4.1. Therapeutic indications

KORSERDU monotherapy is indicated for the treatment of postmenopausal women, and men, with estrogen 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 including a CDK 4/6 inhibitor.

4.2. Posology and method of administration

Treatment with KORSERDU should be initiated by a physician experienced in the use of anticancer therapies.

Patients with ER-positive, HER2-negative advanced breast cancer should be selected for treatment with KORSERDU based on the presence of an activating ESR1 mutation in plasma specimens, using a CE marked in vitro diagnostic (IVD) with the corresponding intended purpose. If the CE-marked IVD is not available, the presence of an activating ESR1 mutation in plasma specimens should be assessed by an alternative validated test.

Posology

The recommended dose is 345 mg (one 345 mg film-coated tablet), once daily.

The maximum recommended daily dose of KORSERDU is 345 mg.

Treatment should continue as long as clinical benefit is observed or until unacceptable toxicity occurs.

Missed dose

If a dose is missed, it can be taken immediately within 6 hours after the time it is usually taken. After more than 6 hours, the dose should be skipped for that day. On the next day, KORSERDU should be taken at the usual time.

Vomiting

If the patient vomits after taking the KORSERDU dose, the patient should not take an additional dose on that day and should resume the usual dosing schedule the next day at the usual time.

Dose modifications

The recommended elacestrant dose modifications for patients with adverse reactions (see section 4.8) are provided in Tables 1 and 2:

Table 1: KORSERDU dose reduction for adverse reactions

KORSERDU dose level

Dose and schedule

Number and strength of tablets

Dose reduction

258 mg once daily

Three 86 mg tablets

If further dose reduction below 258 mg once daily is required, discontinue KORSERDU.

Table 2: KORSERDU dose modification guidelines for adverse reactions

Severity

Dose modification

Grade 2

Consider interruption of KORSERDU until recovery to Grade ≤ 1 or baseline. Then resume KORSERDU at the same dose level.

Grade 3

KORSERDU should be interrupted until recovery to Grade ≤ 1 or baseline. The dose should be reduced to 258 mg once daily when resuming therapy.

If the Grade 3 toxicity recurs, KORSERDU should be interrupted until recovery to Grade ≤ 1 or baseline. The reduced dose of 258 mg may be resumed at the discretion of the treating physician the patient is benefiting from treatment. If a Grade 3 or intolerable adverse reaction recurs, KORSERDU should be permanently discontinued.

Grade 4

Interrupt KORSERDU until recovery to Grade ≤ 1 or baseline. The dose should be reduced to 258 mg once daily when resuming therapy.

If a Grade 4 or intolerable adverse reaction recurs, permanently discontinue KORSERDU.

Use of KORSERDU with CYP3A4 inhibitors

Concomitant use of strong or moderate CYP3A4 inhibitors should be avoided and an alternative concomitant medicinal product with no or minimal potential to inhibit CYP3A4 should be considered. If a strong CYP3A4 inhibitor must be used, the elacestrant dose should be reduced to 86 mg once daily with careful monitoring of tolerability. If a moderate CYP3A4 inhibitor must be used, the elacestrant dose should be reduced to 172 mg once daily with careful monitoring of tolerability. Subsequent dose reduction to 86 mg once daily may be considered with moderate CYP3A4 inhibitors based on tolerability. If the CYP3A4 inhibitor is discontinued, the elacestrant dose should be increased to the dose used prior to the initiation of the CYP3A4 inhibitor (after 5 half-lives of the CYP3A4 inhibitor) (see sections 4.4, 4.5 and 5.2).No dose adjustments are required for coadministration of KORSERDU with mild CYP3A4 inhibitors (see section 4.5).

Use of KORSERDU with CYP3A4 inducersConcomitant use of strong or moderate CYP3A4 inducers should be avoided and an alternative concomitant medicinal product with no or minimal potential to induce CYP3A4 should be considered. If a strong or moderate CYP3A4 inducer must be used for a short duration of time (i.e. ≤ 3 days) or intermittently (i.e. treatment periods ≤ 3 days separated by at least 2 weeks or 1 week + 5 half-lives of the CYP3A4 inducer, whichever is longer), continue elacestrant without increasing the dose. No dose adjustments are required for coadministration of KORSERDU with mild CYP3A4 inducers (see sections 4.4, 4.5 and 5.2).

Special populations

Elderly

No dose adjustment is required on the basis of patient age. Limited data are available in patients ≥ 75 years of age (see section 5.2).

Hepatic impairment

No dose adjustment is recommended for patients with mild hepatic impairment (Child-Pugh A). In patients with moderate hepatic impairment (Child-Pugh B), KORSERDU dose should be reduced to 258 mg. Elacestrant has not been studied in patients with severe hepatic impairment (Child-Pugh C), therefore no dose recommendation can be made for patients with severe hepatic impairment (see section 4.4).

Renal impairment

No dose adjustment in subjects with renal impairment is necessary. Elacestrant has not been studied in patients with severe renal impairment, therefore no dose recommendation can be made for patients with severe renal impairment (see section 5.2).

Paediatric population

The safety and efficacy of KORSERDU in children from birth to 18 years of age has not been established. No data are available.

Method of administration

KORSERDU is for oral use.

The tablets should be swallowed whole. They should not be chewed, crushed or split prior to swallowing. Patients should take their dose of KORSERDU at approximately the same time each day. KORSERDU should be administered with a light meal. Administration with food may also reduce nausea and vomiting (see section 5.2).

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4. Special warnings and precautions for use

Hepatic impairment

KORSERDU is metabolised by the liver, and impaired hepatic function can increase the risk for adverse reactions. Therefore, KORSERDU should be used cautiously in patients with hepatic impairment and patients should be regularly and closely monitored for adverse reactions. Administration of elacestrant should be undertaken with caution at a dose of 258 mg once daily in patients with moderate hepatic impairment (see section 4.2). In the absence of clinical data, elacestrant is not recommended in patients with severe hepatic impairment (Child-Pugh C) (see section 4.2).

Concomitant use with CYP3A4 inhibitors

Concomitant administration of KORSERDU with strong CYP3A4 inhibitors including, but not limited to: clarithromycin, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, saquinavir, telaprevir, telithromycin, voriconazole, and grapefruit or grapefruit juice should be avoided. An alternative concomitant medicinal product with no or minimal potential to inhibit CYP3A4 should be considered. If the strong CYP3A4 inhibitor cannot be avoided, KORSERDU dose adjustment should be applied (see sections 4.2 and 4.5).

Concomitant administration of KORSERDU with moderate CYP3A4 inhibitors including, but not limited to: aprepitant, ciprofloxacin, conivaptan, crizotinib, cyclosporine, diltiazem, dronedarone, erythromycin, fluconazole, fluvoxamine, grapefruit juice, imatinib, isavuconazole, tofisopam and verapamil should be avoided. An alternative concomitant medicinal product with no or minimal potential to inhibit CYP3A4 should be considered. If the moderate CYP3A4 inhibitor cannot be avoided, KORSERDU dose adjustment should be applied (see sections 4.2 and 4.5).

Concomitant use with CYP3A4 inducers

Concomitant administration of KORSERDU with strong CYP3A4 inducers including, but not limited to: phenytoin, rifampicin, carbamazepine and St John's Wort (Hypericum perforatum) should be avoided. An alternative concomitant medicinal product with no or minimal potential to induce CYP3A4 should be considered. If the strong CYP3A4 inducer cannot be avoided, KORSERDU dose adjustment should be applied (see sections 4.2 and 4.5).

Concomitant administration of KORSERDU with moderate CYP3A4 inducers including, but not limited to: bosentan, cenobamate, dabrafenib, efavirenz, etravirine, lorlatinib, phenobarbital, primidone, and sotorasib should be avoided. An alternative concomitant medicinal product with no or minimal potential to induce CYP3A4 should be considered. If the moderate CYP3A4 inducer cannot be avoided, KORSERDU dose adjustment should be applied (see sections 4.2 and 4.5).

Thromboembolic events

Thromboembolic events are commonly observed in patients with advanced breast cancer and have been observed in clinical studies with KORSERDU (see section 4.8). This should be taken into consideration when prescribing KORSERDU to patients at risk.

4.5. Interaction with other medicinal products and other forms of interaction

KORSERDU is primarily metabolised by CYP3A4 and is a substrate of the Organic Anion Transporting Polypeptide 2B1 (OATP2B1). KORSERDU is an inhibitor of P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) efflux transporters.

Effect of other medicinal products on KORSERDU

CYP3A4 Inhibitors

Co-administration of the strong CYP3A4 inhibitor itraconazole (200 mg once daily for 7 days) with KORSERDU (172 mg once daily for 7 days) increased elacestrant plasma exposure (AUCinf) and the peak concentration (Cmax) in healthy subjects 5.3 and 4.4-fold, respectively.

Physiologically based pharmacokinetic (PBPK) simulations in cancer patients suggested that the concomitant administration of multiple daily doses of elacestrant 345 mg and itraconazole 200 mg may increase elacestrant steady-state AUC and Cmax 5.5- and 3.9-fold, respectively, which may increase the risk of adverse reaction.

PBPK simulations in cancer patients suggested that concomitant administration of multiple daily doses of elacestrant 345 mg with moderate CYP3A4 inhibitors may increase elacestrant steady-state AUC and Cmax by 2.3- and 1.9-folds, respectively, with fluconazole (200 mg once daily), and by 3.9- and 3.0-folds, respectively, with erythromycin (500 mg four times a day), which may increase the risk of adverse reaction.

CYP3A4 Inducers

Co-administration of the strong CYP3A4 inducer rifampicin (600 mg once daily for 7 days) with a single dose of KORSERDU 345 mg decreased elacestrant plasma exposure (AUCinf) and the peak concentration (Cmax) in healthy subjects by 86% and 73%, respectively, which may decrease elacestrant activity.PBPK simulations in cancer patients suggested that the concomitant administration of multiple daily doses of elacestrant 345 mg and rifampicin 600 mg may decrease elacestrant steady-state AUC and Cmax by 84% and 77%, respectively, which may decrease elacestrant activity.PBPK simulations in cancer patients suggested that the concomitant administration of multiple daily doses of elacestrant 345 mg and the moderate CYP3A4 inducer efavirenz (600 mg) may decrease elacestrant steady-state AUC and Cmax by 57% and 52%, respectively, which may decrease elacestrant activity.

OATP2B1 inhibitors Elacestrant is a substrate of OATP2B1 in vitro. As it cannot be excluded that the coadministration of OATP2B1 inhibitors may increase the exposure of elacestrant, which may increase the risk of adverse reactions, caution is recommended in case of concomitant use of KORSERDU with OATP2B1 inhibitors.

Effect of KORSERDU on other medicinal products

P-gp substrates

Co-administration of KORSERDU (345 mg, single dose) with digoxin (0.5 mg, single dose) increased digoxin exposure by 27% for Cmax and 13% for AUC. Digoxin administration should be monitored and its dose reduced as necessary.

Concomitant use of KORSERDU with other P-gp substrates may increase their concentrations, which may increase the adverse reactions associated with the P-gp substrates. The dose of coadministered P-gp substrates should be reduced according to their Summary of Product Characteristics.

BCRP substrates

Co-administration of KORSERDU (345 mg, single dose) with rosuvastatin (20 mg, single dose) increased rosuvastatin exposure by 45% for Cmax and 23% for AUC. Rosuvastatin administration should be monitored and its dose reduced as necessary.

Concomitant use of KORSERDU with other BCRP substrates may increase their concentrations, which may increase the adverse reactions associated with the BCRP substrates. The dose of coadministered BCRP substrates should be reduced according to their Summary of Product Characteristics.

4.6. Fertility, pregnancy and lactation

Women of childbearing potential/Contraception in males and females

KORSERDU should not be used during pregnancy or in women of childbearing potential not using contraception. Based on the mechanism of action of elacestrant and findings from reproductive toxicity studies in animals, KORSERDU can cause foetal harm when administered to pregnant women. Females of reproductive potential should be advised to use effective contraception during treatment with KORSERDU and for one week after the last dose.

Pregnancy

There are no data from the use of elacestrant in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). KORSERDU should not be used during pregnancy or in women of childbearing potential not using contraception. The pregnancy status of females of reproductive potential should be verified prior to starting treatment with KORSERDU. If pregnancy occurs while taking KORSERDU, the patient must be informed of the potential hazard to the foetus and potential risk of miscarriage.

Breast-feeding

It is unknown whether elacestrant/metabolites are excreted in human milk. Because of the potential for serious adverse reactions in the breast-fed infant, it is recommended that lactating women should not breast-feed during treatment with KORSERDU and one week after the last dose of KORSERDU.

Fertility

Based on findings from animal studies (see section 5.3) and its mechanism of action, KORSERDU may impair fertility in females and males of reproductive potential.

4.7. Effects on ability to drive and use machines

KORSERDU has no or negligible influence on the ability to drive and use machines. However, since fatigue, asthenia, and insomnia have been reported in some patients taking elacestrant (see section 4.8), caution should be observed by patients who experience those adverse reactions when driving or operating machinery.

4.8. Undesirable effects

Summary of the safety profile

The most common (≥ 10%) adverse reactions with KORSERDU were nausea, triglycerides increased, cholesterol increased, vomiting, fatigue, dyspepsia, diarrhoea, calcium decreased, back pain, creatinine increased, arthralgia, sodium decreased, constipation, headache, hot flush, abdominal pain, anaemia, potassium decreased, and alanine aminotransferase increased. The most common Grade ≥3 (≥2%) adverse reactions of elacestrant were nausea (2.7%), AST increased (2.7%), ALT increased (2.3%), anaemia (2%), back pain (2%), and bone pain (2%).

Serious adverse reactions reported in ≥ 1% of patients included nausea, dyspnoea, and thromboembolism (venous).

Adverse reactions leading to discontinuation in ≥ 1% of patients included nausea and decreased appetite.

Adverse reactions leading to dose reduction in ≥ 1% of patients included nausea.

Adverse reactions leading to dose interruption in ≥ 1% of patients were nausea, abdominal pain, alanine aminotransferase increased, vomiting, rash, bone pain, decreased appetite, aspartate aminotransferase increased, and diarrhoea.

Tabulated list of adverse reactions

Adverse reactions described in the list below reflect exposure to elacestrant in 301 patients with breast cancer in three open label studies (RAD1901-005, RAD1901-106, and RAD1901-308) in which patients received elacestrant 400mg once daily as a single agent. The frequencies of adverse reactions are based on all-cause adverse event frequencies identified in patients exposed to elacestrant at the recommended dose in the target indication, whereas frequencies for changes in laboratory parameters are based on worsening from baseline by at least 1 grade and shifts to ≥ grade 3. The median duration of treatment was 85 days (range 5 to 1288).

The adverse reaction frequencies from clinical trials are based on all-cause adverse event frequencies, where a proportion of the events for an adverse reaction may have other causes than the drug, such as the disease, other medication or unrelated causes.

The following convention is used for the classification of the frequency of an adverse drug reaction (ADR) and is based on the Council for International Organizations of Medical Sciences (CIOMS) guidelines: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1 000 to < 1/100); rare (≥ 1/10 000 to < 1/1 000); very rare (< 1/10 000); not known (cannot be estimated from the available data).

Table 3. Adverse reactions in patients treated with elacestrant monotherapy 345 mg in metastatic breast cancer

Elacestrant

N=301

Infections and infestations

Common

Urinary tract infection

Blood and lymphatic system disorders

Very common

Anaemia

Common

Lymphocyte count decreased

Metabolism and nutrition disorders

Very common

Decreased appetite

Psychiatric disorders

Common

Insomnia

Nervous system disorder

Very common

Headache

Common

Dizziness, Syncope

Vascular disorders

Very common

Hot flush*

Uncommon

Thromboembolism (venous)*

Respiratory, thoracic and mediastinal disorders

Common

Dyspnoea, Cough*

Gastrointestinal disorders

Very common

Nausea, Vomiting, Diarrhoea, Constipation, Abdominal pain*, Dyspepsia*

Common

Stomatitis

Hepatobiliary disorders

Uncommon

Acute hepatic failure

Skin and subcutaneous tissue disorders

Common

Rash*

Musculoskeletal and connective tissues disorders

Very common

Arthralgia, Back pain

Common

Pain in extremity, Musculoskeletal chest pain *, Bone pain

General disorders and administration site conditions

Very common

Fatigue

Common

Asthenia

Investigations

Very common

Aspartate aminotransferase increased, Triglycerides increased, Cholesterol increased, Alanine aminotransferase increased, Calcium decreased, Creatinine increased, Sodium decreased, Potassium decreased

Common

Blood alkaline phosphatase increased

*Incidence represents a grouping of similar terms.

ADRs listed by system organ class and by decreasing frequency.

Description of selected adverse reactions

Nausea

Nausea was reported in 35% of patients. Grade 3-4 nausea events were reported in 2.5% of patients. Nausea was generally reported early, with a median time to the first onset 14 days (range: 1 to 490 days). Nausea occurred more frequently in the first cycle and from Cycle 2 onward, the incidence of nausea was generally lower in subsequent cycles (i.e., over time). Prophylactic treatment for nausea was prescribed for 12 (5%) subjects in the elacestrant arm and 28 (11.8%) received an antiemetic for the treatment of nausea during the on-treatment period.

Elderly

In the RAD1901-308 study, 104 patients who received elacestrant were ≥ 65 years and 40 patients were ≥ 75 years. Gastrointestinal disorders were reported more frequently in patients aged ≥ 75 years. Monitoring of treatment emergent adverse reactions by the treating physician, should include consideration of the patient's age and comorbidities, when selecting personalised interventions.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme (www.mhra.gov.uk/yellowcard) or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

The highest dose of KORSERDU administered in clinical studies was 1000 mg per day. The adverse drug reactions reported in association with doses higher than the recommended dose were consistent with the established safety profile (see section 4.8). The frequency and severity of gastrointestinal disorders (abdominal pain, nausea, dyspepsia and vomiting) appeared to be dose-related. There is no known antidote for an overdose of KORSERDU. Patients should be closely monitored and treatment of overdose should consist of supportive treatment.