Orserdu Drug Information

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, with disease progression following at least one line of endocrine therapy.

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

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.

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.

Dosage Modifications for Adverse Reactions

• The recommended dose reduction levels for adverse reactions are listed in Table 1: Table 1: ORSERDU Recommended dosage modifications of ORSERDU for adverse reactions are provided in Table 2.
• Table 2: ORSERDU s for CYP3A4 Inducers and Inhibitors Avoid concomitant use of ORSERDU with strong or moderate CYP3A4 inducers and inhibitors.

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).

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. 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. 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 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 2

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, which may increase the risk of adverse reactions of ORSERDU.

Concomitant use of a strong or moderate CYP3A4 inducer decreases elacestrant exposure, which may decrease effectiveness of ORSERDU.

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, which may increase the adverse reactions associated with a P-gp substrate.

Elacestrant is a BCRP inhibitor. Concomitant use of ORSERDU with a BCRP substrate increased the plasma concentrations of BCRP substrate, which may increase the adverse reactions associated with a BCRP substrate.

Pregnancy Risk Summary Based on findings in animals and its mechanism of action, ORSERDU can cause fetal harm when administered to a pregnant woman. 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).

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