Elacestrant

ORSERDU is indicated for the treatment of postmenopausal women or adult men with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)‑negative, ESR1 -mutated advanced or metastatic breast cancer, as detected by an FDA-authorized test [see Dosage and Administration ( 2.1 )] , with disease progression following at least one line of endocrine therapy. ORSERDU is an estrogen receptor antagonist indicated for: treatment of postmenopausal women or adult men, with ER-positive, HER2-negative, ESR1 -mutated advanced or metastatic breast cancer, as detected by an FDA-authorized test, with disease progression following at least one line of endocrine therapy ( 1 )

Tablets: Elacestrant 345 mg (equivalent to 400 mg elacestrant hydrochloride) and 86 mg (equivalent to 100 mg elacestrant hydrochloride): 345 mg: light blue, unscored, oval film-coated biconvex tablet, imprinted with “MH” on one side and plain on the other side. 86 mg: light blue, unscored, round film-coated biconvex tablet, imprinted with “ME” on one side and plain on the other side. Tablets: 345 mg and 86 mg ( 3 )

None. None ( 4 )

Dyslipidemia : ORSERDU may cause hypercholesterolemia and hypertriglyceridemia. Monitor lipid profile prior to starting treatment and periodically thereafter. ( 5.1 ) Embryo-Fetal Toxicity : ORSERDU can cause fetal harm. Advise of the potential risk to a fetus and to use effective contraception. ( 5.2 , 8.1 , 8.3 )

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 )] .

The following clinically significant adverse reactions are described elsewhere in the labeling: Dyslipidemia [see Warnings and Precautions ( 5.1 )] 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. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Stemline Therapeutics, Inc. at 1-877-332-7961 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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. Table 3: Adverse Reactions (>10%) in Patients with ER-positive, HER2-negative, Advanced or Metastatic Breast Cancer Who Received ORSERDU in EMERALD a a Adverse reactions were graded using NCI CTCAE version 5.0. b Includes other related terms c Only includes Grade 3 adverse reactions. Adverse Reaction ORSERDU (n=237) Fulvestrant or an Aromatase Inhibitor (n=230) All Grades (%) Grade 3 or 4 c (%) All Grades (%) Grade 3 or 4 c (%) Musculoskeletal and connective tissue disorders Musculoskeletal pain b 41 7 39 1 Gastrointestinal disorders Nausea 35 2.5 19

0.9 Vomiting b 19 0.8 9 0 Diarrhea 13 0 10 1 Constipation 12 0 6 0 Abdominal pain b 11 1 10

0.9 Dyspepsia 10 0 2.6 0 General disorders Fatigue b 26 2 27 1 Metabolism and nutrition disorders Decreased appetite 15 0.8 10

0.4 Nervous system Headache 12 2 12 0 Vascular disorders Hot flush 11 0 8 0 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. Table 4: Select Laboratory Abnormalities (>10%) That Worsened from Baseline in Patients with ER-positive, HER2-negative, Advanced or Metastatic Breast Cancer Who Received ORSERDU in EMERALD a a The denominator used to calculate the rate varied from 29 to 236 for ORSERDU and from 37 to 225 for fulvestrant or an aromatase inhibitor based on the number of patients with a baseline value and at least one post-treatment value. Laboratory Abnormality ORSERDU a Fulvestrant or an Aromatase Inhibitor a All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Chemistry Cholesterol increased 30 1 17 0 Aspartate aminotransferase increased 29 0 34 1 Triglycerides increased 27 2 15 1 Alanine aminotransferase increased 17 0 24 1 Sodium decreased 16 1 15 0 Creatinine increased 16 0 6 0 Hematology Hemoglobin decreased 26 1 20 2

Strong and Moderate CYP3A4 Inducers : Avoid concomitant use. ( 7.1 ) Strong and Moderate CYP3A4 Inhibitors : Avoid concomitant use. ( 7.1 )

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.

Lactation : Advise not to breastfeed. ( 8.2 ) Hepatic Impairment : Avoid use in patients with severe hepatic impairment (Child-Pugh C). Reduce the dosage for patients with moderate hepatic impairment (Child-Pugh B). ( 2.5 , 8.6 )

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. Data 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 )] .

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.