Dr Meisel on the Mechanism of Action of Palazestrant in ER+, HER2– Breast Cancer

“Palazestrant is an oral medication that has 2 main mechanisms of action. It works as a complete ER antagonist and as a selective ER degrader.”

Jane L. Meisel, MD, FASCO, a professor in the departments of Hematology and Medical Oncology as well as Gynecology and Obstetrics and the codirector of Breast Medical Oncology, Department of Hematology and Medical Oncology, at Emory University School of medicine discussed the mechanism of action ofpalazestrant for the treatment of patients with estrogen receptor (ER)–positive, HER2 negative advanced or metastatic breast cancer.

Palazestrant is an oral agent with a dual mechanism of action, working as a complete ER antagonist (CERAN) and selective ER degrader (SERD), Meisel began. The CERAN mechanism of action reduces cancer cell growth by blocking ER activation and suppresses ER activity through the SERD mechanism, she added. This dual approach is novel, as most agents in this class only have a single mechanism of action, she emphasized.

Early clinical trial data have shown that palazestrant has good activity against both normal ERs and mutated forms, Meisel explained. This should lead to some patients responding to palazestrant even after developing resistance to other ER-directed therapies, she concluded.

Palazestrant is being evaluated in patients with ER-positive, HER2-negative advanced or metastatic breast cancer following treatment with an endocrine therapy and CDK4/6 inhibitors in the ongoing phase 3 OPERA-01 trial (NCT06016738). The study is enrolling patients who experienced disease progression or relapse on 1 to 2 prior lines of endocrine therapy, including a CDK4/6 inhibitor, with an ECOG performance status of 1.

The primary end point is progression-free survival per blinded independent central review in patients with and without ESR1 mutations in the intention-to-treat population. Secondary end points include overall survival, objective response rate, and safety.