Comparison of Palazestrant + Ribociclib and Letrozole + Ribociclib as First-Line Treatment for Advanced Hormone Receptor-Positive, HER2-Negative Breast Cancer

Breast cancer develops when cells in the breast tissue—specifically the milk ducts and lobules—become malignant and begin to grow uncontrollably. In hormone receptor (HR)-positive breast tumors, the cancer cells have binding sites (receptors) on their surface for the female sex hormones estrogen and progesterone. When estrogen binds to these receptors, it can stimulate the growth and proliferation of tumor cells. HER2 is a growth factor receptor that is also located on the surface of the cells and can transmit signals for growth and cell division into the cell interior. In HER2-negative tumors, HER2 is not present in elevated levels. At the same time, the presence of hormone receptors provides a target for various therapies. Letrozole belongs to the class of aromatase inhibitors, which inhibit the enzyme aromatase—the enzyme that controls the final step in estrogen production in the body—thereby reducing estrogen production. Palazestrant belongs to a newer class of drugs that target the estrogen receptor, known as complete estrogen receptor antagonists (CERANs). The drug is designed to completely block the estrogen receptor in breast cancer cells and also promote its degradation. Ribociclib, in turn, belongs to the class of cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors, which inhibit the proteins CDK4 and CDK6, thereby preventing the cell cycle and, consequently, uncontrolled cell division.

The goal of this Phase 3 study is to investigate the efficacy and tolerability of the active ingredient palazestrant in combination with ribociclib compared to letrozole in combination with ribociclib as the first systemic treatment for advanced breast cancer. The main objective (primary endpoint) is the time to disease progression (progression-free survival, PFS) during treatment. Another objective, among others, is to assess overall survival (OS). To this end, patients are randomly assigned to two parallel treatment groups. The study arm receives palazestrant and ribociclib, while the control arm receives letrozole and ribociclib. To ensure the comparison remains meaningful, each group also receives a placebo—a medication containing no active ingredient—that looks identical to the other medication. The active ingredients are all administered once daily as tablets, with ribociclib given during the first three weeks of a four-week treatment cycle. The study is triple-blind. This means that neither the patients nor the study physicians nor anyone else involved in the study knows which of the two treatments is being administered. The observation period for individual patients is up to approximately 3.5 years for the primary endpoint, and overall survival is tracked for up to approximately 5.5 years.

Eligible participants are patients aged 18 and older with hormone receptor-positive, HER2-negative, locally advanced, or metastatic breast cancer for which no curative treatment is available. For the advanced stage, no prior systemic cancer therapy may have been administered. A relapse (recurrence) following completion of supportive (adjuvant) anti-hormone therapy is permitted if it occurred more than twelve months afterward.