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American Society of Clinical Oncology (ASCO) clinical practice guidelines now at recurrence or progression on endocrine therapy -- with or without a CDK4/6 inhibitor -- in patients with metastatic, estrogen receptor (ER)-positive, HER2-negative breast cancer.

While two previous ASCO guideline updates concluded that data were insufficient to recommend routine testing, an ASCO Expert Panel co-chaired by Harold Burstein, MD, PhD, of the Dana-Farber Cancer Institute in Boston, determined that the results from the phase III EMERALD trial provided a "strong signal" for updating ASCO's metastatic breast cancer guidelines by demonstrating the efficacy of elacestrant (Orserdu) in patients with advanced ER-positive/HER2-negative disease and ESR1 mutations.

The trial led to approval of the oral selective estrogen receptor degrader earlier this year for this patient population.

In EMERALD, investigators randomly assigned 477 postmenopausal women or men with advanced breast cancer to receive either elacestrant or standard-of-care endocrine therapy.

The trial showed that compared with standard of care, there was improved progression-free survival (PFS) with elacestrant in both the overall study population (HR 0.70, 95% CI 0.55-0.88, P=0.002) and in patients with ESR1 mutations in their circulating tumor (ct)DNA (HR 0.55, 95% CI 0.39-0.77, P=0.0005).

In patients with ESR1 mutations, median PFS was 3.8 months for those on elacestrant and 1.9 months for those on standard of care, while 6-month PFS rates were 41% and 19%, respectively. Among patients without detectable ESR1 mutations, there was no significant improvement in PFS with elacestrant compared with standard of care (HR 0.86, 95% CI 0.63-1.19, P=0.308).

Objective response rates were 4% in each arm in the overall population and were not significantly different between elacestrant and standard of care in patients with ESR1 mutations (7.1% vs 4.7%, P=0.455).

Regarding safety, elacestrant therapy was associated with more toxicity than standard of care, including nausea and vomiting.

The updated ASCO guidelines recommend the following:

• Testing with a Clinical Laboratory Improvement Amendments–certified assay "should be performed on blood or tissue obtained at the time of progression," and blood-based ctDNA testing is preferred because of its greater sensitivity
• Testing for PIK3CA mutations should also be performed to guide further therapy
• Patients whose tumor or ctDNA tests remain ESR1 wild-type should consider retesting upon subsequent progression to determine if an ESR1 mutation has emerged

The ASCO Expert Panel also suggested several alternatives for patients who want to continue with endocrine therapy after previous treatment with endocrine therapy and a CDK 4/6 inhibitor.

The panel observed that appropriate options for patients with prior CDK 4/6 inhibitor treatment and ESR1 wild-type tumors include fulvestrant (Faslodex), an aromatase inhibitor, or tamoxifen monotherapy; endocrine therapy in combination with targeted agents such as alpelisib (Piqray) for PIK3CA-mutated tumors; or everolimus (Afinitor).

For patients with prior CDK4/6 inhibitor treatment and a detectable ESR1 mutation, options include elacestrant, or other endocrine therapy either alone or in combination with targeted agents such as alpelisib (for PIK3CA-mutated tumors) or everolimus.

However, the panel noted there are no safety or efficacy data supporting elacestrant use in combination with targeted agents.

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