orally available Selective Estrogen Receptor Degrader, it provides a convenient and more potent alternative to the injectable SERD fulvestrant. Its dual mechanism of action—combining ER antagonism with proteasomal degradation—offers a comprehensive blockade of the estrogen-driven signaling pathway that fuels tumor growth.

The pivotal contribution of Elacestrant to oncology lies in its proven efficacy against tumors harboring acquired ESR1 mutations, a common and challenging mechanism of resistance to first-line aromatase inhibitors. The results of the Phase III EMERALD trial unequivocally established its superiority over standard-of-care endocrine therapy in this specific, biomarker-defined population, significantly improving progression-free survival. This has cemented its role as a new standard of care and a prime example of precision medicine in action, where a therapeutic agent is matched to a specific molecular driver of resistance.

The clinical utility of Elacestrant is further enhanced by a manageable safety profile, with predictable and predominantly low-grade adverse events that can be managed with supportive care and dose modifications. Subgroup analyses from the EMERALD trial have provided valuable clinical insights, suggesting that the greatest benefit is observed in patients with demonstrated prior endocrine sensitivity, as indicated by a longer duration of benefit from previous CDK4/6 inhibitor therapy.

The journey of Elacestrant is far from over. Its approval has opened new avenues of research, with a robust pipeline of ongoing clinical trials. These studies are poised to define its role in combination with other targeted agents to further improve outcomes in the metastatic setting, and critically, to evaluate its potential as an adjuvant therapy to prevent recurrence in patients with high-risk early-stage breast cancer. Elacestrant is not merely a new drug; it is a foundational agent upon which future therapeutic strategies for hormone receptor-positive breast cancer will be built.

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