Longer CDK 4/6 inhibitor therapy enhances elacestrant benefit in metastatic breast cancer
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SAN ANTONIO — Longer duration of cyclin-dependent kinase 4/6 inhibitor therapy in the metastatic setting appeared associated with extended PFS among elacestrant-treated patients with advanced breast cancer, according to study results.
The benefit appeared more pronounced among patients with ESR1 mutations, findings of the randomized phase 3 EMERALD trial showed.
The results — presented at San Antonio Breast Cancer Symposium — suggest elacestrant (Menarini Group/Radius Health) may be a new standard of care as a monotherapy endocrine sequencing option for patients with ER-positive, HER2-negative advanced or metastatic breast cancer who progress on CDK 4/6 inhibitors, researchers concluded.
“It has to be the right patient population. We want to make sure we pick patients we have deemed to still have endocrine-sensitive disease but, for many of those patients, I think the single-agent option will be very appropriate,” Virginia G. Kaklamani, MD, DSc, professor of medicine in the division of hematology/oncology at UT Health San Antonio and leader of the breast cancer program at UT Health San Antonio MD Anderson Cancer Center, told Healio.
Background
Standard treatment for ER-positive, HER2-negative metastatic breast cancer consists of endocrine therapy plus a CDK 4/6 inhibitor. However, most patients with ER-positive metastatic disease develop treatment resistance, sometimes due to development of ESR1 mutations.
Fulvestrant, administered via intramuscular injections, is the only selective estrogen receptor degrader approved for breast cancer treatment.
Elacestrant is an orally administered selective estrogen receptor degrader.
The multicenter, open-label EMERALD trial compared elacestrant with standard endocrine therapy for postmenopausal patients with ER-positive, HER2-negative metastatic breast cancer who received one or two prior lines of endocrine therapy and no more than one prior line of chemotherapy.
All 478 patients had progressed on prior CDK 4/6 inhibitor treatment, and 228 had ESR1 mutations.
Researchers randomly assigned 239 patients to 400 mg elacestrant daily. The other 239 received standard of care, which consisted of investigator’s choice of fulvestrant or an aromatase inhibitor.
PFS by blinded independent review committee assessment among patients with ESR1 mutations, as well as PFS among all patients regardless of ESR1 mutation status, served as primary endpoints. OS, safety, tolerability and quality of life served as secondary endpoints.
As Healio previously reported, the study met both primary endpoints. Results presented at last year’s San Antonio Breast Cancer Symposium showed reduced risk for disease progression or death with elacestrant among all patients (HR = 0.69; 95% CI, 0.55-0.88) and among those with ESR1 mutations (HR = 0.54; 95% CI, 0.38-0.76).
Post-hoc analysis
Researchers performed a post-hoc analysis of PFS results to evaluate whether duration of CDK 4/6 inhibitor therapy in the metastatic setting had an effect on PFS outcomes.
“Interestingly, we found out it does,” Kaklamani said.
Results showed longer duration of CDK 4/6 inhibitor therapy appeared associated with improved median PFS among elacestrant-treated patients in the overall study population:
at least 6 months duration: 2.8 months vs. 1.9 months (HR = 0.69; 95% CI, 0.54-0.88);
at least 12 months duration: 3.8 months vs. 1.9 months (HR = 0.61; 95% CI, 0.45-0.83); and
at least 18 months duration: 5.5 months vs. 3.3 months (HR = 0.7; 95% CI, 0.48-1.02).
The association between CDK 4/6 inhibitor therapy duration and longer median PFS with elacestrant appeared more pronounced among patients with ESR1 mutations:
at least 6 months duration: 4.1 months vs. 1.9 months (HR = 0.52; 95% CI, 0.36-0.74);
at least 12 months duration: 8.6 months vs. 1.9 months (HR = 0.41; 95% CI, 0.26-0.63); and
at least 18 months duration: 8.6 months vs. 2.1 months (HR = 0.47; 95% CI, 0.2-0.79).
“In the primary analysis, elacestrant performed better than standard of care, but neither did as well as we would have wanted,” Kaklamani told Healio. “But when you look at the patients who have endocrine-sensitive tumors, and many of them do, you start to see a meaningful improvement in PFS — importantly with a treatment that has very little toxicity.”
Safety
Most adverse events observed in the EMERALD trial — including nausea — were grade 1 or grade 2. Adverse events required 3.4% of patients assigned elacestrant and 0.9% of those assigned standard care to discontinue therapy.
Researchers reported antiemetic use by 8% of those assigned elacestrant, 3.7% of those assigned fulvestrant and 10.3% assigned an aromatase inhibitor.
Investigators observed no hematologic safety signals, and no patients in either treatment group had sinus bradycardia.
Next steps
OS data had not matured. The analysis is pending, but the trial was not powered to assess that outcome, Kaklamani said.
The FDA granted priority review to elacestrant in August for ER-positive, HER2-negative advanced or metastatic breast cancer.
The agency is expected to make a decision about approval by Feb. 17.
“If elacestrant gets approved by the FDA, clinicians are going to have to decide if monotherapy with this drug is appropriate for every patient, and maybe not,” Kaklamani told Healio. “Some patients deemed to be endocrine-resistant, for whom the duration of CDK 4/6 inhibitor therapy was only a few months, may need to go to chemotherapy or another doublet endocrine therapy.
“But for the large number of patients who have been on a CDK 4/6 inhibitor for more than 18 months, single-agent elacestrant is going to give them more than 8 months of PFS, and I believe that will be beneficial.”
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Bardia A, et al. Abstract GS3-01. Presented at: San Antonio Breast Cancer Symposium; Dec. 6-10, 2022; San Antonio.
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