ORSERDU

1 INDICATIONS AND USAGE 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 )

2 DOSAGE AND ADMINISTRATION Select patients for treatment with ORSERDU based on the presence of ESR1 mutations. ( 2.1 ) The recommended dosage of ORSERDU is one 345 mg tablet taken orally, once daily, with food ( 2.2 ) Dose interruption, reduction, or permanent discontinuation may be required due to adverse reactions. ( 2.3 ) 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-authorized test [see Indications and Usage ( 1 ) and Clinical Studies ( 14 )] . Information on FDA-authorized 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 : Table 1: ORSERDU Dose Reduction Levels for Adverse Reactions 1 If further dose reduction below 172 mg once daily is required, permanently discontinue ORSERDU. Dose Reduction Dosage Number and Strength of Tablets First-dose reduction 258 mg once daily Three 86 mg tablets Second-dose reduction 172 mg once daily 1 Two 86 mg tablets Recommended dosage modifications of ORSERDU for adverse reactions are provided in Table 2 [see Adverse Reactions ( 6.1 )] . Table 2: ORSERDU Dosage Modification Guidelines for Adverse Reactions Severity Dosage Modification Grade 1 Continue ORSERDU at current dose level. Grade 2 Consider interruption of ORSERDU until recovery to Grade ≤ 1 or baseline. Then resume ORSERDU at the same dose level. Grade 3 Interrupt ORSERDU until recovery to Grade ≤ 1 or baseline. Then resume ORSERDU at the next lower dose level. If the Grade 3 toxicity recurs, interrupt ORSERDU until recovery to Grade ≤ 1 or baseline. Then resume ORSERDU reduced by another dose level. Grade 4 Interrupt ORSERDU until recovery to Grade ≤ 1 or baseline. Then resume ORSERDU reduced by one dose level. If a Grade 4 or intolerable adverse reaction recurs, permanently discontinue ORSERDU. 2.4 Dosage Modifications for CYP3A4 Inducers and Inhibitors Avoid concomitant use of ORSERDU with strong or moderate CYP3A4 inducers and inhibitors [see Drug Interactions ( 7.1 )] . 2.5 Recommended Dosage in Patients with 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 )] .

3 DOSAGE FORMS AND STRENGTHS 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 )

4 CONTRAINDICATIONS None. None ( 4 )

6 ADVERSE REACTIONS 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%) 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 …

7 DRUG INTERACTIONS 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.

8 USE IN SPECIFIC POPULATIONS 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 )] .

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.

11 DESCRIPTION Elacestrant hydrochloride is the salt form of elacestrant, an estrogen receptor antagonist, that has the chemical name: (6R)-6-(2-(N-(4-(2-(ethylamino)ethyl)benzyl)-N-ethylamino)-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol dihydrochloride. Elacestrant hydrochloride is the dihydrochloride salt and the molecular formula is C 30 H 38 N 2 O 2 .2HCL. The relative molecular mass is 531.56 g/mol. The chemical structure of elacestrant hydrochloride is shown below: Elacestrant hydrochloride is a white to off-white to grey solid and is freely soluble in 0.01N HCI. ORSERDU (elacestrant) 345 mg film-coated tablet contains 400 mg of elacestrant hydrochloride (approximately 345 mg of elacestrant free base). ORSERDU (elacestrant) 86 mg film-coated tablet contains 100 mg of elacestrant hydrochloride (approximately 86 mg of elacestrant free base). Both tablet strengths contain the following inactive ingredients: colloidal silicon dioxide, crospovidone, magnesium stearate (non-bovine), microcrystalline cellulose, and silicified microcrystalline cellulose. The tablets also contain Opadry II Blue (polyvinyl alcohol, titanium dioxide, polyethylene glycol, FD&C Blue #1 and talc). Chemical Structure

16 HOW SUPPLIED/STORAGE AND HANDLING ORSERDU (elacestrant) film-coated tablets for oral use are supplied as follows: Tablet Strength Tablet Color and Shape Tablet Markings Pack Size NDC Code Elacestrant 345 mg (equivalent to 400 mg elacestrant hydrochloride) Light blue; Oval “MH” Bottle of 30 Tablets with Child Resistant Closure (CRC). NDC 72187-0102-3 Elacestrant 86 mg (equivalent to 100 mg elacestrant hydrochloride) Light blue; Round “ME” Bottle of 30 Tablets with Child Resistant Closure (CRC). NDC 72187-0101-3 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].