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ESR1 Mutation Testing May be Informative for Personalizing SERD Treatment, SABCS Studies Show


NEW YORK – Findings from two Phase III trials released at the San Antonio Breast Cancer Symposium may help oncologists identify which metastatic breast cancer patients will benefit most from selective estrogen receptor degraders, or SERDs.

One study, the Phase III EMERALD trial, showed Radius Health and Menarini Group's SERD elacestrant improved outcomes compared to standard of care in previously treated estrogen receptor (ER)-positive, HER2-negative metastatic breast cancer. The positive results support Boston-based Radius' plans to file for regulatory approval for elacestrant in this indication.

The other trial, the Phase III PADA-1 study, compared the combination of the CDK4/6 inhibitor palbociclib (Pfizer's Ibrance) plus the SERD fulvestrant versus palbociclib plus an aromatase inhibitor as a first-line therapy for ER-positive, HER2-negative metastatic breast cancer. This study also considered the clinical utility of regularly monitoring patients for ESR1 mutations to guide SERD treatment decisions.

In both trials, researchers considered treatment benefit in patients based on whether they had ESR1 mutations in their tumors. Prior research shows that mutations in ESR1, or estrogen receptor 1, are found more frequently in metastatic breast tumors. These mutations, which occur in 30 percent to 40 percent of breast cancer patients who progress after first-line aromatase inhibitor treatment, can also make them resistant to endocrine and aromatase therapy.

The results of both studies may ultimately refine oncologists' understanding of how ESR1 mutation-positive patients respond to SERDs, elacestrant and fulvestrant.

PADA-1 trial

The Phase III PADA-1 trial, presented by Francois-Clement Bidard, a medical oncologist at Institute Curie, at a press briefing Monday, explored the effect of switching treatment to include a SERD once an ESR1 mutation was detected in circulating tumor DNA. This study involved around 1,000 patients with ER alpha-positive, HER2-negative breast cancer who were receiving first-line treatment with an aromatase inhibitor plus palbociclib.

Patients provided blood samples every two months so they could be screened for ESR1 mutations using a droplet digital PCR assay Bidard and his research colleagues had developed. The ESR1 mutation was detected in about half of the study participants — 279 out of 407 patients — who experienced disease progression. In 219 of the mutation-positive patients, the alteration was identified prior to disease progression detected via imaging, and in 60 of these patients it was detected concurrent with progression.

For patients whose ESR1 mutation was detected prior to treatment, half were assigned to continue on treatment with palbociclib with an aromatase inhibitor and half were switched to palbociclib plus fulvestrant.

The median progression-free survival among 88 ESR1-mutated breast cancer patients who switched to fulvestrant was about twice as long as those who remained on an aromatase inhibitor, 11.9 months and 5.7 months, respectively.

ESR1 mutation-positive patients who remained on the aromatase inhibitor but progressed on treatment were also allowed to crossover to the fulvestrant arm. In that group, the median progression-free survival was much shorter, 3.5 months.

Bidard said his group's method of tracking ESR1 mutations in blood samples could be easily implemented into practice using next-generation sequencing.

"PADA-1 is the first clinical trial to demonstrate the clinical utility of ESR1 mutation monitoring," Bidard said during the press conference, adding that this monitoring could allow oncologists to determine the optimal endocrine therapy to give patients in combination with CDK4/6 inhibitors.

"We observed a doubling in median progression-free survival from the switch from aromatase inhibitors and palbociclib to fulvestrant and palbociclib," he said. "This clinical benefit may justify implementation of the parallel treatment strategy as a valid option in routine care."

Bidard noted that the benefit of the switch to fulvestrant in this trial may have been supported by the low ESR1 mutation burden in patients at the time of testing. In contrast, the cohort that switched to fulvestrant later after disease progression saw less benefit, suggesting that regular monitoring and early detection of ESR1 mutations can lead to better outcomes for these patients.

Carlos Arteaga, SABCS co-director and director of the Simmons Comprehensive Cancer Center at the University of Texas Southwestern, said this trial validates a previous discovery that estrogen receptor mutations occur independent of the estrogen hormone, which he noted explains why aromatase inhibitors were inferior to fulvestrant in this study.

"Even in these late-stage patients, we need to continue to inhibit that estrogen receptor with a strategy other than estrogen suppression with aromatase inhibitors," Arteaga said in a discussion of the PADA-1 trial.


While PADA-1 explored the efficacy of an already approved SERD, fulvestrant, the EMERALD trial compared standard-of-care fulvestrant injection to the investigational oral SERD elacestrant. EMERALD 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 randomized to receive either elacestrant or the investigator's choice of standard-of-care therapy: fulvestrant or an aromatase inhibitor. In the standard-of-care arm, about two-thirds of patients received fulvestrant and around half of the study participants had ESR1-mutated tumors.

Among all patients, there was a 30 percent lower risk of death or disease progression on treatment with elacestrant versus standard-of-care treatment. Among patients with an ESR1 mutation, however, the benefit was greater with a 45 percent lower chance of death or progression on elacestrant.

The 12-month progression-free survival rate for the whole study population was 22.3 percent in the elacestrant arm compared to 9.4 percent in the standard-of-care arm. For ESR1 mutant patients, the 12-month progression-free survival rate was 26.8 percent on elacestrant compared to 8.2 percent on standard-of-care therapy.

"A majority of patients in the trial received fulvestrant as the standard-of-care endocrine therapy," trial investigator Aditya Bardia, who is also a medical oncologist at Massachusetts General Hospital, said at the press conference, meaning the difference in outcomes wasn't being driven by those receiving aromatase inhibitors. "When you look at the results on [patients with] ESR1 mutations and look at only the fulvestrant group, the magnitude of the difference remains," he added.

An interim analysis of overall survival did not show a statistically significant difference between the elacestrant and standard-of-care arms in either the whole cohort or in the ESR1-mutant subgroup. However, Bardia said in his presentation that an "evident trend favoring elacestrant was noted in both groups." Researchers will report final overall survival data from this trial in late 2022 or early 2023.

"Clinically, elacestrant has the potential to become the new standard of care in the studied population," Bardia said. "Further study of elacestrant in earlier lines combined with other targeted therapies, including CDK4/6 inhibitors and mTOR inhibitors, are ongoing or planned for patients with ER-positive, HER2-negative breast cancer."

Earlier this year, Radius and Menarini Group, which holds rights to elacestrant in Europe, began planning regulatory filings in the US and Europe for elacestrant in this indication based on the results from EMERALD. The firms plan to submit regulatory applications seeking approval for the drug in the US and EU next year.

"This is an important study of the first SERD, other than fulvestrant, in patients that progressed after CDK4/6 inhibitors, which is a major therapeutic priority in patients with ER-positive breast cancer," Arteaga said in a discussion of the EMERALD trial. "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."