ORSERDU Film-coated tablet Ref.[51290] Active ingredients: Elacestrant

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.

The steady-state mean (CV) maximum concentration (C_max) 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 C_max 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 C_max 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 C_max 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.

Table 5. Effect of Other Drugs on Elacestrant:

^a Predicted changes in C_max and AUC of elacestrant.

Table 6. 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.

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).

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.

Figure 1. Kaplan-Meier Curve for PFS in EMERALD (Patients with ESR1 Mutations, BIRC Assessment):

⁺ Censored times