According to the World Health Organization (WHO), there were 2.3 million women worldwide diagnosed with breast cancer, resulting in 685 000 deaths. However, as a result of ongoing research and a growing understanding of the biology of cancer, a growing number of women are being cured with early-stage disease, and women with advanced disease are living longer.

And at the end of 2020, there were nearly 7.8 million women alive who had been diagnosed with breast cancer in the past 5 years.[1]

A better understanding of the biology of breast cancer started with the appreciation of the role of molecular subtypes of the disease, leading to significant therapeutic advances.

Estrogen receptor-positive (ER+) breast cancer is among the largest observed subgroups.

Early understanding of the importance of estrogen signaling in ER+ breast cancer dates back to 1896 when Sir George Thomas Beatson, MD observed impressive disease responses after performing bilateral oophorectomy in 3 patients at the Glasgow Cancer and Skin Institute (later known as the Glasgow Cancer Hospital).[2]

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Sir George Thomas Beatson, MD. Photograph by T. & R. Annan & Sons. Wellcome Collection. Photo courtesy: Welcome Trust. Public Domain

Ongoing development
The ongoing development of new treatment options for metastatic and/or advanced breast cancer from progestins, [3][4] to the selective estrogen receptor modulator tamoxifen (Nolvadex®; AstraZeneca, Soltamox®; Mayne Pharma/Fortovia Therapeutics) which resulted in the reduction of incidences of invasive ER+ breast cancer for women with a high risk of developing breast cancer, [5] and aromatase inhibitors like anastrozole (Arimidex®; AstraZeneca), exemestane (Aromasin®; Pfizer Oncology) and letrozole (Femara®; Novartis). [6] Finally, adding to the treatment arsenal is the selective estrogen receptor degraded (SERD) fulvestrant (Faslodex®; AstraZeneca).

Today, fulvestrant, which is delivered through intramuscular injections, is the only SERD approved for patients with breast cancer.[6]

But the ongoing development of novel treatment options did not end here. Researchers have worked on improving single-agent endocrine treatments, leading to an explosion of new drugs that have shown improved efficacy in combination with endocrine approaches, including the mTOR inhibitor everolimus (Afinitor®; Novartis), 3 cyclin-dependent kinase 4 and 6 inhibitors (CDK 4/6i) such as palbociclib (Ibrance®; Pizer), ribociclib (Kisqali®; Novartis), and abemaciclib (Verzenio™; Eli Lilly and Company), and, more recently the PI3-kinase inhibitor alpelisib (Piqray®; Novartis). In addition, chemotherapy is still used where endocrine-based treatment options are no longer working.

Aditya Bardia, MD, MPH, director of the breast cancer research program at Mass General Cancer Center, and associate professor at Harvard Medical School.

Current Standard of Care
Today, patients with metastatic ER+ breast cancer are typically treated with endocrine therapy. In addition, the combination of CDK4/6i with endocrine therapy has significantly increased progression-free survival, leading to their approval and inclusion into the metastatic breast cancer treatment paradigm.

However, while these inhibitors are routinely used for patients with advanced ER+ breast cancer, resistance to these agents commonly develops, in some cases due to mutation of the ESR1 gene.

Considering the central role of ER in driving the growth of ER+ breast cancers, and endocrine agents being a mainstay of available treatment options, the effects of prior CDK4/6i exposure on ER signaling and the relevance of ER-targeted therapy, scientists started to evaluate the anti-tumor activity of elacestrant, a novel oral selective estrogen receptor degrader (SERD), in preclinical models of CDK4/6i resistance.[7]

“There is an urgent unmet need for alternative SERDs that are effective against ER-positive metastatic breast cancer, including those with ESR1 mutations,” said

An Alternative SERD
Elacestrant (RAD1901), an investigational oral selective estrogen receptor degrader (SERD), is being developed by Radius Health and out-licensed to Menarini Group, significantly decreased the risk of death or disease progression and increased progression-free survival compared with standard-of-care endocrine therapy for postmenopausal patients with estrogen receptor (ER)+/HER2-negative metastatic breast cancers that progressed on prior endocrine and targeted therapies.

This conclusion is based on results from the phase III EMERALD trial, which were presented at the San Antonio Breast Cancer Symposium (SABCS), held in San Antonio, Texas, December 7-10, 2021.

Elacestrant, unlike fulvestrant, is administered orally. Bardia explained that elacestrant has greater absorption, improved pharmokinetics, and enhanced inhibition of ER compared with fulvestrant. In addition, elacestrant has demonstrated greater antitumor activity in mouse xenograft models of ER-positive breast cancer.A phase I clinical trial found that elacestrant treatment had an acceptable safety profile and led to responses in heavily pretreated postmenopausal patients with ER-positive/HER2-negative metastatic breast cancer.

To understand how elacestrant compares to the current standard–of care, Bardia and colleagues initiated the phase III EMERALD trial, making elacestrant the first oral SERD to be studied in a randomized phase III clinical trial.

The trial enrolled 477 postmenopausal patients with ER-positive/HER2-negative metastatic breast cancer who had received one or two prior lines of endocrine therapy without chemotherapy in the metastatic setting, and who had progressed on prior treatment with a CDK4/6 inhibitor. Patients were randomly assigned to receive either elacestrant or standard of care (investigator’s choice of fulvestrant or an aromatase inhibitor). Among the enrolled patients, 228 had tumors with mutated ESR1 (115 in elacestrant arm and 113 in standard-of-care arm).

Bardia and colleagues found that patients in the elacestrant arm had a 30percent lower risk of death or disease progression compared with those in the standard-of-care arm. Among patients whose tumors had ESR1 mutations, those in the elacestrant arm had a 45 percent reduced risk of death or disease progression. Subgroup analyses showed that elacestrant improved outcomes regardless of the presence of visceral metastases, the number of prior lines of therapy, pretreatment with fulvestrant, or geographic region.

At 12 months, patients in the elacestrant arm had a significantly higher rate of progression-free survival than those who received the standard of care (22.32 percent vs. 9.42). Among patients with ESR1-mutated tumors, 26.76 percent of those treated with elacestrant had progression-free survival at 12 months compared with 8.19 percent of patients treated with standard of care. An interim analysis of overall survival showed a trend in favor of elacestrant, including in patients with ESR1-mutated tumors, according to Bardia.

Certain grade 1 or 2 treatment-related adverse events were more common among patients treated with elacestrant compared with standard of care, including nausea(25.3 percent vs. 8.7 percent), vomiting (11 percent vs. 2.6percent), and fatigue (11 percent vs 7.9 percent). Grade 3 or higher treatment-related adverse events were observed among 7.2 percent of patients in the elacestrant arm and3.1 percent of those in the standard-of-care arm. There were no treatment-related deaths in either arm.

“Elacestrantis the first oral SERD to demonstrate a statistically significant and clinically meaningful improvement of progression-free survival in patients with ER-positive/HER2-negative metastatic breast cancer in the second-and third-line settings, including for patients whose tumors harbor ESR1 mutations,” said Bardia.

“Elacestrant was well tolerated with manageable and reversible side effects. This therapy has the potential to become the new standard of care for patients with this cancer.”

Bardia noted that future studies will aim to understand the efficacy of elacestrant during earlier lines of treatment and in combination with other therapies. A planned phase II trial will examine the impact of elacestrant in combination with abemaciclib specifically for patients with brain metastases.

A limitation of this study was that all enrolled patients had received prior treatment with a CDK4/6 inhibitor; thus, the efficacy of elacestrant in patients without prior CDK4/6 inhibitor treatment remains unknown.

Clinical Trials
Phase 3 Trial of Elacestrant vs. Standard of Care for the Treatment of Patients With ER+/HER2- Advanced Breast Cancer (EMERALD) – NCT03778931

Highlights of Prescribing Information
Fulvestrant (Faslodex) (Prescription Information)
Tamoxifen (Nolvadex®; AstraZeneca)(Prescribing Information)
Tamoxifen (Soltamox®; Mayne Pharma/Fortovia Therapeutics)(Prescribing Information)
Anastrozole (Arimidex®; AstraZeneca)(Prescribing Information)
Exemestane (Aromasin®; Pfizer Oncology)(Prescribing Information)
Letrozole (Femara®; Novartis) (Prescribing Information)
Everolimus (Afinitor®; Novartis)(Prescribing Information)
Palbociclib (Ibrance®; Pizer)(Prescribing Information)
Ribociclib (Kisqali®; Novartis) (Prescribing Information)
Abemaciclib (Verzenio™; Eli Lilly and Company) (Prescribing Information)
Alpelisib (Piqray®; Novartis)(Prescribing Information)

Meeting Abstracts
GS2-02Elacestrant, an oral selective estrogen receptor degrader (SERD), vs investigator’s choice of endocrine monotherapy for ER+/HER2-advanced/metastatic breast cancer (mBC) following progression on prior endocrine and CDK4/6 inhibitor therapy: Results of EMERALD phase 3 trial

[1] Breast cancer. World Health Organization. Online. Last accessed on December 6, 2021.
[2] Macmahon CE, Cahill JL. The evolution of the concept of the use of surgical castration in the palliation of breast cancer in pre-menopausal females. Ann Surg. 1976 Dec;184(6):713-6. doi: 10.1097/00000658-197612000-00009. PMID: 63270; PMCID: PMC1345413.
[3] Samson M, Porter N, Orekoya O, Hebert JR, Adams SA, Bennett CL, Steck SE. Progestin and breast cancer risk: a systematic review. Breast Cancer Res Treat. 2016 Jan;155(1):3-12. doi: 10.1007/s10549-015-3663-1. Epub 2015 Dec 23. PMID: 26700034; PMCID: PMC4706804.
[4] McAndrew NP, Finn RS. Management of ER-positive metastatic breast cancer. Semin Oncol. 2020 Oct;47(5):270-277. doi: 10.1053/j.seminoncol.2020.07.005. Epub 2020 Aug 29. PMID: 32958261.
[5] Li F, Dou J, Wei L, Li S, Liu J. The selective estrogen receptor modulators in breast cancer prevention. Cancer Chemother Pharmacol. 2016 May;77(5):895-903. doi: 10.1007/s00280-016-2959-0. Epub 2016 Jan 20. PMID: 26787504.
[6] Buzdar AU. New generation aromatase inhibitors–from the advanced to the adjuvant setting. Breast Cancer Res Treat. 2002 Oct;75 Suppl 1:S13-7; discussion S33-5. doi: 10.1023/a:1020305615033. PMID: 12353818.
[7] Patel HK, Tao N, Lee KM, Huerta M, Arlt H, Mullarkey T, Troy S, Arteaga CL, Bihani T. Elacestrant (RAD1901) exhibits anti-tumor activity in multiple ER+ breast cancer models resistant to CDK4/6 inhibitors. Breast Cancer Res. 2019 Dec 18;21(1):146. doi: 10.1186/s13058-019-1230-0. PMID: 31852484; PMCID: PMC6921513.

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