Evaluation of a Triple-Combination Therapy for Hormone-Receptor-Positive, Locally Advanced, or Metastatic 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 of the disease depends on numerous factors, such as the patient’s overall health, the stage (extent) of the disease, the tumor’s growth rate (Ki-67 index), the presence of detectable hormone receptors on the surface of the cancer cells (estrogen receptor-positive, progesterone receptor-positive), and the increased presence of HER2 receptors on the cells (HER2-positive). In a locally advanced stage (Stage 3) or when breast cancer has already spread to other parts of the body (metastases, Stage 4), the disease is often no longer curable. In such cases, the goal is to “keep the disease at bay” for as long as possible.

Hormone receptor-positive breast cancer is treated with anti-hormone therapy, for which medications from various classes may be used. Aromatase inhibitors (e.g., letrozole) or drugs that degrade the estrogen receptor (SERDs, e.g., fulvestrant) or modulate it (SERMs, e.g., tamoxifen). In addition, this anti-hormone therapy can be combined with CDK4/6 inhibitors (e.g., abemaciclib), as studies have shown that this combination can increase the effectiveness of anti-hormone therapy. Capivasertib is a recently approved drug with a novel mechanism of action that blocks specific enzymes in tumor cells, causing them to die. A triple combination of these different mechanisms of action has not yet been approved.

The goal of the CAPItello-292 study is to test this combination therapy. Since the optimal dose for the combination is not yet known, the study consists of two phases. First, the optimal dose will be tested for tolerability and efficacy; then, in a second phase, the determined dose will be tested in two study arms. One group will receive capivasertib, fulvestrant (anti-hormonal therapy), and one of several CDK4/6 inhibitors, as determined by the treating physician at the study site. The other group will not receive capivasertib. The first phase of the study lasts one month; the second phase lasts up to 4 years, depending on the response to treatment and any potential side effects; the total follow-up period is approximately 69 months. Participants are randomly assigned to one of the two study arms.

Women and men aged 18 and older with hormone receptor-positive, HER2-negative breast cancer at the locally advanced (Stage 3) or metastatic (Stage 4) stage are eligible to participate in the study. Patients must have previously received anti-hormone therapy that resulted in disease progression. However, they must not have been treated with an AKT inhibitor, and in cases of metastatic disease, they must not have received treatment with a CDK4/6 inhibitor or more than one course of chemotherapy. In addition to other exclusion criteria, patients with brain metastases are not eligible for inclusion in the study.