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Menarini's Orserdu, Guardant's ctDNA CDx Net FDA Approval for ESR1-Mutated Breast Cancer Patients

NEW YORK – The US Food and Drug Administration on Friday approved Menarini's Orserdu (elacestrant) as a second-line treatment for estrogen receptor (ER)-positive HER2-negative advanced breast cancer harboring ESR1 mutations.

The agency approved the selective estrogen receptor degrader (SERD) for postmenopausal women and adult men who have progressed on at least one prior endocrine therapy. The FDA also approved Guardant Health's Guardant360 CDx as a blood-based assay for identifying patients with ESR1 mutations who are eligible for treatment.

The FDA's decision was based on data from the EMERALD trial, in which previously treated patients were randomized to Orserdu or investigator's choice of endocrine therapy, including fulvestrant or an aromatase inhibitor. In the study, 228 out of 478 patients had ESR1 missense mutations in the ligand binding domain as determined by the Guardan360 CDx.

Researchers previously reported that in the all-comer population in EMERALD, Orserdu-treated patients had a 30 percent lower risk of death or disease progression versus those in the comparator arm. Orserdu benefited patients with ESR1 mutations even more, however, reducing their risk of death or disease progression by 45 percent compared to the control arm.

In the 228 patients with ESR1 mutations, median progression-free survival was 3.8 months with Orserdu and 1.9 months with fulvestrant or aromatase inhibitors. In an exploratory analysis involving the subset of 250 patients without ESR1 mutations, however, Orserdu reduced the risk of death or disease progression by only 14 percent compared to those in the control arm. This indicates, the FDA said in a statement, "that the improvement in the intent-to-treat population was primarily attributed to the results seen in the ESR1-mutated population."

In EMERALD, patients on Orserdu commonly experienced musculoskeletal pain, nausea, and increased cholesterol, among other lab abnormalities.

Patients who become resistant to aromatase inhibitors, SERDs, or selective estrogen receptor modulators commonly do so through ESR1 mutations. As such, ESR1 mutations are increasingly of interest as a predictive biomarker to identify best responders to ER-targeted drugs and may even offer a way to salvage drugs that have failed in all-comer populations.

For example, in the AMEERA-5 trial, Sanofi's SERD amcenestrant failed to improve progression-free survival over physician's choice of therapy in ER-positive HER2-negative advanced breast cancer patients but did show a trend favoring amcenestrant in those with ESR1 mutations. Based on the results, Sanofi stopped all studies of amcenestrant. Similarly, in the acelERA trial, Roche's giredestrant didn't meet its progression-free survival endpoint against physician's choice of endocrine monotherapy in ER-positive HER2-negative metastatic breast cancer patients but the SERD performed more robustly in patients with ESR1-mutated tumors. Roche is continuing to study the drug.