2.1 Patient Selection

Select patients for treatment of ER-positive, HER2-negative advanced or metastatic breast cancer with ORSERDU based on the presence of ESR1 mutation(s) in plasma specimen using an FDA-approved test [see Indications and Usage (1) and Clinical Studies (14)].

Information on FDA-approved tests for detection of ESR1 mutations in breast cancer is available at: http://www.fda.gov/CompanionDiagnostics.

2.2 Recommended Dosage

The recommended dosage of ORSERDU is 345 mg taken orally with food once daily until disease progression or unacceptable toxicity occurs.

Take ORSERDU at approximately the same time each day. Take with food to reduce nausea and vomiting [see Adverse Reactions (6.1)].

Swallow ORSERDU tablet(s) whole. Do not chew, crush, or split prior to swallowing. Do not take any ORSERDU tablets that are broken, cracked, or that look damaged.

If a dose is missed for more than 6 hours or vomiting occurs, skip the dose and take the next dose the following day at its regularly scheduled time.

2.3 Dosage Modifications for Adverse Reactions

The recommended dose reduction levels for adverse reactions are listed in Table 1:

Recommended dosage modifications of ORSERDU for adverse reactions are provided in Table 2 [see Adverse Reactions (6.1)].

2.4 Dosage Modifications for Use with Concomitant CYP3A4 Inducers and Inhibitors

Avoid concomitant use of ORSERDU with strong or moderate CYP3A4 inducers and inhibitors [see Drug Interactions (7.1)].

2.5 Dosage Modifications for Hepatic Impairment

Avoid use of ORSERDU in patients with severe hepatic impairment (Child-Pugh C). Reduce the ORSERDU dosage to 258 mg once daily for patients with moderate hepatic impairment (Child-Pugh B). No dosage adjustment is recommended for patients with mild hepatic impairment (Child-Pugh A) [see Clinical Pharmacology (12.3)].

5.1 Dyslipidemia

Hypercholesterolemia and hypertriglyceridemia occurred in patients taking ORSERDU at an incidence of 30% and 27%, respectively. The incidence of Grade 3 and 4 hypercholesterolemia and hypertriglyceridemia were 0.9% and 2.2%, respectively [see Adverse Reactions (6.1)].

Monitor lipid profile prior to starting and periodically while taking ORSERDU.

5.2 Embryo-Fetal Toxicity

Based on findings in animals and its mechanism of action, ORSERDU can cause fetal harm when administered to a pregnant woman. Administration of elacestrant to pregnant rats resulted in adverse developmental outcomes, including embryo-fetal mortality and structural abnormalities, at maternal exposures below the recommended dose based on area under the curve (AUC).

Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with ORSERDU and for 1 week after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with ORSERDU and for 1 week after the last dose [see Use in Specific Populations (8.1, 8.3) and Clinical Pharmacology (12.1)].

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of ORSERDU was evaluated in 467 patients with ER+/HER2- advanced breast cancer following CDK4/6 inhibitor therapy in EMERALD, a randomized, open-label, multicenter study [see Clinical Studies (14)]. Patients received ORSERDU 345 mg orally once daily (n=237) or standard of care (SOC) consisting of fulvestrant or an aromatase inhibitor (n=230). Among patients who received ORSERDU, 22% were exposed for 6 months or longer and 9% were exposed for greater than one year.

Serious adverse reactions occurred in 12% of patients who received ORSERDU. Serious adverse reactions in >1% of patients who received ORSERDU were musculoskeletal pain (1.7%) and nausea (1.3%). Fatal adverse reactions occurred in 1.7% of patients who received ORSERDU, including cardiac arrest, septic shock, diverticulitis, and unknown cause (one patient each).

Permanent discontinuation of ORSERDU due to an adverse reaction occurred in 6% of patients. Adverse reactions which resulted in permanent discontinuation of ORSERDU in >1% of patients were musculoskeletal pain (1.7%) and nausea (1.3%).

Dosage interruptions of ORSERDU due to an adverse reaction occurred in 15% of patients. Adverse reactions which resulted in dosage interruption of ORSERDU in >1% of patients were nausea (3.4%), musculoskeletal pain (1.7%), and increased ALT (1.3%).

Dosage reductions of ORSERDU due to an adverse reaction occurred in 3% of patients. Adverse reactions which required dosage reductions of ORSERDU in >1% of patients were nausea (1.7%).

The most common (≥10%) adverse reactions, including laboratory abnormalities, of ORSERDU were musculoskeletal pain, nausea, increased cholesterol, increased AST, increased triglycerides, fatigue, decreased hemoglobin, vomiting, increased ALT, decreased sodium, increased creatinine, decreased appetite, diarrhea, headache, constipation, abdominal pain, hot flush, and dyspepsia.

Table 3 summarizes the adverse reactions in EMERALD.

Clinically relevant adverse reactions in < 10% of patients who received ORSERDU included rash, insomnia, dyspnea, cough, dizziness, stomatitis and gastroesophageal reflux disease.

Table 4 summarizes the laboratory abnormalities in EMERALD.

7.1 Effect of Other Drugs on ORSERDU

Strong and Moderate CYP3A4 Inhibitors

Avoid concomitant use of strong or moderate CYP3A inhibitors with ORSERDU.

Elacestrant is a CYP3A4 substrate. Concomitant use of a strong or moderate CYP3A4 inhibitor increase elacestrant exposure [see Clinical Pharmacology (12.3)], which may increase the risk of adverse reactions of ORSERDU.

Strong and Moderate CYP3A4 Inducers

Avoid concomitant use of strong or moderate CYP3A inducers with ORSERDU.

Elacestrant is a CYP3A4 substrate. Concomitant use of a strong or moderate CYP3A4 inducer decreases elacestrant exposure [see Clinical Pharmacology (12.3)], which may decrease effectiveness of ORSERDU.

7.2 Effect of ORSERDU on Other Drugs

P-gp Substrates

Reduce the dosage of P-gp substrates per their Prescribing Information when minimal concentration changes may lead to serious or life-threatening adverse reactions.

Elacestrant is a P-gp inhibitor. Concomitant use of ORSERDU with a P-gp substrate increased the concentrations of P-gp substrate [see Clinical Pharmacology (12.3)], which may increase the adverse reactions associated with a P-gp substrate.

BCRP Substrates

Reduce the dosage of BCRP substrates per their Prescribing Information when minimal concentration changes may lead to serious or life-threatening adverse reactions.

Elacestrant is a BCRP inhibitor. Concomitant use of ORSERDU with a BCRP substrate increased the plasma concentrations of BCRP substrate [see Clinical Pharmacology (12.3)], which may increase the adverse reactions associated with a BCRP substrate.

8.1 Pregnancy

Risk Summary

Based on findings in animals and its mechanism of action, ORSERDU can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available human data on ORSERDU use in pregnant women to inform the drug-associated risk. In an animal reproduction study, oral administration of elacestrant to pregnant rats during organogenesis caused embryo-fetal mortality and structural abnormalities at maternal exposures below the recommended dose based on AUC (see Data). Advise pregnant women and females of reproductive potential of the potential risk to a fetus.

The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively.

Animal Data

In an embryo-fetal development study in pregnant rats, administration of oral doses of elacestrant up to 30 mg/kg/day during the period of organogenesis resulted in maternal toxicity (reduced body weight gain, low food consumption, red vulvar discharge) and embryo-fetal mortality (increased resorptions, post-implantation loss, and reduced number of live fetuses) at ≥ 3 mg/kg/day (approximately 0.1 times the human AUC at the recommended dose). Additional adverse effects included reduced fetal weight and external malformations of the limbs (hyperflexion, malrotation) and head (domed, misshapen, flattened) with corresponding skeletal malformations of the skull at doses ≥ 10 mg/kg/day (approximately 0.5 times the human AUC at the recommended dose).

8.2 Lactation

Risk Summary

There are no data on the presence of elacestrant in human milk, its effects on milk production, or the breastfed child. Because of the potential for serious adverse reactions in the breastfed child, advise lactating women to not breastfeed during treatment with ORSERDU and for 1 week after the last dose.

8.3 Females and Males of Reproductive Potential

ORSERDU can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

Pregnancy Testing

Verify the pregnancy status in females of reproductive potential prior to initiating ORSERDU treatment.

Contraception

Females

Advise females of reproductive potential to use effective contraception during treatment with ORSERDU and for 1 week after the last dose.

Males

Advise male patients with female partners of reproductive potential to use effective contraception during treatment with ORSERDU and for 1 week after the last dose.

Infertility

Based on findings from animal studies, ORSERDU may impair fertility in females and males of reproductive potential [see Nonclinical Toxicology (13.1)].

8.4 Pediatric Use

The safety and effectiveness of ORSERDU in pediatric patients have not been established.

8.5 Geriatric Use

Of 237 patients who received ORSERDU in the EMERALD trial, 43% were 65 years of age or older and 17% were 75 years of age or older. No overall differences in safety or effectiveness of ORSERDU were observed between patients 65 years or older of age compared to younger patients. There are an insufficient number of patients 75 years of age or older to assess whether there are differences in safety or effectiveness.

8.6 Hepatic Impairment

Avoid use of ORSERDU in patients with severe hepatic impairment (Child-Pugh C). Reduce the dose of ORSERDU in patients with moderate hepatic impairment (Child-Pugh B). No dosage adjustment is recommended for patients with mild hepatic impairment (Child-Pugh A) [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3)].

12.1 Mechanism of Action

Elacestrant is an estrogen receptor antagonist that binds to estrogen receptor-alpha (ERα). In ER-positive (ER+) HER2-negative (HER2-) breast cancer cells, elacestrant inhibited 17β-estradiol mediated cell proliferation at concentrations inducing degradation of ERα protein mediated through proteasomal pathway. Elacestrant demonstrated in vitro and in vivo antitumor activity including in ER+ HER2- breast cancer models resistant to fulvestrant and cyclin-dependent kinase 4/6 inhibitors and those harboring estrogen receptor 1 gene (ESR1) mutations.

12.2 Pharmacodynamics

Elacestrant exposure-response relationships and the time course of pharmacodynamics have not been fully characterized.

Cardiac Electrophysiology

ORSERDU does not cause a mean increase in QTc interval > 20 msec at the approved recommended dose.

12.3 Pharmacokinetics

The steady-state mean (%CV) maximum concentration (Cmax) of elacestrant is 119 ng/mL (43.6%) and the area under the concentration-time curve (AUC0-24h) is 2440 ng*h/mL (44.3%) after administration of the recommended dosage of 345 mg once daily. The Cmax and AUC of elacestrant increase more than proportionally over a dosage range from 43 mg to 862 mg once daily (0.125 to 2.5 times the approved recommended dosage). Steady state is reached by Day 6 and the mean accumulation ratio based on AUC0-24h is 2-fold.

Absorption

The time to achieve peak plasma concentration (tmax) ranges from 1 to 4 hours. The elacestrant oral bioavailability is approximately 10%.

Effect of Food

Administration of ORSERDU 345 mg with a high-fat meal (800 to 1000 calories, 50% fat) increased Cmax by 42% and AUC by 22% compared to fasted administration.

Distribution

The estimated apparent volume of distribution is 5800L. Plasma protein binding of elacestrant is >99% and independent of concentration.

Elimination

The elimination half-life of elacestrant is 30 to 50 hours. The estimated mean (% CV) clearance of elacestrant is 186 L/hr (43.5%) and renal clearance is ≤ 0.14 L/hr.

Metabolism

Elacestrant is primarily metabolized by CYP3A4 and to a lesser extent by CYP2A6 and CYP2C9.

Excretion

Following a single radiolabeled oral dose of 345 mg, 82% was recovered in feces (34% unchanged) and 7.5% was recovered in urine (< 1% unchanged).

Specific Populations

There were no clinically significant differences in the pharmacokinetics of elacestrant based on age (24 to 89 years), sex, and body weight (41 to 143 kg).

Patients with Hepatic Impairment

There were no clinically significant differences in the Cmax and AUC of elacestrant in subjects with mild hepatic impairment (Child-Pugh A). The AUC of elacestrant increased in subjects with moderate hepatic impairment (Child-Pugh B) by 83%.

Elacestrant has not been studied in subjects with severe hepatic impairment (Child-Pugh C).

Drug Interaction Studies

Clinical Studies

There were no clinically significant differences in the pharmacokinetics of elacestrant when used concomitantly with cimetidine (weak CYP3A inhibitor), omeprazole (gastric acid-reducing agent), or warfarin (highly protein-bound drug).

Table 5 describes the effect of other drugs on the pharmacokinetics of elacestrant and Table 6 describes the effect of elacestrant on the pharmacokinetics of other drugs.

In Vitro Studies

Cytochrome P450 (CYP) Enzymes: Elacestrant is not an inhibitor of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A.

Elacestrant is not an inducer of CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, or CYP3A.

Transporter Systems: Elacestrant is a substrate for OATP2B1, but not P-gp.

Elacestrant is not an inhibitor of OAT1, OAT3, OCT2, MATE1, MATE2-K, OCT1, OATP1B1, OATP1B3 or OATP2B1.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies have not been conducted with elacestrant.

Elacestrant was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay or clastogenic in either in vitro chromosome aberration assays or an in vivo rat bone marrow micronucleus assay.

Fertility studies with elacestrant in animals have not been conducted. In repeated-dose toxicity studies up to 26 weeks duration in rats and 39 weeks duration in cynomolgus monkeys, adverse reactions were observed in female reproductive organs including atrophy of the vagina, cervix, and uterus and follicular cysts in the ovary at doses ≥ 10 mg/kg/day in rats and cynomolgus monkeys (≥ 0.3 times the human AUC at the recommended dose). Decreased cellularity of Leydig cells and degeneration/atrophy of the seminiferous epithelium in the testis were observed in male rats at a dose of 50 mg/kg/day (approximately 2.6 times the human AUC at the recommended dose).

Storage and Handling

Store at 20°C to 25°C (68°F to 77°F). Excursions permitted from 15°C to 30°C (59°F to 86°F). [see USP controlled room temperature].