Gedatolisib as a new drug in combination with antihormonal therapy and CDK4/6 inhibitors as first-line treatment for advanced or metastatic hormone receptor-positive, HER2-negative breast cancer

Breast cancer (mammary carcinoma) is a malignant disease of the breast gland tissue characterized by the uncontrolled proliferation of breast gland cells. Treatment depends, among other factors, on the stage of the disease, the presence of hormone receptors (estrogen and progesterone receptors), and the HER2 status of the tumor cells. For hormone receptor-positive breast cancer, medications are used that inhibit the effect of the female sex hormone estrogen on the cancer cells or suppress its production. These include, among others, aromatase inhibitors (e.g., letrozole) or selective estrogen receptor degraders (SERDs, e.g., fulvestrant), which are administered as intramuscular injections. Anti-hormone therapy is often combined with a CDK4/6 inhibitor (e.g., palbociclib or ribociclib), as this combination is intended to increase the effectiveness of the treatment. In advanced or metastatic stages (Stage 4), when metastases are already detectable in the body, a cure is generally no longer possible. In these cases, the goal is to slow the progression of the disease for as long as possible. Gedatolisib is a novel drug that has not yet been approved and is administered as an intravenous infusion. It specifically inhibits certain proteins in the tumor cells—known as phosphoinositide-3-kinases (PI3K) and mTOR—that play a role in the growth of cancer cells. Changes (mutations) in the PIK3CA gene can cause tumor cells to grow more rapidly and respond less effectively to certain treatments.

The goal of this Phase 3 study is to investigate whether adding the new drug gedatolisib to standard therapy can more effectively delay disease progression. Patients will first be divided into two cohorts, depending on whether they are sensitive to therapy with the aromatase inhibitor letrozole or not. They will then be randomly assigned to one of two study arms within each cohort. In the study arm, patients receive gedatolisib and a CDK4/6 inhibitor in addition to letrozole or fulvestrant. In the control arm, the standard therapy consisting of letrozole or fulvestrant and a CDK4/6 inhibitor is administered. This is an open-label study (not blinded), meaning that both the patients and the study physicians know which treatment is being administered. The primary objective of the study is to investigate whether the additional administration of gedatolisib can prolong the time until disease progression (progression-free survival).

Eligible participants include women and men aged 18 and older who have not previously received systemic therapy for advanced breast cancer. Premenopausal women may also participate if they are willing to receive an additional LHRH agonist to suppress hormone production. Otherwise, patients must be healthy enough to undergo the therapy (e.g., good heart, liver, and kidney function).