Orserdu Combo Shows Potential for ER+/HER2– Breast Cancer

Orserdu (elacestrant) in combination with Afinitor (everolimus) or Verzenio (abemaciclib) continued to demonstrate favorable tolerability and produced a clinically meaningful progression-free survival benefit in patients with estrogen receptor (ER)–positive, HER2-negative metastatic breast cancer, particularly in those who had previously received treatment with a CDK4/6 inhibitor and endocrine therapy. These findings support the potential role of Orserdu-based combinations as an all-oral strategy in managing patients who have developed resistance to prior therapies.

Data from the phase 2 portion of the study, presented during the 2025 San Antonio Breast Cancer Symposium, highlighted the efficacy of these combinations. Patients treated with Orserdu plus Afinitor, totaling 50 individuals, achieved a median progression-free survival of 8.3 months. The disease control rate was 89% and the overall response rate was 20%, with a median duration of response of 8.5 months. For patients who received Orserdu plus Verzenio, comprising 60 participants, median progression-free survival reached 14.3 months. Disease control rate was 91%, the overall response rate was 25%, and median duration of response was 14.8 months. These results were consistent across all patient subgroups, indicating a robust benefit in diverse populations within this trial.

“There were low rates of drug withdrawal or dose reduction and no new safety signals based on this analysis,” explained Dr. Hope S. Rugo, principal investigator of the study, chief of the Division of Breast Oncology, and director of the Women’s Cancer Program at City of Hope in Duarte, California. “[Based on these data], Orserdu has the potential to become one of the endocrine backbones for a combination strategy with Verzenio or Afinitor, supporting an entirely oral approach for patients with advanced disease.”

The rationale for evaluating Orserdu in combination with other targeted agents stems from the known challenges of hormone receptor–positive metastatic breast cancer. Resistance mechanisms in patients previously treated with first-line endocrine therapy and CDK4/6 inhibitors clearly reduce the efficacy of subsequent treatments. Orserdu is the only oral selective estrogen receptor degrader that has demonstrated significant improvement in progression-free survival versus standard-of-care endocrine therapy in patients with metastatic disease. Its oral formulation also allows for convenient integration with other oral targeted therapies, supporting patient-centered care.

The study enrolled pre-, peri-, or postmenopausal women or men with ER-positive, HER2-negative advanced or metastatic breast cancer who had received one to two prior lines of endocrine therapy, with or without CDK4/6 inhibition, and had at least one measurable lesion. In phase 2, patients received 345 milligrams (mg) of Orserdu daily combined with either 7.5 mg of Afinitor or 150 mg of Verzenio. The primary end point of the study was progression-free survival, while secondary end points included overall response rate, duration of response, clinical benefit, overall survival, and safety.

Both Orserdu-based combinations were associated with a safety profile consistent with prior experience of the partner agents or Orserdu monotherapy. No new safety signals were observed. In the Orserdu plus Afinitor arm, side effects led to treatment withdrawal in 6% of patients and dose reduction in 2%. In the Orserdu plus Verzenio arm, 5% of patients required dose reduction, with no withdrawals. The most common side effects, reported in at least 20% of patients, included diarrhea, nausea, fatigue, vomiting, stomatitis, hypercholesterolemia, anemia, neutropenia, abdominal pain, decreased appetite, rash, dysgeusia, mucosal inflammation, weight loss, constipation, dizziness, headache, thrombocytopenia, leukopenia, and hyperglycemia.

Overall, these results reinforce the potential of Orserdu in combination with targeted therapies as a flexible and effective approach for managing pretreated ER-positive, HER2-negative metastatic breast cancer. The study supports further exploration of these combinations to enhance patient outcomes and expand oral treatment options in this challenging disease setting.

References

1. “Elacestrant in combination with everolimus or abemaciclib in patients with ER+/HER2- locally advanced or metastatic breast cancer (mBC): phase 2 results from ELEVATE, an open-label, umbrella study,” by Dr. Hope Rugo. Presented at: 2025 San Antonio Breast Conference Symposium; December 9-12, 2024; San Antonio, TX. Abstract RF7-01.
2. “FDA approves elacestrant for ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer,” by U.S. FDA. News release. January 27, 2023.

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