The National Cancer Institute defines progression-free survival (PFS) as “the length of time during and after the treatment of a disease, such as cancer, that a patient lives with the disease but it does not get worse”. Simply put, a longer PFS period is a testament to how well a new treatment can keep disease progression at bay. Elacestrant is the first oral estrogen receptor degrader (SERD) to prolong PFS in advanced breast cancer patients.
Italy-based pharmaceutical company Menarini Group and US-based Radius Health Inc., published that the novel elacestrant — a nonsteroidal oral drug that degrades the estrogen receptor alpha (ERα) — became the first oral SERD to decrease the risk of disease progression in patients with advanced breast cancer. This result came from the promising Phase III EMERALD global clinical trial (NCT03778931).
“There is an urgent unmet need for oral SERDs that are safe and effective against ER-positive metastatic breast cancer after progression on earlier lines of therapy, including CDK4/6 inhibitors,” said Dr. Aditya Bardia, principal investigator of the EMERALD clinical trial in their press release statement.
The randomized, open label trial was comprised of patients with advanced breast cancer, specifically metastatic estrogen receptor (ER)–positive/human epidermal growth factor receptor 2 (HER2)–negative breast cancer, including patients with the ESR1 (estrogen receptor 1) mutation.
The trial showed that elacestrant slowed disease progression or death by 30 percent in all patients and by 45 percent in patients with mutation in ESR1. Compared to standard of care (SOC) therapy — fulvestrant injections or aromatase inhibitors (AI) with a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor — elacestrant improved PFS and subsequently disease progression, by 32 percent in all patients and 52 percent in patients with the ESR1 mutation. Patients had been pretreated with one or two lines of endocrine therapy and chemotherapy.
What is ER+/HER2- Breast Cancer?
The American Cancer Society has labeled breast cancer as “the second leading cause of cancer death in women.” In the US, about 30 percent of cancers in females have been attributed to breast cancer, and incidence rates have been rising steadily by 0.5 percent each year. In addition, they estimate about 287,850 new cases of invasive breast cancer for the year 2022.
ER+/HER2- cancer is an invasive and more common type of breast cancer. In the US, this subtype of cancer was reported in 73 percent of females between 2012 and 2016. Although this type of cancer is considered less aggressive and makes for an easier prognosis, recent studies have shown that some tumors are resistant to treatment or acquire new resistance over the duration of the treatment. Treatment resistance has been in part attributed to mutation in the ESR1 gene which plays a significant role in sexual and reproductive health. The ESR1 gene has also been detected in recurrent local and metastatic cancer cells.
What is Elacestrant and How Does It Work?
In ER-positive patients, cancer cells display estrogen receptors that bind to estrogen, allowing them to grow. Elacestrant is a selective estrogen receptor degrader (SERD), a drug that brings about estrogen receptor degradation by binding to the receptor and destabilizing it, thereby inhibiting the receptor signaling pathway. This is unlike SERMs (selective estrogen receptor modulators) which bind to the receptor and inactivate it.
Recent studies in mouse models implanted with human tumor cells (xenografts) have shown that elacestrant exhibits significant anti-tumor activity, even in ESR1 mutated models resistant to hormone therapy. This oral drug binds to ERα — a subtype of the estrogen receptor found predominantly in breasts and reproductive organs — on tumor cells and degrades it a dose-dependent manner. Elacestrant inhibits ERα which is encoded by the ESR1 gene in humans.
What Was the Study About?
The goal of this newest study about the EMERALD trial was to demonstrate the efficacy of elacestrant as a single-agent endocrine therapy compared to SOC therapies. 477 patients — men aged 18 years or older and post-menopausal women — with ER+/HER2- breast cancer and recurrent local tumors or metastasized tumors were selected. 239 patients were given elacestrant and 238 were given SOC monotherapy (fulvestrant or AI). Patients that were previously treated with fulvestrant received AI during the study and vice versa. 228 patients had detectable ESR1 mutation.
This study arrives on the heels of the Phase I study published in the Journal of Oncology that established the recommended daily dosage of elacestrant to be 400 mg with an acceptable safety profile. The SOC arm of the study was given the investigator’s choice of monotherapy based on the dosage recommended on the label.
The primary endpoint in the Phase III trial was based on a blinded independent central review. At the end of the follow-up period, elacestrant improved PFS rates to 22.3 percent vs 9.4 percent with SOC in the overall patient population and 26.8 percent vs 8.2 percent in the ESR1 mutated population. The most common adverse event among patients was nausea and backpain with a grade 3/4 level of severity, reported in 2.5 percent of patients with elacestrant vs 0.9 percent with SOC.
What is Unique About Elacestrant?
Compared with fulvestrant, elacestrant displayed manageable safety and toxicity, consistent efficacy, robust inhibition of the tumor cells and a longer PFS rate. In addition, this SERD is available as an oral option unlike fulvestrant which is currently given as an intramuscular injection. Overall, the PFS profile improved significantly at the 6-month and 12-month landmarks. However, some patients without the ESR1 mutation did not show improved PFS which might require an additional line(s) of CDK4/6 treatment targeting alternate pathways.
Unlike existing SERMs and SERDs, elacestrant can also cross the blood-brain barrier which is important for breast cancer patients with brain metastasis. The inclusion of elacestrant as the preferred hormonal agent might also benefit existing combination therapies with fulvestrant.
One of the major concerns with endocrine therapy is resistance to the treatment. Some tumors develop de novo resistance, while others lose estrogen receptors or develop gene mutations during the treatment, giving them acquired resistance. The pathways that contribute to this resistance remain mostly elusive. However, combination therapies might help with this research.
“EMERALD is the first study to demonstrate a significant improvement in clinical outcomes with elacestrant, an oral SERD monotherapy, versus standard of care in a randomized, global Phase III study for patients with ER-positive/HER2-negative advanced breast cancer. Further research is needed to develop combination therapies as well as evaluate novel endocrine therapies for patients with early breast cancer,” added Dr. Bardia.
A 2020 window-of-opportunity study by AstraZeneca compared the pharmacodynamic effects of another orally available SERD, AZD9496, with fulvestrant. Although the drug initially showed promising tumor inhibition results, it was not deemed superior to fulvestrant at the tested study dose.
Eli Lily is currently recruiting patients for the Phase III clinical trial (NCT04975308) of its new SERD imlunestrant in conjunction with a CDK4/6 inhibitor. A few ongoing CDK4/6 inhibitor Phase III studies plan to focus on advanced breast cancer in postmenopausal women. New studies are also underway to evaluate the potential of elacestrant with abemaciclib (a CDK4/6 inhibitor) in ER+/HER2- patients with brain metastasis.