Orserdu Boosts PFS in ESR1-Mutated Metastatic Breast Cancer Subgroups

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Patients with ER-positive, HER2-negative, ESR1-mutant advanced breast cancer experienced improvements in progression-free survival when being treated with Orserdu, study results showed.

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Findings from the phase 3 EMRALD trial showed that all relevant subgroups of patients with ER-positive/HER2-negative, ESR1-mutated advanced or metastatic breast cancer tended to experience improved progression-free survival (PFS; time from treatment until disease progression or death) with orserdu (elacestrant) compared to standard of care.

The study analysis — which was presented at the 2023 San Antonio Breast Cancer Symposium — revealed that exposure to CDK4/6 inhibitors plus estrogen therapy for at least 12 months improved PFS, suggesting that the estrogen receptor (ER) pathway could be the main driver of disease, regardless of the metastatic site or coexistence of PIK3CA or TP53 mutation.

“We evaluated eigh subsets, including patients with bone, liver and lung metastases, HER2-low expression and HER2-zero expression, PIK3A mutation, and TP53 mutation,” coauthor Dr. Janice Lu, professor, Northwestern University Lurie Comprehensive Cancer Center, Chicago, Illinois, said during the presentation of data.

Patients (478) were randomly assigned to receive Orserdu (239 patients) or standard of care (239 patients) and 228 patients were identified with an ESR1 mutation. In the ESR1 mutation group, 159 patients were treated with prior CDK4/6 inhibitors for 12 months, 71% had liver and or lung metastases, 39% had a PIK3CA mutation, 38% had a TP53 mutation and 48% had HER2-low expression.

Among all patients with an ESR1 mutation, median PFS in the treatment arm was 8.61 months, compared to 1.91 months in the control arm.

In the current analysis, in patients with accompanying liver and/or lung metastases, the median PFS among patients in the Orserdu arm was 7.26 months compared with 1.87 months among patients treated with standard of care. In patients with PIK3CA mutation, median PFS was 5.45 months compared to 1.94 months, respectively. In patients with TP53 mutation, median PFS was 8.61 months vs 1.87 months, respectively. In patients with HER2-low expression, median PFS was 9.03 months vs 1.87 months, respectively.

The EMERALD trial enrolled patients with ER-positive/HER2-negative metastatic breast cancer who were previously treated with one to two lines of endocrine therapy and an CDK4/6 inhibitor. Investigators allowed for previous treatment with Faslodex (fulvestrant). In the trial, patients either received 345 mg Orserdu or investigator’s choice of Faslodex or an aromatase inhibitor.

Randomization was stratified by ESR1 mutation status (detected vs not detected), prior treatment with Faslodex (yes vs no), and visceral metastasis (yes vs no). The major efficacy outcome measure was PFS, assessed by a blinded imaging review committee. A statistically significant difference in PFS was observed in the intention to treat (ITT) population and in the subgroup of patients with ESR1 mutations. Efficacy results from the EMERALD study led to the FDA approval of the agent.

Regarding safety, most side effects, including nausea, were grade 1 and 2, and no grade 4 (severe) treatment-related side effects were reported. Investigators reported that quality of life was maintained between treatment groups and no differences were observed between all patients and patients with ESR1 mutation.

No hematologic safety signal was observed, and no patients in either treatment arm exhibited sinus bradycardia. Further, no deaths were reported as treatment-related in either arm of the trial.

The most common all-grade side effects (10% or greater) reported in patients with ESR1 mutation in the treatment arm were musculoskeletal pain (50%), nausea (38.5%) and fatigue (25.6%). In the control arm, the most common all grade side effects (10% or greater) were musculoskeletal pain (37.3%), nausea (14.7%) and fatigue (22.7%).

“A clinically meaningful improvement in PFS favoring (Orserdu) compared with standard of care was consistent across all relevant subgroups with ESR1-mutation tumors and assumed endocrine-sensitivity,” concluded Lu.

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