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SAN ANTONIO -- Patients with progressive advanced hormone receptor (HR)-positive breast cancer had significant improvement in progression-free survival (PFS) with an investigational selective estrogen receptor degrader (SERD) instead of standard therapy, a randomized trial showed.

Overall, median PFS increased by less than a month with elacestrant (2.79 vs 1.91 months), which nonetheless achieved statistical significance. In the subgroup of patients with estrogen receptor 1 (ESR1) mutation, who accounted for almost half of the study population, treatment with elacestrant doubled median PFS from 1.87 months with standard care to 3.78 months.

Two to three times as many patients were alive without disease progression at 12 months in the elacestrant group, reported Aditya Bardia, MD, of Massachusetts General Hospital Cancer Center in Boston, at the (SABCS).

"Elacestrant is the first oral SERD that demonstrated a statistically significant and clinically meaningful improvement in PFS versus standard of care endocrine therapy in a randomized, global, phase III study in men and postmenopausal women with estrogen receptor-positive/HER2-negative metastatic breast cancer in the second and third line post-CDK4/6-inhibitor setting," said Bardia.

"Elacestrant was well tolerated, with a predictable and manageable safety profile consistent with other endocrine therapies. A final (OS) overall survival analysis is expected next year. Clinically, elacestrant has the potential to become a new standard of care in the studied patient population," he added.

The results suggest that elacestrant has the potential to fill a major unmet need in the management of HR-positive breast cancer, according to SABCS Co-director Carlos Arteaga, MD, of the Simmons Comprehensive Cancer Center at UT Southwestern Medical Center in Dallas.

"This is an important study of the first selective estrogen receptor degrader, other than fulvestrant, in patients that progress after CDK4/6 inhibitors, which is a major therapeutic priority in patients with ER-positive breast cancer," he said. "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."

Endocrine therapy plus a CDK4/6 inhibitor has become the for first-line treatment of HR-positive/HER2-negative metastatic breast cancer. However, eventually occurs in most patients, often associated with development of ESR1 mutations. In the post-CDK4/6-inhibitor setting, single-agent endocrine therapy is associated with a median PFS of about 2 months, emphasizing the need for better endocrine therapy, said Bardia.

Elacestrant blocks the estrogen receptor in a dose-dependent manner and has in postmenopausal women with HR-positive/HER2-negative metastatic breast cancer. The findings provided support for the phase III study, involving men and postmenopausal women with advanced/metastatic HR-positive/HER2-negative breast cancer that had progressed or relapsed after treatment with the combination of an endocrine agent and a CDK4/6 inhibitor.

Investigators randomized 477 patients to elacestrant or investigator's choice of standard-of-care endocrine therapy. Treatment continued until disease progression, intolerable toxicity, or withdrawal from the study. The co-primary endpoints were PFS in all patients and PFS in patients with ESR1 mutations.

The primary analysis in the overall population showed that elacestrant reduced the hazard for disease progression or death by 30% versus standard therapy (95% CI 0.552-0.880). In the subgroup of patients with ESR1 mutations (n=228), treatment with elacestrant reduced the hazard by 45% (95% CI 0.387-0.768, P=0.0005). The 12-month PFS favored elacestrant in the overall population (22.3% vs 9.4%) and in the ESR1-mutation subgroup (26.8% vs 8.2%).

A subgroup analysis showed a consistent trend toward benefit from treatment with elacestrant.

Preliminary analyses of overall survival yielded trends in favor of elacestrant in all patients (median not yet reached in either group, P=0.0821) and in the ESR1-mutation subgroup (not reached vs 36 months, P=0.0325).

Treatment with elacestrant and standard-of-care endocrine therapy was associated with low rates of grade 3/4 treatment-emergent adverse events (TRAEs). The most frequent grade 3/4 TRAEs in the elacestrant arm were nausea (2.5% of patients), back pain (2.5%), increased liver tests (alanine aminotransferase, 2.1%; aspartate aminotransferase, 1.7%), and headache (1.7%).

Bardia said ongoing and planned studies of elacestrant include evaluations of the SERD in earlier lines of therapy and in combination with targeted therapies, including CDK4/6 inhibitors and mTOR inhibitors.

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