SAN ANTONIO – Updated analysis presented at the San Antonio Breast Cancer Symposium on Thursday suggested that the longer patients are exposed to prior CDK4/6 inhibitors, the better they are likely to do on Menarini Group's selective estrogen receptor degrader (SERD) elacestrant.
Researchers led by Virginia Kaklamani, professor of medicine in the division of hematology/oncology at University of Texas Health Science Center at San Antonio, reported updated analysis from the Phase III EMERALD trial, in which 477 advanced metastatic breast cancer patients with estrogen receptor (ER)-positive, HER2-negative breast cancer were randomized to elacestrant or investigator's choice of endocrine therapy with fulvestrant or an aromatase inhibitor. Patients had to have progressed on one or two lines of endocrine therapy prescribed for advanced tumors, and one of these endocrine therapies had to be given with a CDK4/6 inhibitor. They could also have prior chemo or fulvestrant.
A year ago at this same meeting, researchers presented data from the registrational EMERALD trial showing that in the all-comer population, elacestrant treatment reduced the risk of death or disease progression by 30 percent compared to standard-of-care treatment. In those with ESR1 mutations, the SERD led to a 45 percent reduction in the risk of death or progression.
This year, Kaklamani presented updated analysis from the same study to try to get a better understanding of whether the duration of prior CDK4/6 inhibitors impacted patients' progression-free survival on elacestrant. This is important, Kaklamani said, since CDK4/6 inhibitors given with endocrine therapies is a mainstay treatment strategy for ER-positive, HER2-negative metastatic breast cancer, but patients eventually develop hormonal resistance, often through the emergence of ESR1 mutations.
In fact, between 30 percent and 40 percent of breast cancer patients who progress after first-line aromatase inhibitor treatment have ESR1 mutations. At that point, patients are often prescribed endocrine monotherapy or combinations like Novartis' Afinitor (everolimus) plus exemestane, or Piqray (alpelisib) plus fulvestrant for those with PIK3CA-mutated tumors. But progression-free survival is low with single-agent endocrine therapy, and the combination endocrine therapy approaches have toxicity that causes patients to discontinue treatment.
In this context, there is a need to identify early on which patients are endocrine-resistant and which patients aren't. There is convincing data from EMERALD and other studies that patients who can only remain on CDK4/6 inhibitors for less than six months have resistant tumors and will likely have to consider chemotherapy and potentially combination endocrine therapy. "But those treatments are toxic for our patients," Kaklamani said. "[And, so, for the] a large number of patients that are on a CDK 4/6 inhibitor for more than 12 months, more than 18 months, we need to make a decision after their tumors progress. Should we give combination endocrine therapy if they have a PIK3CA mutation or should we give [SERD] monotherapy?"
Recognizing that having six months of CDK4/6 inhibitor treatment is an indicator of endocrine sensitivity, Kaklamani and colleagues divided patients into three groups based on whether they had prior CDK4/6 inhibitors for six, 12, and 18 months. She noted that while there are multiple studies investigating SERDs as a second-line option in hormone receptor (HR)-positive, HER2-negative breast cancer, EMERALD is the only one that mandated that 100 percent of enrolled patients have prior CDK4/6 inhibitor treatment.
Enrolled patients were on CDK4/6 inhibitors for a median of 17 months. The median progression-free survival for those who had prior CDK4/6 inhibitors for at least a year was 3.8 months on elacestrant and 1.9 months on standard-of-care treatment with fulvestrant or an aromatase inhibitor. For those on CDK4/6 inhibitors for 18 months, the median progression-free survival was 5.5 months on the SERD and 3.3 months on the control arm. These results show, Kaklamani said, that with longer CDK4/6 inhibitor therapy, the benefit in the endocrine therapy comparator arm also increased, "reflecting a more endocrine-sensitive tumor."
The results were even better in the ESR1-mutated subset. More than 70 percent of patients with ESR1 mutations had previously gotten a CDK4/6 inhibitor for at least a year and 50 percent had done so for 18 months. Among patients with at least a year exposure to CDK4/6 inhibitor therapy, median progression-free survival was 8.6 months on elacestrant compared to 1.9 months with standard of care; for those who were on CDK4/6 inhibitors for 18 months, median progression-free survival was also 8.61 months on elacestrant and 2.1 months on standard of care.
"There were no patients with ESR1-mutated tumors on the standard-of-care arm who were progression-free at 18 months," Kaklamani said. "But … 30 percent of patients on elacestrant were progression-free at this time point."
To get a sense of the dynamics of endocrine sensitivity, researchers looked at outcomes in the six-to-12-month period and noted that this appeared to be when patients start to develop ESR1 mutation-driven resistance. However, they noted that there were still some patients who received CDK4/6 inhibitors for less than six months that responded to elacestrant.
The researchers also updated their safety analysis in EMERALD and noted that adverse events were in line with what they reported previously. Most adverse events were grade 1/2 and there were no grade 4 treatment-related toxicities. Only 3.4 percent of patients on elacestrant and less than 1 percent on standard of care discontinued treatment due to adverse events.
"These updated results demonstrate that monotherapy use of elacestrant is safe and significantly prolongs median progression-free survival versus standard of care and meaningfully extends landmark progression-free survival rates," Kaklamani said. "Elacestrant can become an important oral endocrine monotherapy in the second- and third-line treatment as an alternative to combination [endocrine] therapies that are associated with challenging safety profiles."
Given the insight in EMERALD and other trials that patients with a short progression-free survival on prior CDK4/6 inhibitors don't derive much benefit from single-agent SERDs, Fabrice Andre, director of medical oncology research at Gustave Roussy, questioned whether these patients should be excluded from future registrational studies of this class of drugs.
He further proposed the need to identify endocrine-resistant patients at the time of diagnosis and treat them with modern cytotoxic agents or targeted drugs. With the use of modern diagnostic tools and therapies, one can challenge the dogma that all ER-positive metastatic breast cancer patients should receive first-line endocrine therapy, he reflected.
If patients have ESR1 mutations at diagnosis, for example, that could be used to identify patients with estrogen-driven resistance to endocrine therapy. Further, Andre said that it is important to identify the 40 percent of patients who have primary resistance to SERDs and recognize that ESR1 mutations have high inter-patient heterogeneity in terms of allelic frequency. "Most of the trials now should report what is the clonality of ESR1 mutations" in studies of SERDs, Andre suggested.
It's unclear, however, whether ESR1 mutation testing will be mandated by regulators as a way to identify best responders to elacestrant. Italian pharmaceutical and diagnostics company Menarini Group garnered the global licensing rights for elacestrant in 2020 from Radius Health, which was responsible for conducting and completing the EMERALD trial. Menarini is now in charge of taking the drug through registration and commercialization.
The company is seeking regulatory approval in the US for elacestrant as a treatment for ER-positive, HER2-negative advanced or metastatic breast cancer and has highlighted that the registrational EMERALD trial met its two primary endpoints by improving progression-free survival in both the all-comer population and the ESR1-mutated subgroup. The FDA is conducting a priority review of the drug and is expected to issue a decision by Feb. 17, 2023.
At SABCS, experts wondered whether based on the results of the EMERALD trial, the FDA will restrict elacestrant's indication to patients with ESR1-mtuated tumors and require a companion diagnostic to identify eligible patients. Kaklamani declined to speculate, noting that this is for the FDA to decide.
However, she pointed out that among patients with non-mutated tumors in EMERALD, the progression-free survival hazard ratio was .86, which translates to a 14 percent reduction in the risk of death or progression. "There is potentially still a small benefit, but most of that benefit is in the ESR1-mutated tumors," she said, adding that knowing a patient's ESR1 mutation status "will be important" in this setting.
In 2020, Guardant Health had announced its Guardant360 CDx liquid biopsy test was being used by Radius Health to identify patients with ESR1 mutations in the EMERALD trial. In a separate announcement on Thursday, Guardant said it was also working with AstraZeneca to develop and pursue regulatory approval and commercialization of a liquid biopsy-based companion diagnostic to identify ESR1-mutated, HR-positive, HER2-negative metastatic breast cancer patients eligible for AstraZeneca's investigational SERD camizestrant in the SERENA-6 Phase III trial. In this study, AstraZeneca is comparing the activity of camizestrant in combination with CDK4/6 inhibitors against aromatase inhibitors plus CDK4/6 inhibitors.