US Food and Drug Administration Approval Summary: Elacestrant for Estrogen Receptor–Positive, Human Epidermal Growth Factor Receptor 2–Negative, ESR1-Mutated Advanced or Metastatic Breast Cancer

Abstract

PURPOSE

The US Food and Drug Administration (FDA) approved elacestrant for the treatment of postmenopausal women or adult men with estrogen receptor–positive (ER+), human epidermal growth factor receptor 2–negative (HER2–), estrogen receptor 1 (ESR1)–mutated advanced or metastatic breast cancer with disease progression after at least one line of endocrine therapy (ET).

PATIENTS AND METHODS

Approval was based on EMERALD (Study RAD1901-308), a randomized, open-label, active-controlled, multicenter trial in 478 patients with ER+, HER2– advanced or metastatic breast cancer, including 228 patients with ESR1 mutations. Patients were randomly assigned (1:1) to receive either elacestrant 345 mg orally once daily (n = 239) or investigator's choice of ET (n = 239).

RESULTS

In the ESR1-mut subgroup, EMERALD demonstrated a statistically significant improvement in progression-free survival (PFS) by blinded independent central review assessment (n = 228; hazard ratio [HR], 0.55 [95% CI, 0.39 to 0.77]; P value = .0005). Although the overall survival (OS) end point was not met, there was no trend toward a potential OS detriment (HR, 0.90 [95% CI, 0.63 to 1.30]) in the ESR1-mut subgroup. PFS also reached statistical significance in the intention-to-treat population (ITT, N = 478; HR, 0.70 [95% CI, 0.55 to 0.88]; P value = .0018). However, improvement in PFS in the ITT population was primarily attributed to results from patients in the ESR1-mut subgroup. More patients who received elacestrant experienced nausea, vomiting, and dyslipidemia.

CONCLUSION

The approval of elacestrant in ER+, HER2– advanced or metastatic breast cancer was restricted to patients with ESR1 mutations. Benefit-risk assessment in the ESR1-mut subgroup was favorable on the basis of a statistically significant improvement in PFS in the context of an acceptable safety profile including no evidence of a potential detriment in OS. By contrast, the benefit-risk assessment in patients without ESR1 mutations was not favorable. Elacestrant is the first oral estrogen receptor antagonist to receive FDA approval for patients with ESR1 mutations.

INTRODUCTION

First-line treatment with cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) and endocrine therapy (ET) has improved long-term outcomes for patients with estrogen receptor–positive (ER+), human epidermal growth factor receptor 2–negative (HER2–) advanced or metastatic breast cancer. After a CDK4/6i and ET, oncologists typically treat patients with sequential ET-based regimens as long as possible because these are usually associated with less toxicity than chemotherapy. Unfortunately, acquired tumor resistance to ET is common.

A frequent cause of acquired tumor resistance to ET, particularly aromatase inhibitors (AIs), is an activating mutation in the ligand-binding domain of the estrogen receptor 1 (ESR1) gene.^1-3 After treatment with an AI, approximately 20%-40% of patients with ER+, HER2– metastatic breast cancer will develop a tumor ESR1 mutation.⁴ Factors that may influence development of an ESR1 mutation include longer duration of exposure to an AI and exposure to an AI in the metastatic setting rather than in the adjuvant setting.⁵ Before elacestrant, no approved therapy specifically treated ER+, HER2–, ESR1-mutated metastatic breast cancer.

Elacestrant is an oral ER antagonist that exerts its intended therapeutic effect by binding to and degrading ERα. In ER+, HER2– breast cancer cells, elacestrant inhibited 17β-estradiol–mediated cell proliferation at concentrations that also resulted in degradation of ERα protein through a proteasomal pathway.⁶ Evaluation of elacestrant in in vitro and in vivo animal studies demonstrated antitumor activity in ER+, HER2– breast cancer models resistant to fulvestrant and CDK4/6i and in breast cancer models with ESR1 mutations.⁷ Before approval of elacestrant, fulvestrant was the only approved estrogen receptor antagonist and is administered intramuscularly.⁸ Several oral estrogen receptor antagonists have been evaluated, including amcenestrant, giredestrant, and camizestrant. Emerging data from trials evaluating these products suggest that oral estrogen receptor antagonists might have better activity in the presence of tumor ESR1 mutations.^9-11

On January 27, 2023, US Food and Drug Administration (FDA) granted traditional approval to elacestrant for the treatment of patients with ER+, HER2–, ESR1-mutated advanced or metastatic breast cancer with disease progression after at least one line of ET on the basis of the results from EMERALD.¹² Elacestrant is the first oral ER antagonist approved specifically for the treatment of patients with tumor ESR1 mutations and is a new ET option for patients with ER+, HER2– metastatic breast cancer after disease progression on a treatment regimen including a CDK4/6i. This article summarizes FDA's rationale for determining a favorable benefit-risk assessment for elacestrant for the treatment of ER+, HER2–, ESR1-mutated metastatic breast cancer.¹³

PATIENTS AND METHODS

Clinical Trial Design

EMERALD (Study RAD1901-308, ClinicalTrials.gov identifier: NCT03778931) was a randomized, open-label, active-controlled, multicenter trial in postmenopausal women and men with ER+, HER2– advanced or metastatic breast cancer (Fig 1).¹⁴ To be eligible, patients must have experienced disease progression on one or two previous lines of ET, and one line must have included a CDK4/6 inhibitor. Patients were randomly assigned in a 1:1 ratio to receive either elacestrant or standard-of-care (SOC) ET with fulvestrant or an AI (exemestane, letrozole, or anastrozole). Random assignment was stratified according to tumor ESR1 mutation status (detected or not detected), previous treatment with fulvestrant (yes or no), and the presence of visceral metastases (yes or no). ESR1 mutational status was determined using the Guardant360 CDx assay.¹⁵ ESR1 mutation results were not shared with patients or providers at enrollment; however, trial sites could request this information when a patient discontinued trial treatment.

FIG 1.

Trial schema for study RAD1901-308. AI, aromatase inhibitor; BICR, blinded independent central review; CDK4/6i, cyclin-dependent kinase 4 and 6 inhibitors; ER, estrogen receptor; ESR1, estrogen receptor-alpha; HER2, human epidermal growth factor receptor 2; ITT, intention-to-treat; OS, overall survival; PFS, progression-free survival; SOC, standard-of-care.

The dosage for elacestrant was 345 mg orally once daily with food. This dosage was selected on the basis of the results of a dose-escalation trial evaluating doses ranging from 173 to 863 mg orally once daily. The 345-mg daily dosage was determined to be the recommended phase II dosage (RP2D), as doses higher than 345 mg orally once daily were associated with increased GI toxicity.¹⁶ In all clinical trials, elacestrant was administered with food to minimize GI adverse reactions (ARs). The SOC ET options were administered at the dosages recommended in their labeling. Patients received treatment until disease progression or unacceptable toxicity. Tumor assessments occurred every 8 weeks.

Statistical Analysis

The primary end point of progression-free survival (PFS) assessed by the blinded imaging review committee (BICR) according to RECIST v1.1 was tested in two groups: patients with ESR1 mutations (ESR1-mut subgroup) and all patients (intention-to-treat [ITT] population). The key secondary end point of overall survival (OS) was also tested in the ESR1-mut subgroup and in the ITT population. The primary and key secondary end points were analyzed using the stratified log-rank test. The testing procedure for PFS and OS was performed using a truncated Hochberg¹⁷ procedure to control the overall type I error rate at an alpha level of 5% (two-sided). A final analysis of PFS and two analyses of OS were prespecified: an interim OS analysis would occur at the time of the final PFS analysis, and a final OS analysis would occur when approximately 50% of patients had died. There was no formal testing of PFS or OS in the subgroup of patients without ESR1 mutations detected (ESR1 mutation not detected hereafter referred to as ESR1-mut-nd).

Other secondary end points included PFS assessed by the investigator, overall response rate (ORR) assessed by BICR and by the investigator, and duration of response assessed by BICR and the investigator. FDA considered these secondary end points exploratory as they were not alpha-controlled.

RESULTS

Efficacy

A total of 478 patients were randomly assigned (1:1) to receive elacestrant (n = 239) or investigator’s choice SOC ET (n = 239), which included either fulvestrant (n = 166) or an AI (n = 73, anastrozole, letrozole, or exemestane). In the entire trial population, 228 patients had ESR1 mutations including 115 patients in the elacestrant arm and 113 patients in the SOC arm. Male patients were eligible for EMERALD, and 1.7% of patients enrolled were male although there were no male patients in the ESR1-mut subgroup. Race data were missing for 18% of patients in the ESR1-mut subgroup. A summary of demographic and baseline characteristics for patients with ESR1 mutations enrolled to EMERALD is shown in Table 1.

TABLE 1.

Summary of Demographic and Baseline Disease Characteristics for EMERALD (ITT and ESR1-mut Subgroup)

Demographic/Disease Characteristic	ITT		US Food and Drug Administration–Approved Population: ESR1-mut Subgroup
	Elacestrant (n = 239)	SOC (n = 239)	Elacestrant (n = 115)	SOC (n = 113)
Age, years
Median (range)	63 (24-89)	63 (32-83)	64 (28-89)	63 (32-83)
<65, No. (%)	135 (56)	128 (54)	62 (54)	62 (55)
≥65, No. (%)	104 (44)	111 (46)	53 (46)	51 (45)
Race, No. (%)
Asian	16 (7)	16 (7)	5 (4)	8 (7)
Black	5 (2)	8 (3)	4 (3)	4 (4)
White	168 (70)	170 (71)	84 (73)	80 (71)
Other	1 (0.4)	1 (0.4)	1 (1)	0 (0)
Missing	49 (21)	44 (18)	21 (18)	21 (19)
Sex, No. (%)
Female	233 (97)	238 (99.6)	115 (100)	113 (100)
Male	6 (3)	1 (0.4)	0 (0)	0 (0)
Region, No. (%)
North America	65 (27)	76 (32)	33 (29)	42 (37)
Europe	137 (57)	121 (51)	63 (55)	50 (44)
Asia	23 (10)	27 (11)	10 (9)	16 (14)
Other	14 (6)	15 (6)	9 (8)	5 (4)
ECOG PS, No. (%)
0	143 (60)	135 (57)	67 (58)	62 (55)
1	96 (40)	103 (43)	48 (42)	51(45)
Previous treatment with a CDK4/6i, No. (%)
Yes	239 (100)	239 (100)	115 (100)	113 (100)
Previous treatment with fulvestrant, No. (%)
Yes	70 (29)	75 (31)	27 (23)	28 (25)
Presence of visceral metastases, No. (%)
Yes	158 (66)	164 (69)	79 (69)	80 (71)
Previous lines of endocrine therapy in the metastatic setting, No. (%)
1	129 (54)	142 (59)	73 (63)	69 (61)
2	110 (46)	97 (41)	42 (37)	44 (39)
Previous chemotherapy in the metastatic setting, No. (%)
Yes	48 (20)	59 (25)	26 (23)	32 (28)
Previous targeted therapy in the metastatic setting, No. (%)
Yes	10 (4)	9 (4)	6 (5)	3 (3)

Abbreviations: CDK4/6i, cyclin-dependent kinase 4 and 6 inhibitors; ECOG PS, Eastern Cooperative Oncology Group performance status; ESR1, estrogen receptor 1; ITT, intention-to-treat; SOC, standard-of-care.

In the final PFS analysis (data cutoff date: September 6, 2021), EMERALD demonstrated a statistically significant improvement in PFS per BICR in the ESR1-mut subgroup, with an estimated PFS hazard ratio (HR) of 0.55 ([95% CI, 0.39 to 0.77]; P value = .0005). The median PFS was 3.8 months (95% CI, 2.2 to 7.3) in the elacestrant arm and 1.9 months (95% CI, 1.9 to 2.1) in the SOC arm. EMERALD also demonstrated a statistically significant improvement in PFS per BICR in the ITT population with an estimated PFS HR of 0.70 ([95% CI, 0.55 to 0.88]; P value = .0018). In an exploratory analysis of PFS in the ESR1-mut-nd subgroup, the HR was 0.86 (95% CI, 0.63 to 1.19), with the median PFS of 1.9 months (95% CI, 1.9 to 3.6) in the elacestrant arm and 2.0 months (95% CI, 1.9 to 2.2) in the SOC arm.

In the primary PFS analysis, 40% of patients in the elacestrant arm and 35% of patients in the SOC arm in the ITT population were censored. The most common reason for censoring was that patients experienced disease progression per investigator assessment but not per BICR, which affected 25% of patients in the elacestrant arm and 18% of patients in the SOC arm. In addition, patients were permitted to receive palliative radiation treatment (RT) without being censored or considered as having a PFS event. In the ITT population, 5% of patients in the elacestrant arm and 2% of patients in the SOC arm received palliative RT. In PFS sensitivity analyses to assess the impact of censoring, palliative RT, and other factors, results in the ESR1-mut subgroup were consistent with the primary PFS analysis. Conversely, in the ESR1-mut-nd subgroup, the PFS benefit of elacestrant was not maintained.

In the final OS analysis (data cutoff date: November 15, 2022), although there was no statistically significant OS improvement in the ESR1-mut subgroup (HR, 0.90 [95% CI, 0.63 to 1.30]) or ITT population (HR, 0.91 [95% CI, 0.71 to 1.17]), there was no trend toward OS detriment in either group. In an exploratory OS analysis in the ESR1-mut-nd subgroup, the estimated HR was 0.92 (95% CI, 0.65 to 1.31). However, asymmetric withdrawal of consent specific to the ESR1-mut-nd subgroup could result in bias and increased uncertainty in the OS estimates in this group of patients. Within the ESR1-mut-nd subgroup, five of 124 patients (4.0%) in the elacestrant arm withdrew consent, whereas 16 of 125 patients (12.8%) in the SOC arm withdrew consent. OS sensitivity analyses conducted under varying assumptions for patients who withdrew consent resulted in a wide range of HR point estimates. Efficacy results including PFS, OS, and ORR for the ESR1-mut subgroup, ITT population, and ESR1-mut-nd subgroup are shown in Table 2.

TABLE 2.

Efficacy Results From EMERALD on the Basis of FDA Review

Efficacy Parameter	Intention-to-Treat		FDA-Approved Population: ESR1-mut Subgroup		ESR1-mut-nd Subgroupa
	Elacestrant (n = 239)	SOC (n = 239)	Elacestrant (n = 115)	SOC (n = 113)	Elacestrant (n = 124)	SOC (n = 126)
Progression-free survival per BICR
No. of events (%)	144 (60)	156 (65)	62 (54)	78 (69)	82 (66)	78 (62)
Median monthsb (95% CI)	2.8 (1.9 to 3.8)	1.9 (1.9 to 2.1)	3.8 (2.2 to 7.3)	1.9 (1.9 to 2.1)	1.9 (1.9 to 3.6)	2.0 (1.9 to 2.2)
Hazard ratioc (95% CI)	0.70 (0.55 to 0.88)		0.55 (0.39 to 0.77)		0.86 (0.63 to 1.19)
P valued	.002		.0005		NS
Overall survival
No. of events (%)	124 (52)	121 (51)	61 (53)	60 (53)	63 (51)	61 (48)
Median monthsb (95% CI)	24.6 (20.7 to 29.5)	22.6 (18.1 to 28.9)	24.2 (20.5 to 28.7)	23.5 (15.6 to 29.9)	26.1 (18.8 to NR)	22.6 (18.4 to 31.0)
Hazard ratioc (95% CI)	0.91 (0.71 to 1.17)		0.90 (0.63 to 1.30)		0.92 (0.65 to 1.31)
P valued	NS		NS		NS
Overall response rate per BICR
Response evaluation populatione	n = 179	n = 182	n = 85	n = 86	n = 94	n = 96
No. (%) (95% CI)	8 (4.5) (1.9% to 8.6%)	8 (4.4) (1.9 to 8.5%)	6 (7.1) (2.6 to 14.7)	4 (4.7) (1.3 to 11.5)	2 (2.1) (0.3 to 7.5)	4 (4.2) (1.1 to 10.3)
Duration of response per BICR
Months, median (95% CI)	NR (NR to NR)	5.6 (3.8 to NR)	NR (NR to NR)	5.6 (3.7 to NR)	NR (NR to NR)	5.6 (3.8 to NR)

Abbreviations: BICR, blinded imaging review committee; ESR1, estrogen receptor 1; FDA, US Food and Drug Administration; NR, not reached; SOC, standard-of-care.

^a All results in this subgroup are considered exploratory.

^b Kaplan-Meier estimate; 95% CI on the basis of the Brookmeyer-Crowley method using a linear transformation.

^c Cox proportional hazards model stratified by previous treatment with fulvestrant (yes v no) and visceral metastasis (yes v no).

^d Stratified log-rank test two-sided P value.

^e Response-evaluable population includes patients who had measurable disease at baseline and at least one postbaseline assessment on any lesions and/or had a new lesion.

Safety

Nonclinical Toxicology

In repeat-dose toxicology studies, oral administration of elacestrant in rats for up to 26 weeks and monkeys for up to 39 weeks led to GI and reproductive organ toxicities. Elacestrant caused ovarian follicular cysts and atrophy of the vagina, cervix, and uterus in rats and monkeys. In rats, effects on male reproductive organs included decreased cellularity of Leydig cells and degeneration/atrophy of the seminiferous epithelium in the testes. On the basis of these findings, elacestrant may impair fertility in males and females of reproductive potential. GI toxicities were common adverse events observed in clinical trials.

In an embryo-fetal development study, elacestrant was teratogenic and embryo lethal when administered to pregnant rats. Embryo-fetal toxicity was included under Warnings and Precautions in elacestrant labeling.

Clinical Safety

The safety of elacestrant was evaluated in 467 patients who received at least one dose of trial treatment in EMERALD. Common ARs in EMERALD are summarized in Table 3. Most ARs experienced by patients in EMERALD were Grade 1 or 2 in severity, as would be expected with ET. Grade 3 ARs were slightly more frequent in patients who received elacestrant compared with SOC ET: 27% versus 21%.

TABLE 3.

Common ARs in EMERALD^a

AR	Elacestrant (n = 237), %		SOC (n = 230), %
	All Grade	Grade 3 or 4c	All Grade	Grade 3 or 4c
Musculoskeletal and connective tissue disorders
Musculoskeletal painb	41	7	39	1
Gastrointestinal disorders
Nausea	35	2.5	19	0.9
Vomitingb	19	0.8	9	0
Diarrhea	13	0	10	1
Constipation	12	0	6	0
Abdominal painb	11	1	10	0.9
Dyspepsia	10	0	2.6	0
General disorders
Fatigueb	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

Abbreviations: AR, adverse reaction; SOC, standard-of-care.

^a ARs were graded using National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0.

^b Includes other related terms.

^c Only includes grade 3 ARs.

The most common Grade 3 AR (≥5%) experienced by patients receiving elacestrant was musculoskeletal pain (7%). Most patients who experienced musculoskeletal pain had pre-existing pain at trial baseline, and in some cases, musculoskeletal pain occurred in the setting of disease progression in bone. There was only one Grade 4 AR in patients who received elacestrant (dyslipidemia). The frequencies of dosage interruptions, dose reductions, and drug discontinuations were overall low, although higher in patients receiving elacestrant compared with SOC ET: 15% versus 5%, 3 versus 0%, and 6% versus 4.3%, respectively. Of note, dose reductions were not permitted for AIs per labeling and were allowed only for fulvestrant for hepatic impairment.

GI toxicity was an important safety signal for elacestrant. Patients receiving elacestrant compared with SOC ET experienced higher frequencies of nausea: 35% versus 19%; vomiting: 19% versus 9%; decreased appetite: 15% versus 10%; and dyspepsia: 10% versus 2.6%. In addition, use of serotonin receptor antagonists (eg, ondansetron) was more common in patients who received elacestrant (17%) compared with SOC ET (10%).

Dyslipidemia is included in elacestrant labeling under Warnings and Precautions. The incidences of hypertriglyceridemia and hypercholesterolemia were greater in patients who received elacestrant compared with SOC ET: 30% versus 17% and 27% versus 15%, respectively. Because of the relatively high incidences of hypertriglyceridemia and hypercholesterolemia, the possible relationship to cardiovascular disease, and the need for close monitoring, FDA included dyslipidemia under Warnings and Precautions. Health care providers are recommended to monitor a patient’s lipid profile before starting elacestrant and periodically while on treatment.

Companion Diagnostic

All patients enrolled in EMERALD had plasma samples tested for ESR1 mutation(s) using the Guardant360 CDx assay, a qualitative next-generation sequencing–based in vitro diagnostic device. The device used high-throughput hybridization-based capture technology to assess for the presence of certain genetic alterations in circulating cell-free DNA from plasma. The Guardant360 CDx detects ESR1 missense mutations between codons 310 and 547. Any patient with one or more ESR1 mutation(s) detected was included in the ESR1-mut population in EMERALD. Tissue testing for ESR1 mutation(s) was not performed for any patient.

Analytical and clinical performance of the assay supported the approval of the Guardant360 CDx assay as a companion diagnostic device for identifying ESR1 mutations in patients with ER+, HER2– advanced breast cancer who may receive treatment with elacestrant. Analytical validation studies included evaluation of the limit of detection, sample stability, accuracy, and precision. Clinical performance was established in EMERALD.¹⁵

DISCUSSION

Elacestrant received traditional approval for the treatment of postmenopausal women or adult men with ER+, HER2–, ESR1-mutated advanced or metastatic breast cancer, as identified by an FDA-approved companion diagnostic device, with disease progression after at least one line of ET. The Guardant360 CDx assay was approved as a companion diagnostic device to identify patients with ESR1 mutations for treatment with elacestrant. The basis for the favorable benefit-risk assessment for patients in the ESR1-mut subgroup was demonstration of a statistically significant improvement in PFS, which was robust to multiple sensitivity analyses, no potential detriment in OS, and an acceptable safety profile (Table 4). To our knowledge, this is the first approval of an oral estrogen receptor antagonist and the first approval specifically for patients with ESR1 mutations.

TABLE 4.

FDA Benefit-Risk Assessment of Elacestrant for the Treatment of ER+/HER2– Advanced or Metastatic Breast Cancer

Dimension	Evidence and Uncertainties	Conclusions and Reasons
Analysis of condition	Approximately 70% of patients with breast cancer have ER-positive, HER2-negative disease If disease is advanced or metastatic, it is incurable and associated with a limited life expectancy	Metastatic breast cancer is incurable and is a serious and life-threatening condition
Current treatment options	After 1L treatment with a CDK4/6i and ET, treatment options include ET alone, ET in combination with targeted agents, or chemotherapy. All treatments are palliative Approximately 20%-40% of patients will develop tumor ESR1 mutations after exposure to an AI in the 1L metastatic setting There are no FDA-approved oral estrogen receptor antagonist options available	Patients with ER-positive, HER2-negative advanced or metastatic breast cancer need therapies which improve clinical outcomes No FDA-approved treatments specifically target the ESR1 mutation
Benefit	In the ESR1-mut subgroup, EMERALD demonstrated a statistically significant improvement in PFS (HR, 0.55 [95% CI, 0.39 to 0.77]; P = .0005) and no trend toward OS detriment (HR, 0.90 [95% CI, 0.63 to 1.30]) In the intention-to-treat population, there was also a statistically significant improvement in PFS; however, these results were primarily attributable to patients in the ESR1-mut subgroup In the ESR1-mut-nd subgroup, exploratory analyses demonstrated a marginally favorable PFS trend (HR, 0.86 [95% CI, 0.65 to 1.31]) and uncertainty in OS because of asymmetric withdrawal of consent External data suggest that oral estrogen receptor antagonists might have better activity in the presence of tumor ESR1 mutations	Elacestrant was associated with a statistically significant and clinically meaningful improvement in PFS, supported by a favorable trend in OS, for patients with ESR1 mutations The oral route of administration is considered a new option for patients who may prefer this oral treatment There was uncertainty regarding clinical benefit for patients without ESR1 mutations
Risk and risk management	Patients who received elacestrant compared with placebo experienced increased GI toxicity including nausea, vomiting, decreased appetite, and dyspepsia Elacestrant was associated with increased dyslipidemia, including elevations in total cholesterol and triglycerides, compared with standard-of-care ET.	For patients with tumor ESR1 mutations, the safety of elacestrant was acceptable and manageable through labeling, which includes a warning for dyslipidemia and embryo-fetal toxicity For patients without tumor ESR1 mutations, the increased toxicity of elacestrant was not acceptable as there was uncertainty regarding clinical benefit

Abbreviations: AI, aromatase inhibitor; CDK4/6i, cyclin dependent kinase four and six inhibitor; ER, estrogen receptor; ESR1, estrogen receptor-1; ET, endocrine therapy; FDA, US Food and Drug Administration; HR, hazard ratio; HER2, human epidermal growth factor receptor 2; OS, overall survival; PFS, progression-free survival.

EMERALD was an active-controlled trial with a replacement design in which elacestrant, an investigational ET, was replacing available SOC ET. In oncology, two common trial designs are an add-on design in which the investigational agent is added on to SOC and compared with SOC alone or a replacement or head-to-head design in which the investigational agent is replacing SOC. In an add-on trial, the magnitude of effect on an efficacy end point (eg, PFS) has to be large enough (eg, clinically meaningful) to justify the added toxicity of the investigational agent, which is given in addition to SOC. By contrast, a superior PFS result in a replacement or head-to-head trial can be incremental in magnitude given that the benefit is in addition to the known benefit of the active standard therapy. Traditional approval does not have a comparative efficacy requirement, meaning that an investigational therapy has to be more effective than placebo, but does not need to be better than all other SOC therapy options. In the setting of a replacement design, even a small PFS improvement supports the conclusion that the investigational therapy is at least as effective as the SOC therapy and more effective than placebo. Such a design can fulfill the regulatory requirements of a traditional approval if the trial is adequate and well-controlled with a statistically persuasive superiority result.

FDA acknowledges that even in the setting of a replacement design, the efficacy result in the ITT population of EMERALD was marginal given the poor activity demonstrated in the control arm. Despite the poor performance of the control arm, FDA determined that a statistically robust treatment effect on PFS was seen in the ESR1-mut subgroup on the basis of multiple sensitivity analyses. In addition to a modest PFS improvement, the review also took into consideration the fact that elacestrant would provide patients with a new oral route of administration. These benefits were looked at in the context of increased toxicity of elacestrant compared with SOC treatment, but the side effect profile was felt to be acceptable, particularly in light of OS results that did not indicate potential harm. Taken together, the review of safety and efficacy yielded an overall favorable benefit-risk assessment for patients with ESR1 mutations.

By contrast, FDA concluded that the benefit-risk assessment in the ESR1-mut-nd subgroup was not favorable. The PFS improvement in the ESR1-mut-nd subgroup was notably smaller than that in those with an ESR1 mutation, with a marginally positive PFS HR trend that did not withstand FDA sensitivity analyses. In addition, while ORRs were low across EMERALD, as would be anticipated for ET, the ESR1-mut-nd subgroup reported ORR estimates that were numerically lower in the elacestrant arm compared with the SOC arm. While a similar safety profile was seen, there was greater uncertainty in the OS results for the ESR1-mut-nd subgroup because of asymmetric withdrawal of consent between the elacestrant and SOC arms. Given the lack of statistically robust PFS results, lack of internal consistency with other efficacy measures, and uncertainty in OS results, the benefit-risk was felt to be unfavorable in those who did not harbor an ESR1 mutation.

While exploratory subgroup analyses must be interpreted with caution, FDA has used such analyses to restrict indications when there has been evidence of substantive differential benefit-risk with a strong clinical and mechanistic rationale.¹⁸ Factors that increased confidence in interpretation of exploratory results included that the ESR1-mut-nd subgroup was relatively large, comprising 52% of the trial population. In addition, tumor ESR1-mut status was a stratification factor, so random assignment was preserved in the subgroup analyses, and the ESR1-mut subgroup was adequately powered and tested with alpha control. In addition, emerging clinical data from trials of other oral estrogen receptor antagonists suggested that this class of drugs might have greater benefit in the presence of an ESR1 mutation.^9-11 Similar findings across multiple trials decrease the probability that observations are coincidental.

To our knowledge, EMERALD is the first trial leading to an FDA approval in ER+, HER2– advanced or metastatic breast cancer in which all patients had previous treatment with a CDK4/6i and ET. When the EMERALD trial was enrolling patients, therapeutic options after 1L treatment with a CDK4/6i and ET included a different ET alone or ET with a targeted therapy such as everolimus or alpelisib for patients with tumor PIK3CA mutations. Some patients and providers might have chosen treatment with ET alone to minimize toxicity. However, emerging data from EMERALD and other trials regarding the limited activity of ET alone will likely lead to reconsideration of the best 2L therapies for patients in both the clinic and clinical trials.

Male patients were eligible for EMERALD, and seven male patients were enrolled although no male patient had an ESR1 mutation. Despite this, FDA included male patients in the elacestrant indication because of the biologic rationale that elacestrant would be expected to have similar activity in male and female patients with ESR1 mutations. Because of the rarity of male breast cancer, male patients are often excluded from breast cancer clinical trials. FDA released a guidance encouraging inclusion of male patients in breast cancer clinical trials.¹⁹ The guidance stipulates that even if a trial includes few or no male patients and if there are no anticipated differences in efficacy or safety between male patients and female patients, FDA may extrapolate findings from female patients to support inclusion of male patients in the indication, as was performed for elacestrant.

Race data were missing for approximately 18% of patients enrolled to EMERALD. As FDA could not determine if the trial population was representative of US patients with ER+HER2– metastatic breast cancer with respect to race and ethnicity, a postmarketing commitment was issued to further characterize the efficacy and safety of elacestrant in patients from under-represented racial and ethnic groups. A postmarketing commitment indicates that the drugmaker has agreed to conduct a particular study although the study is not required under FDA regulations. Generally, enrollment of a representative patient population to clinical trials before drug approval is preferable to provide equitable access to investigational therapies, so that any differences in pharmacology, safety, or efficacy across racial and ethnic groups may be identified early. An FDA draft guidance provides recommendations to drugmakers on creation and implementation of Diversity Plans during premarket drug development.²⁰ FDA also concluded that there were insufficient data to recommend an elacestrant dosage for patients with severe hepatic impairment. A postmarketing requirement was issued to determine an appropriate elacestrant dosage in patients with severe hepatic impairment. A PMR indicates that completion of the study is required under FDA regulations.

In summary, elacestrant represents a new oral ET option for patients with ER+, HER2–, ESR1-mutated advanced or metastatic breast cancer after experiencing disease progression on at least one line of ET. FDA concluded that the benefit-risk assessment for elacestrant was favorable for only the ESR1-mut population. However, it is important to note that even in the indicated population, the PFS improvement was modest, which is consistent with emerging data from other clinical trials in the post-CDK4/6i setting.^9,21,22

AUTHOR CONTRIBUTIONS

Conception and design: Mirat Shah, Hima Lingam, Abdelrahmman Abukhdeir, Bronwyn D. Mixter, Richard Pazdur, Paul Kluetz, Laleh Amiri-Kordestani

Administrative support: Amy Tilley, Bronwyn D. Mixter, Richard Pazdur

Collection and assembly of data: Mirat Shah, Hima Lingam, Xin Gao, Haley Gittleman, Danielle Krol, Abdelrahmman Abukhdeir, Amy Tilley

Data analysis and interpretation: All authors

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

US Food and Drug Administration Approval Summary: Elacestrant for Estrogen Receptor–Positive, Human Epidermal Growth Factor Receptor 2–Negative, ESR1-Mutated Advanced or Metastatic Breast Cancer

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.

Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).