1. Froelich, Warren

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Patients with estrogen receptor-positive (ER+), HER2-negative (HER2-) advanced or metastatic breast cancer experienced greater progression-free survival versus standard-of-care endocrine therapy with elacestrant, an investigational oral selective estrogen receptor degrader (SERD), according to results from the Phase III EMERALD clinical trial.

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The findings-presented at the San Antonio Breast Cancer Symposium (SABCS), held December 7-10, 2021-showed that elacestrant in this population group slashed the risk of disease progression or death by 30 percent versus standard-of-care endocrine therapy. For those with mutations in the ESR-1 gene-commonly linked to resistance to endocrine therapy-progression-free survival (PFS) or death was cut by about 45 percent.


"Clinically, elacestrant has the potential to become the new standard of care in the studied population," said Aditya Bardia, MD, MPH, Director of the Breast Cancer Research Project at Mass General Cancer Center, and Associate Professor at Harvard Medical School, who presented the study's findings during a press briefing. "Elacestrant was well-tolerated with a predictable and manageable safety profile," he added.


"The results clearly suggest that this new SERD may become a new treatment option for patients with breast cancer not only as a single therapy, but also in combination with other targeted therapies," said Carlos Arteaga, MD, Director of the Simmons Comprehensive Cancer Center, Associate Dean of Oncology Programs at UT Southwestern Medical Center, and co-Chair of the SABCS.


Currently, endocrine therapy plus cyclin-dependent kinases 4 and 6 inhibitors (CDK4/6) are the mainstay and first line of therapy for the management of estrogen ER+/HER2- metastatic breast cancer in men and postmenopausal women. However, most of these patients eventually experience disease progression, including the development of estrogen receptor-1 (ESR-1) mutations.


"In the post-CDK4/6 setting, standard single-agent endocrine therapy, example fulvestrant, is associated with median progression-free survival of about 2 months, highlighting the clinical need for better endocrine therapy for patients with ER+ metastatic breast cancer," Bardia said.


Fulvestrant is the only SERD approved to treat breast cancer that, unlike orally administered elacestrant, is delivered through intramuscular injection. In this study, supported by Radius Health, some 477 patients with ER+/HER2- metastatic breast cancer were randomly chosen, with 239 receiving elacestrant and 238 patients on standard-of-care endocrine therapy.


Patients enrolled in this study were required to receive prior therapy for advanced disease, one of which was a combination that included CDK4/6 inhibitor.


The trial's two primary endpoints were PFS in all patients and PFS among patients with mutant ESR-1. Results were reviewed by an independent committee. As outlined by Bardia in a press briefing, the results demonstrated that patients who received elacestrant had a lower risk of disease progression or death compared to patients who received standard-of-care endocrine therapy.


About 30 percent of all patients with ER+/HER2- metastatic breast cancer experienced a "statistically significant and clinically meaningful" lower risk of disease progression or death with elacestrant versus standard-of-care estrogen therapy, with a hazard ratio of .697 (95% confidence with an interval of .55-2.88). In patients with ESR-1 mutations, treatment with elacestrant reduced disease progression or death by about 45 percent compared to standard-of-therapy, with a hazard ratio of .54 (95% confidence in an interval of .38-2.76).


At 12 months, the PFS among all patients on elacestrant was 22.3 percent versus 9.4 percent for standard-of-care endocrine therapy. In patients with ESR-1 mutations, PFS was 26.8 percent versus 8.2 percent with standard endocrine therapy.


"The PFS rate at 12 months essentially tells whether a patient would remain on therapy at the end of one year," said Bardia. "So, if I'm a patient with breast cancer, it's clear that the odds are much better with elacestrant than currently available endocrine therapies."


All patient subgroups-regardless of visceral metastases, geographic region, the number of prior lines of therapy or prior treatment with fulvestrant-benefited from elacestrant compared to standard-of-care estrogen therapy.


The most common side effect witnessed during the trial was nausea; about 35 percent experienced nausea among the elacestrant cohort compared to 18.5 percent receiving standard-of-care endocrine therapy. No other major adverse effect differences were experienced among elacestrant patients compared to those on standard-of-care endocrine therapies.


"The absence of Grade 3 nausea was very low-only 2.5 percent-and patients did not discontinue the trial because of nausea," Bardia said. "So, while nausea is a side effect of elacestrant, it's unlikely that it will impact the efficacy of this agent and that is what we saw in this trial as well."


Final overall survival results from the study will not be made available till late 2022 or early 2023, though Bardia said an initial analysis favored a positive trend among patients who received elacestrant versus standard of care.


Future studies will aim to understand the efficacy of elacestrant during earlier lines of treatment and in combinations with other drugs including CDK4/6 and mTOR inhibitors. A planned Phase II trial will examine the impact of elacestrant in combination with abemaciclib with patients with brain metastases.


Warren Froelich is a contributing writer.