EMERALD: Phase III trial of elacestrant (RAD1901) vs endocrine therapy for previously treated ER+ advanced breast cancer

Breast cancer continues to be the leading malignancy among women with over 260,000 cases diagnosed annually in the USA and 2.1 million cases globally [1,2]. Approximately 75% of all breast cancers are estrogen receptor (ER)-positive and HER2-negative (ER+/HER2-) [3]. Among postmenopausal women with locally advanced or metastatic ER+/HER2- breast cancer, endocrine therapy remains the cornerstone of treatment [4–6].

Endocrine therapy regimens most commonly consist of an agent targeting peripheral estrogen production or the ER itself [4,5]. Aromatase inhibitors (AI; e.g., letrozole, anastrozole and exemestane) decrease peripheral estrogen synthesis through inhibition of aromatase, the enzyme that catalyzes the conversion of androgens to estrogens [7,8]. Agents that target the ER directly include selective ER modulators (SERMs; e.g., tamoxifen and toremifene) and selective ER degraders (SERDs; e.g., fulvestrant). SERMs reduce ER activity through competitive ER blockade and effects on ER transcriptional machinery [8,9]. SERDs inhibit the ER by creating an unstable SERD–ER protein complex that can be targeted for degradation via proteasome degradation pathways [10]. Currently, fulvestrant is the only marketed SERD.

Endocrine resistance in advanced ER+ breast cancers remains a clinical challenge. Recent advancements have demonstrated emergence of acquired mutations following AI therapy in the ligand-binding domain of estrogen receptor gene α (ESR1), which encodes the ER [11]. These mutations can lead to ligand (estrogen)-independent ER activation. The activity of fulvestrant or AIs in the context of ESR1 mutation (ESR1-mut) has not been fully characterized due to limited and retrospective-only data sets. In a prespecified retrospective analysis of the Phase III SoFEA and PALOMA-3 trials, following AI therapy fulvestrant demonstrated a similar level of activity regardless of patients’ tumor ESR1 mutational status [11]. However, in patients having received multiple lines of prior endocrine therapy for ER+ advanced breast cancer, the objective response rate (ORR) observed with fulvestrant is generally ≤10% [12–14], and recent data examining the ESR1 status of fulvestrant-treated patients in the PALOMA-3 trial demonstrated the selection of the Y537S ESR1-mut after treatment [15]. These data, along with fulvestrant’s low oral bioavailability requiring intramuscular administration, suggest the need for an oral SERD with improved properties.

In addition to endocrine therapies, newer targeted agents, such as CDK 4/6 inhibitors (e.g., palbociclib, abemaciclib and ribociclib), can inhibit pathways related to cellular proliferation in ER+ breast cancer. Combinations of CDK4/6 inhibitors and endocrine therapies (AI or fulvestrant) have been recently shown to delay breast cancer progression beyond that achieved with endocrine monotherapy, forming the basis of these combinations as standard-of-care (SoC) first-line regimens [16–18]. While these combination regimens significantly increase progression-free survival (PFS), patients eventually relapse and will require additional therapies in the second-line and beyond setting. As such, development of novel SERDs with oral administration, improved bioavailability and the potential ability to overcome acquired resistance are of interest for patients with breast cancer.

Elacestrant

Elacestrant is a novel, nonsteroidal, orally bioavailable SERD (Figure 1) that has demonstrated dose-dependent ER degradation and inhibition of estradiol-dependent induction of ER target gene transcription and cell proliferation in multiple ER+ breast cancer cell lines [19–21]. In the in vivo setting, elacestrant inhibited estradiol-stimulated tumor growth in the ER+ MCF-7 cell line xenograft model, as well as multiple patient-derived xenograft models derived from heavily pretreated patients [19–21]. Finally, elacestrant demonstrated antitumor activity in models resistant to CDK4/6 inhibitors and fulvestrant, including those harboring the commonly detected ESR1 mutations Y537S and D538G [19,22,23].

The EMERALD trial

Herein, we describe the design and methodology of the EMERALD trial, an international, multicenter, randomized, open-label, active-controlled, Phase III clinical study comparing the efficacy and safety of elacestrant to the SoC endocrine treatment options of either fulvestrant or an AI in men and postmenopausal women with ER+/HER2- advanced or metastatic breast cancer with or without ESR1 mutations (NCT03778931; EudraCT 2018-002990-24).

Background & rationale

The development of resistance to fulvestrant, AIs and CDK4/6 inhibitors demonstrates a significant unmet medical need for a potent oral agent to treat ER+/HER2- advanced breast cancer. In early clinical trials, elacestrant demonstrated antitumor activity in patients with ER+ breast cancer that was heavily pretreated, including those whose tumors harbored ESR1-mut. Preliminary analysis of a Phase I trial (RAD1901-005) demonstrated antitumor activity of elacestrant 400 mg once daily in 40 heavily pretreated patients with ER+/HER2- advanced/metastatic breast cancer who had received a median of three prior therapies, including prior treatment with a CDK4/6 inhibitor (n = 16; 40%), and ESR1-mut detected by circulating tumor DNA (ctDNA; n = 20; 50%) [25]. The overall response rate was 27.3% in 22 patients evaluable for response, and median PFS was 5.4 months, which compares favorably to response rates of ≤10% and median PFS of approximately 5 months with standard endocrine monotherapies given in earlier lines of therapy (i.e., second or third line) in patients with ER+/HER2- advanced or metastatic breast cancer [12–14,26]. Furthermore, responses or clinical benefit with elacestrant was observed in patients with prior CDK4/6 inhibitor therapy, and in patients with ESR1-mut tumors as well as those with ESR1 mutation not detected (ESR1-mut-nd; includes ESR1 wild-type as well as mutations below limit of detection of the assay) [25]. Grade 1–2 nausea (43%) was the only adverse event reported in ≥20% patients treated with elacestrant 400 mg tablet daily.

Based on these promising Phase I data, the EMERALD study was designed to evaluate safety and efficacy of elacestrant in patients who have progressed following first- or second-line treatment with a CDK4/6 inhibitor/endocrine therapy combination regimen, and to further assess efficacy in patients who have developed ESR1 mutations, as well as the overall population.

Design

Study design

This trial consists of a screening phase, active treatment phase (Figure 2) and a follow-up phase including safety and survival follow-up periods. The EMERALD study protocol and relevant supplementary information will be approved by the institutional review board at each participating site. The trial is performed in accordance with ethical principles that have their origin in the Declaration of Helsinki and are consistent with International Council of Harmonisation/Good Clinical Practice and applicable regulatory requirements. Written informed consent will be obtained from each trial participant.

Eligibility criteria

Eligible patients will meet the following key inclusion criteria: men and postmenopausal women ≥18 years old with a histologically or cytologically proven diagnosis of ER+/HER2- adenocarcinoma of the breast with evidence of locoregionally recurrent or metastatic disease. Postmenopausal is defined as: documented bilateral surgical oophorectomy; age ≥60 years with amenorrhea ≥1 year since last menses; age <60 years with amenorrhea ≥1 year since last menses with no alternative pathological or physiological cause (including ongoing or recent chemotherapy, treatment with tamoxifen or toremifene, or a gonadotropin-releasing hormone agonist), and serum estradiol and follicle stimulating hormone (FSH) level within the laboratory reference range for postmenopausal women; or age <60 years with tamoxifen or toremifene therapy within the last 12 months, with documentation of 12 months of amenorrhea prior to tamoxifen or toremifene therapy and serum estradiol and FSH levels within the laboratory reference range for postmenopausal women.

The breast cancer must have progressed during or within 28 days after treatment with at least one and no more than two prior lines of endocrine therapy for advanced or metastatic disease. Prior therapy must have included a CDK4/6 inhibitor in combination with an AI or fulvestrant. No more than one chemotherapeutic regimen in the advanced/metastatic setting is allowed. Patients must have measurable disease per response evaluation criteria in solid tumors (RECIST) v1.1 [27] or evaluable bone-only disease, Eastern Cooperative Oncology Group performance status 0–1 and adequate organ function. Hormonal monotherapy with one of the SoC drugs (fulvestrant, anastrozole, letrozole and exemestane) must be an appropriate treatment option.

ER+ and HER2- status are to be confirmed per local laboratory testing. ER-positivity is defined as ≥1% staining by immunohistochemistry (IHC) [28], with or without progesterone receptor positivity. HER2-negativity is defined as an immunohistochemistry result of 0 or 1+ for cellular membrane protein expression or an in situ hybridization negative result, as per American Society of Clinical Oncology/College of American Pathologists guidelines [29].

Key exclusion criteria include presence of symptomatic metastatic visceral disease; history of endometrial intraepithelial neoplasia (in patients with an intact uterus); other malignancy within 5 years before enrollment, except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of the cervix; and any of the following within 6 months prior to enrollment: myocardial infarction, severe/unstable angina, ongoing grade ≥2 cardiac dysrhythmias, prolonged QT corrected by Fridericia's formula (QTcF) grade ≥2, uncontrolled atrial fibrillation of any grade, coronary/peripheral artery bypass graft, heart failure of New York Heart Association Class II or greater, cerebrovascular accident including transient ischemic attack and coagulopathy (thrombosis).

Planned sample size

Among all patients (ESR1-mut and ESR1-mut-nd), a total of approximately 340 PFS events will provide 92% power to detect a hazard ratio (HR) of 0.667 at the two-sided α level of 2.5%. Among ESR1-mut patients, approximately 160 PFS events are required for 80% power to detect a HR of 0.610 at the two-sided α level of 2.5%. The two-sided α level of 2.5% is selected to ensure that at least one of the two primary efficacy end points will pass the Hochberg procedure to control the overall α level at 5.0%. This study will need to randomize approximately 220 ESR1-mut patients (n = 110/treatment group) and approximately 466 patients total (ESR1-mut and ESR1-mut-nd; n = 233/treatment group) in a 1:1 ratio to the two treatment groups.

Planned study period

This study is event-driven. Final analysis of the primary end points will be performed after approximately 160 PFS events have occurred among the ESR1-mut patients and 340 PFS events have occurred among the total population, estimated to occur at 30–33 months after the first patient is randomized. The study will be completed when approximately 50% of patients have died. However, patients will be provided with study treatment, if still on active treatment, until all patients discontinue study participation or elacestrant is approved for marketing in a patient’s country, at which time the study may be closed for patient participation.

Study procedures

Patients will be randomized 1:1 to elacestrant or SoC. Randomization will be stratified by ESR1 mutational status detected in ctDNA (ESR1-mut vs ESR1-mut-nd), prior treatment with fulvestrant (yes vs no), and presence of visceral metastases (yes vs no). Study sites are requested to collect ctDNA samples immediately after obtaining informed consent to ensure that samples are analyzed as soon as possible while other eligibility criteria are confirmed. The projected turnaround time is 7–14 days, allowing ample time for analysis within the 35-day screening period. Patients randomized to elacestrant will receive 400 mg orally once daily. Elacestrant may be dose-reduced to 300 mg daily or 200 mg daily for toxicity. Patients randomized to SoC will receive monotherapy with fulvestrant, anastrozole, letrozole or exemestane per the investigator’s choice and dosed according to the product labeling.

At screening, patients will provide medical history and undergo physical exam, including vital signs and 12-lead ECG, and will provide blood samples for hematology, chemistry, coagulation parameters and ctDNA. Blood samples will be analyzed at a central laboratory for ctDNA to determine ESR1 mutational status. Tumor assessments will be performed via computed tomography/MRI (CT/MRI) unless performed within 28 days of randomization and radionuclide bone scan or whole-body MRI unless performed within the prior 12 weeks.

During treatment, vital signs, ECG, hematology, chemistry and coagulation parameters will be obtained predose on day 1 and 15 of cycle 1, day 1 of each remaining cycle, and at end of treatment. For patients receiving elacestrant, additional postdose blood pressure and ECG measurements will be taken on days 1 and 15 of cycle 1 when pharmacokinetic samples are obtained.

Following randomization, tumor assessments via CT/MRI will be performed every 8 weeks (±7 days) during treatment (and in the follow-up period for patients who have discontinued study drug for reasons other than progressive disease and have not yet started new anticancer therapy). Complete responses (CR) or partial responses are to be confirmed at least 4 weeks after the first documented response. For patients with bone metastases at baseline, radionuclide bone scan or whole-body MRI is to be performed every 24 weeks from randomization, at end of treatment, and every 24 weeks during follow-up. Abnormalities will be confirmed with CT scan with bone windows or MRI of bone lesions. Bone scan or whole-body MRI will also be performed to confirm CR.

For patients receiving elacestrant, pharmacokinetic samples will be taken predose and 4 hours postdose on days 1 and 15 of cycle 1; an additional predose sample will be taken on day 1 of cycle 2.

For patients who consent, optional tumor biopsies will be performed pretreatment, ontreatment and at end of treatment. Biopsies will be used for retrospective pharmacodynamic analysis of ER and other oncogenic pathway markers and proliferation markers.

The patient-reported outcomes questionnaires, Euro-Qol-5 Dimension-5 Level (EQ-5D-5L), European Organisation for the Treatment of Cancer (EORTC) Quality of Life Questionnaire C30 (QLQ-C30) and Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE), are to be completed by the patient at the study site on day 1 of each cycle, day 15 of cycle 1, at the end of treatment and at the safety follow-up visit (if visit occurs in person).

Adverse events will be collected throughout the study until 30 days after the last study drug dose. Adverse event severity will be assessed using the National Cancer Institute CTCAE Version 5.0.

Outcome measures

The primary end points of the EMERALD study are blinded imaging review committee (IRC)-assessed PFS in patients with tumors harboring ESR1-mut and in all patients (ESR1-mut and ESR1-mut-nd). Key secondary end points are overall survival (OS) in ESR1-mut patients and in all patients. Other secondary end points analyzed in ESR1-mut and all patients are IRC-assessed ORR, duration of response and clinical benefit rate (defined as the percentage of patients who have achieved either a confirmed CR or partial response, or stable disease [SD] at ≥24 weeks from randomization); investigator-assessed PFS, ORR, duration of response and clinical benefit rate; safety and tolerability; elacestrant pharmacokinetics; and PRO measures.

Statistics

PFS and OS analyses will be performed based on the intention-to-treat population using standard Kaplan–Meier methods. The Cox regression model, including treatment and the stratification factors, will be used to estimate the HR and 95% CI for the difference between treatment groups in PFS and OS. The two primary end points will be evaluated using the Hochberg procedure to maintain the overall two-sided α level at 5.0% as follows: the p-value for each of the two primary end points will be derived without any adjustment; these two p-values will be sorted based on size of p-value; if the larger p-value is <0.05, statistical significance will be claimed for both end points; if the larger p-value is ≥0.05 and the smaller p-value is <0.025, statistical significance will be claimed only for the end point associated with smaller p-value; if the larger p-value is ≥0.05 and the smaller p-value is ≥0.025, no statistical significance will be claimed. Unless otherwise specified, analyses of all other efficacy end points will be performed at the two-sided α level of 5% without adjustment for p-values. To differentiate the benefit of elacestrant for second-line and third-line therapy, subgroup analyses of the primary and key secondary end points for ESR1-mut and all patients (ESR1-mut and ESR1-mut-nd) by the number of lines of the prior therapy will be performed.

Conclusion

The EMERALD study is a pivotal Phase III registration trial evaluating the safety and efficacy of elacestrant, an investigational oral SERD, for treatment of men or postmenopausal women with ER+/HER2-advanced or metastatic breast cancer who have progressed following one or two prior lines of endocrine therapy and CDK4/6 inhibitor therapy in combination with an AI or fulvestrant for advanced or metastatic disease. This trial is the first prospective study to evaluate the efficacy of any agent versus SoC in patients with ESR1 mutations. Results from this study may provide a new treatment option for management of endocrine-resistant ER+ advanced or metastatic breast cancer.

Future perspective

If the EMERALD trial demonstrates safety and efficacy of elacestrant in the setting of previously treated endocrine-resistant advanced or metastatic breast cancer, future studies are warranted to evaluate elacestrant in earlier lines of therapy and early breast cancer. The potential role of a novel SERD such as elacestrant in earlier advanced or metastatic disease, or in the (neo)adjuvant curative setting would be of great interest. Additionally, the potential benefit of combining elacestrant with other active agents in ER-positive breast cancer, such as CDK4/6 inhibitors, mammalian target of rapamycin inhibitors or phosphoinositide 3-kinase inhibitors should be evaluated.