Elacestrant

Elacestrant is a tetrahydronaphthalene compound that acts as a potent, selective, orally active antagonist and degrader of oestrogen receptor-alpha (ERα). Many breast cancers depend on oestrogen signalling through this receptor, which is why endocrine therapy is central to their treatment. Activating mutations in the ESR1 gene, which encodes ERα, can keep the receptor switched on without oestrogen, and elacestrant remains active in models that carry such mutations.

Mechanism of Action

• Receptor antagonism and degradation: elacestrant binds ERα, blocks its transcriptional activity and promotes its degradation through the proteasome. In ER-positive, HER2-negative breast cancer cells it inhibits oestradiol-driven proliferation, slows the movement of the receptor into the nucleus and increases receptor turnover, which disrupts downstream signalling.
• Oestradiol-dependent and independent growth: elacestrant inhibits both the oestradiol-dependent and the oestradiol-independent growth of ERα-positive breast cancer cells, including models with ESR1 mutations.
• Preclinical activity: it showed antitumour activity in patient-derived xenograft models that had been exposed to several endocrine therapies and carried either wild-type ESR1 or ESR1 mutations in the ligand-binding domain. Laboratory and animal models resistant to fulvestrant and to CDK4/6 inhibitors also responded.
• Effect in patients: in patients with ER-positive advanced breast cancer who had received a median of 2.5 earlier lines of endocrine therapy, daily elacestrant (dihydrochloride 400 mg, equal to 345 mg elacestrant) reduced tumour uptake of the oestrogen PET tracer 16α-18F-fluoro-17β-oestradiol (FES) by a median of 88.7% by day 14, which indicates less available oestrogen receptor.
• Brain penetration: elacestrant crosses the blood–brain barrier in a dose-dependent manner.

Pharmacokinetics

• Absorption: elacestrant is absorbed rapidly, with peak levels 1 to 4 hours after a dose, but oral bioavailability is only about 10%. Steady state is reached by day 6. Cmax and AUC rise slightly more than in proportion to dose above 50 mg (salt form). After a single 345 mg dose with food, the geometric mean Cmax was 52.86 ng/mL and AUCinf 1,566 ng·h/mL; at steady state the predicted median AUC is 2,190 ng·h/mL (range 461 to 8,470). A high-fat, high-calorie meal raised Cmax and AUC by 40% and 20%, and a light meal by 30% and 20%, compared with fasting; food may also reduce gastrointestinal side effects. Elacestrant is a P-gp substrate, and this transport is saturated at 258 mg and 345 mg.
• Distribution: plasma protein binding is above 99% and independent of concentration. Elacestrant is extensively distributed in tissues (apparent peripheral volume 5,411 L, central volume 422 L). After 7 days of daily dosing at 200 mg and 500 mg, median concentrations in cerebrospinal fluid were 0.0966 ng/mL and 0.155 ng/mL.
• Metabolism: mainly by CYP3A4, with a possible small contribution from CYP2A6 and CYP2C9. Unchanged elacestrant is a minor component of plasma (under 10% of plasma radioactivity); the main circulating metabolite is the glucuronide of 4-[2-(ethylamino)ethyl]benzoic acid, about 41% of plasma radioactivity.
• Elimination: the half-life is about 30 to 50 hours. After a radiolabelled dose, about 82% was recovered in faeces (34% unchanged) and 7.5% in urine (under 1% unchanged), so excretion is mainly faecal.
• Special populations: the dose is reduced in moderate and severe hepatic impairment, because impaired liver function can increase the risk of adverse reactions. Age needs no adjustment, although data are limited at 75 years or over, and renal impairment needs no adjustment but severe impairment has not been studied.

• ER-positive, HER2-negative advanced breast cancer with an ESR1 mutation: monotherapy for postmenopausal women, and men, with oestrogen receptor (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 that included a CDK4/6 inhibitor.

Patients are selected by the presence of an activating ESR1 mutation in a plasma sample, using a CE-marked in vitro diagnostic (IVD) test with the corresponding intended purpose. If no CE-marked IVD is available, an alternative validated test is used.

• Hypersensitivity to elacestrant or to any of the excipients (microcrystalline cellulose, silicified microcrystalline cellulose, crospovidone, magnesium stearate, colloidal silicon dioxide and the components of the blue film coating).

The frequencies below reflect 301 patients with breast cancer in three open-label studies who took elacestrant 400 mg (dihydrochloride; equal to 345 mg elacestrant) once daily as a single agent. The median treatment duration was 85 days (range 5 to 1,288). Frequencies count all adverse events whatever their cause, so some may be due to the disease or other medicines; for laboratory changes they are based on worsening from baseline by at least one grade and shifts to grade 3 or higher.

The most common reactions (10% or more) were nausea, raised triglycerides, raised cholesterol, vomiting, fatigue, dyspepsia, diarrhoea, low calcium, back pain, raised creatinine, arthralgia, low sodium, constipation, headache, hot flush, abdominal pain, anaemia, low potassium and raised alanine aminotransferase. The most common grade 3 or higher reactions (2% or more) were nausea (2.7%), raised aspartate aminotransferase (2.7%), raised alanine aminotransferase (2.3%), anaemia (2%), back pain (2%) and bone pain (2%). Serious reactions in at least 1% of patients included nausea, dyspnoea and venous thromboembolism. Reactions leading to discontinuation in at least 1% were nausea and decreased appetite; reactions leading to dose reduction were nausea; and reactions leading to dose interruption were nausea, abdominal pain, raised alanine aminotransferase, vomiting, rash, bone pain, decreased appetite, raised aspartate aminotransferase and diarrhoea.

Very common (≥1/10): anaemia, decreased appetite, headache, hot flush, nausea, vomiting, diarrhoea, constipation, abdominal pain, dyspepsia, arthralgia, back pain, fatigue; raised aspartate aminotransferase, triglycerides, cholesterol and alanine aminotransferase; low calcium, sodium and potassium; raised creatinine.

Common (≥1/100 to <1/10): urinary tract infection, decreased lymphocyte count, insomnia, dizziness, syncope, dyspnoea, cough, stomatitis, rash, pain in an extremity, musculoskeletal chest pain, bone pain, asthenia, raised blood alkaline phosphatase.

Uncommon (≥1/1,000 to <1/100): venous thromboembolism, acute hepatic failure.

Nausea was reported in 35% of patients (grade 3 or 4 in 2.5%). It usually appeared early, a median of 14 days (range 1 to 490) to the first episode, and was most frequent in the first cycle and generally less frequent in later cycles. Preventive nausea treatment was prescribed to 5% of patients and 11.8% received an antiemetic during treatment. In study RAD1901-308, 104 patients treated with elacestrant were 65 or older and 40 were 75 or older; gastrointestinal disorders were reported more often in those aged 75 or over.

Elacestrant is metabolised mainly by CYP3A4 and is a substrate of the transporter OATP2B1. It inhibits the efflux transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Dose adjustments are described under Administration and Dosage.

• Strong CYP3A4 inhibitors (clarithromycin, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, saquinavir, telaprevir, telithromycin, voriconazole, and grapefruit or grapefruit juice): avoid, and consider an alternative with no or minimal CYP3A4 inhibition. Itraconazole raised elacestrant AUC 5.3-fold and Cmax 4.4-fold in healthy subjects; simulations in patients predicted 5.5-fold and 3.9-fold at steady state.
• Moderate CYP3A4 inhibitors (aprepitant, ciprofloxacin, conivaptan, crizotinib, ciclosporin, diltiazem, dronedarone, erythromycin, fluconazole, fluvoxamine, grapefruit juice, imatinib, isavuconazole, tofisopam, verapamil): avoid. Simulations predicted that fluconazole would raise steady-state AUC 2.3-fold and Cmax 1.9-fold, and erythromycin 3.9-fold and 3.0-fold. Mild inhibitors need no adjustment.
• Strong CYP3A4 inducers (phenytoin, rifampicin, carbamazepine, St John’s wort): avoid. Rifampicin lowered elacestrant AUC by 86% and Cmax by 73% in healthy subjects (simulations in patients: 84% and 77% at steady state), which may reduce activity.
• Moderate CYP3A4 inducers (bosentan, cenobamate, dabrafenib, efavirenz, etravirine, lorlatinib, phenobarbital, primidone, sotorasib): avoid. Efavirenz was predicted to lower steady-state AUC by 57% and Cmax by 52%. Mild inducers need no adjustment.
• OATP2B1 inhibitors: exposure to elacestrant may rise, so caution is advised.
• P-gp inhibitors: for the lower doses (86 mg and 172 mg) a P-gp inhibitor might increase absorption; there are no clinical data.
• P-gp substrates: a single 345 mg dose raised digoxin Cmax by 27% and AUC by 13%. Digoxin should be monitored and its dose reduced as necessary. Other P-gp substrates may also rise, and their doses should be reduced according to their own SmPC.
• BCRP substrates: a single 345 mg dose raised rosuvastatin Cmax by 45% and AUC by 23%. Rosuvastatin should be monitored and its dose reduced as necessary. The same applies to other BCRP substrates.
• Food and grapefruit: elacestrant is taken with a light meal, which raises exposure modestly and reduces nausea and vomiting. Grapefruit and grapefruit juice inhibit CYP3A4 and should be avoided.

Treatment should be started by a physician experienced in anticancer therapy, after an activating ESR1 mutation has been shown in a plasma sample. The tablets are swallowed whole with a light meal at about the same time each day; they must not be chewed, crushed or split.

Recommended Dose

• 345 mg (one 345 mg tablet) once daily. The maximum recommended daily dose is 345 mg.
• Treatment continues as long as clinical benefit is observed or until unacceptable toxicity occurs.

Dose Adjustments for Side Effects

• The reduced dose is 258 mg once daily (three 86 mg tablets). If a further reduction below 258 mg is needed, elacestrant is discontinued.
• Grade 2: consider interrupting until recovery to grade 1 or less (or baseline), then resume at the same dose.
• Grade 3: interrupt until recovery to grade 1 or less (or baseline) and resume at 258 mg. If grade 3 toxicity recurs, interrupt again until recovery; the physician may resume 258 mg if the patient is benefiting. If a grade 3 or intolerable reaction recurs again, discontinue permanently.
• Grade 4: interrupt until recovery to grade 1 or less (or baseline) and resume at 258 mg. If a grade 4 or intolerable reaction recurs, discontinue permanently.

With CYP3A4 Inhibitors or Inducers

• Inhibitors: avoid strong and moderate inhibitors and consider an alternative medicine. If a strong inhibitor must be used, reduce to 86 mg once daily with careful monitoring. If a moderate inhibitor must be used, reduce to 172 mg once daily with careful monitoring; a further reduction to 86 mg may be considered according to tolerability. After the inhibitor is stopped, return to the earlier dose once 5 half-lives of the inhibitor have passed. Mild inhibitors need no adjustment.
• Inducers: avoid strong and moderate inducers and consider an alternative medicine. If one is needed for a short time (3 days or less) or intermittently (periods of 3 days or less separated by at least 2 weeks, or by 1 week plus 5 half-lives of the inducer, whichever is longer), continue elacestrant without increasing the dose. Mild inducers need no adjustment.

Special Populations

• Elderly: no dose adjustment for age; data are limited at 75 years or over.
• Hepatic impairment: no adjustment in mild impairment (Child-Pugh A); reduce to 258 mg in moderate impairment (Child-Pugh B) and to 86 mg in severe impairment (Child-Pugh C).
• Renal impairment: no adjustment is needed. Elacestrant has not been studied in severe renal impairment, so no dose recommendation can be made there.
• Children and adolescents: safety and efficacy from birth to 18 years have not been established, and no data are available.

Missed or Vomited Dose

• Missed dose: it can be taken immediately if it is within 6 hours of the usual time. After more than 6 hours, skip the dose for that day and take the next dose at the usual time the following day.
• Vomiting: do not take an extra dose that day; resume the usual schedule the next day.

Hepatic Impairment

Elacestrant is metabolised by the liver, and impaired liver function can increase the risk of adverse reactions. It is used cautiously in patients with hepatic impairment, who are monitored regularly and closely for adverse reactions, at 258 mg once daily in moderate and 86 mg once daily in severe impairment.

CYP3A4 Inhibitors and Inducers

Strong and moderate CYP3A4 inhibitors and inducers, grapefruit and grapefruit juice should be avoided, with an alternative medicine considered. When this is not possible, the dose is adjusted as set out under Administration and Dosage.

Thromboembolic Events

Thromboembolic events are common in patients with advanced breast cancer and were observed in clinical studies with elacestrant. This should be taken into account when prescribing to patients at risk.

Pregnancy, Breastfeeding and Fertility

• Contraception: females of reproductive potential should use effective contraception during treatment and for one week after the last dose.
• Pregnancy: elacestrant should not be used during pregnancy or in women of childbearing potential who are not using contraception. There are no human data; animal studies showed reproductive toxicity, and because of its mechanism elacestrant can cause foetal harm. Pregnancy status should be checked before treatment starts. If pregnancy occurs, the patient must be told of the potential hazard to the foetus and the potential risk of miscarriage.
• Breastfeeding: it is unknown whether elacestrant or its metabolites pass into human milk. Because of the potential for serious reactions in the infant, women should not breastfeed during treatment and for one week after the last dose.
• Fertility: based on animal findings and its mechanism, elacestrant may impair fertility in females and males of reproductive potential.

Effect on Driving

Elacestrant has no or negligible influence on the ability to drive and use machines. Fatigue, asthenia and insomnia have been reported, so patients who have these should take care when driving or operating machinery.

Orserdu tablets need no special storage conditions. They are supplied in aluminium-aluminium blisters in cartons of 28 tablets (4 blisters of 7), for both the 86 mg and the 345 mg strength. Keep them out of the sight and reach of children.

3 years. Do not use after the expiry date on the pack.

Prescription only (Rx), on restricted medical prescription (Annex II B): treatment is started by a physician experienced in anticancer therapy, after an activating ESR1 mutation has been shown in a plasma sample. Elacestrant is taken at home as tablets, so it is supplied to the patient or to the treating clinic on prescription. No cold chain is required.