ORSERDU 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 line of endocrine therapy
including a CDK 4/6 inhibitor for at least 12 months.
This indication is approved based on progression free survival. Continued approval of this indication
may be contingent upon verification and description of clinical benefit (overall survival) in the
confirmatory trials.

Posology 

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 a validated test (see sections 4.1 and 5.1)

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 section 4.8.2).

Missed Dose

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 Dose Reduction Levels for Adverse Reactions

Dose Reduction                           Dosage                                Number and Strength of Tablets

First-dose reduction          258 mg once daily                     Three 86 mg film-coated tablets

Second-dose reduction      172 mg once daily¹                            Two 86 mg film-coated tablets

¹If further dose reduction below 172 mg once daily is required, permanently discontinue ORSERDU.

Recommended dosage modifications of ORSERDU for adverse reactions are provided in Table 2 (see section 4.8.2).

Table 2*: ORSERDU Dosage Modification Guidelines for Adverse Reactions

Grade 4 (Potentially Life Threatening). 

Dosage Modifications for Use with Concomitant CYP3A4 Inducers and Inhibitors

Avoid concomitant use of ORSERDU with strong or moderate CYP3A4 inducers and inhibitors (see section 4.5).

Elderly

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.

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 section 5.2).

Pediatric population

The safety and efficacy of ORSERDU in paediatric patients have not been established.

Method of administration 

ORSERDU is for oral use.

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

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 section 4.8.2).

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

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 sections 4.6 and 5.3).

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 section 5.1 and 5.2), 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 section 5.1 and 5.2)), 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 (see section 5.2), 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 section 5.2), which may increase the adverse reactions associated with a BCRP substrate.

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 3 describes the effect of other drugs on the pharmacokinetics of elacestrant and Table 4 describes the effect of elacestrant on the pharmacokinetics of other drugs.

Table 3: Effect of Other Drugs on Elacestrant

Table 4: Effect of Elacestrant on 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^.

Pregnancy 

There are no data on the use of ORSERDU in pregnant women.

Studies in animals have shown reproductive toxicity (see section 5.3).

ORSERDU is not recommended during pregnancy and in women of childbearing potential not using contraception.

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 section 5.3).

Pregnancy Testing

Verify the pregnancy status in females of reproductive potential prior to initiating ORSERDU treatment. ORSERDU can cause fetal harm when administered to a pregnant woman.

Breastfeeding 

Breast-feeding should be discontinued during treatment with ORSERDU.

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.

Fertility 

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

Contraception in males and females

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.

ORSERDU 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.

4.8.1: adverse reactions:

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 section 5.1). 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 5 summarizes the adverse reactions in EMERALD.

Table 5: Adverse Reactions (≥10%) in Patients with ER-positive, HER2-negative, Advanced or Metastatic Breast Cancer Who Received ORSERDU in EMERALD^a

4 (Potentially Life Threatening). ^b Includes other related terms ^c Only includes Grade 3 adverse reactions.

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

Table 6 summarizes the laboratory abnormalities in EMERALD.

Table 6: 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

*Adverse reactions were graded using NCI CTCAE version 5.0. Grade 1 (Mild), Grade 2 (Moderate), Grade 3 (Severe), Grade 4 (Potentially Life Threatening).

To report any side effect(s):

Saudi Arabia:

•   The National Pharmacovigilance Centre (NPC):

⎯ SFDA Call Center: 19999

⎯ E-mail: npc.drug@sfda.gov.sa

⎯ Website: https://ade.sfda.gov.sa/

Other GCC States:

⎯ Please contact the relevant competent authority

The highest dose of ORSERDU administered in clinical studies was 1,000 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 ORSERDU. Patients should be closely monitored and treatment of overdose should consist of supportive treatment.

Pharmacotherapeutic group: estrogen receptor antagonist

ATC code: L02BA04

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.

Pharmacodynamic effects

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.

Clinical efficacy and safety 

The efficacy of ORSERDU was evaluated in EMERALD (NCT03778931), a randomized, open-label, active-controlled, multicenter trial that enrolled 478 postmenopausal women and men with

ER+/HER2- advanced or metastatic breast cancer of which 228 patients had ESR1 mutations. Patients were required to have disease progression on one or two prior lines of endocrine therapy, including one line containing a CDK4/6 inhibitor. Eligible patients could have received up to one prior line of chemotherapy in the advanced or metastatic setting.

Patients were randomized (1:1) to receive ORSERDU 345 mg orally once daily (n=239), or investigator’s choice of endocrine therapy (n=239), which included fulvestrant (n=166), or an aromatase inhibitor (n=73; anastrozole, letrozole or exemestane). Randomization was stratified by ESR1 mutation status (detected vs not detected), prior treatment with fulvestrant (yes vs no), and visceral metastasis (yes vs no). ESR1 mutational status was determined by blood circulating tumor deoxyribonucleic acid (ctDNA) using the Guardant360 CDx assay and was limited to ESR1 missense mutations in the ligand binding domain (between codons 310 to 547). Patients were treated until disease progression or unacceptable toxicity.

The major efficacy outcome was progression-free survival (PFS), assessed by a blinded imaging review committee (BIRC). An additional efficacy outcome measure was overall survival (OS). A statistically significant difference in PFS was observed in the intention to treat (ITT) population and in the subgroup of patients with ESR1 mutations. An exploratory analysis of PFS in the 250 (52%) patients without ESR1 mutations showed a HR 0.86 (95% CI: 0.63, 1.19) indicating that the improvement in the ITT population was primarily attributed to the results seen in the ESR1 mutated population.

Among the patients with ESR1 mutations (n=228), the median age was 63 years (range: 28-89); 100% were female; 72% were White, 5.7% Asian, 3.5% Black, 0.4% Other, 18.4% unknown/not reported; 8.8% were Hispanic/Latino; and baseline ECOG performance status was 0 (57%) or 1 (43%). Most patients had visceral disease (71%); 62% had received 1 line of endocrine therapy and 39% had received 2 lines of endocrine therapy in the advanced or metastatic setting. All patients had received prior treatment with a CDK4/6 inhibitor, 24% had received prior fulvestrant, and 25% had received prior chemotherapy in the advanced or metastatic setting.

Efficacy results are presented in Table 7 and Figure 1 for patients with ESR1 mutations.

Table 7: Efficacy Results for EMERALD (Patients with ESR1 Mutations)

CI=confidence interval; ESR1=estrogen receptor 1  ^a PFS results based on blinded imaging review committee.  ^b Kaplan-Meier estimate; 95% CI based on the Brookmeyer-Crowley method using a linear transformation.  ^c Cox proportional hazards model stratified by prior treatment with fulvestrant (yes vs no) and visceral metastasis (yes vs no).  ^d Stratified log-rank test two-sided p-value. 

^e NS – Not statistically significant.

The steady-state mean (%CV) maximum concentration (Cmax) of elacestrant is 119 ng/mL (43.6%) and the area under the concentration-time curve (AUC_0-24h) 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 AUC_0-24h is 2-fold.

Absorption 

The time to achieve peak plasma concentration (t_max) 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.

Biotransformation

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

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.

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).

Non-Clinical Toxicology; 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).

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).

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).

Not applicable. 

Do not store above 30° C.

ORSERDU (elacestrant) film-coated tablets for oral use are supplied as follows (Table 8):

Table 8: Supply of ORSERDU

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.