Effect of the PIK3 inhibitor inavolisib, added to anti-hormone therapy and HER2 inhibitors, on the treatment of HER2- and hormone receptor-positive breast cancer when breast cancer cells have a PIK3CA mutation

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 of the disease, the presence of detectable hormone receptors on the surface of the cancer cells (estrogen receptor-positive, progesterone receptor-positive), and the increased expression of the HER2 receptor on the cells (HER2-positive). If hormone receptors are present on the surface of the cancer cells, the tumor responds to the hormones estrogen and/or progesterone by growing. In these cases, anti-hormone therapy may be administered. HER2 expression is another common characteristic of breast cancer cells; when present in higher amounts, it also promotes cell growth. In many treatment strategies, it serves as a targeted point of attack for inhibiting tumor growth. In this study, dual inhibition is achieved using a fixed-dose combination of two drugs that target the HER2 receptor (pertuzumab and trastuzumab).

In up to 30% of patients with breast cancer, the cancer cells carry a PIK3CA mutation. A major problem here is that standard chemotherapy and anti-hormone therapy are less effective in these cases. The study drug, inavolisib, is a so-called PI3K inhibitor that specifically blocks the signaling pathway activated by the mutation. This is intended to restore the effectiveness of the other therapies.

The goal of the GeparPiPPA study is to investigate whether adding Inavolisib to standard anti-hormone therapy and HER2 blockade can lead to a better response to treatment. This is a Phase 2 study in which patients are randomly assigned to two groups: one group receives inavolisib daily in addition to their standard therapy, while the other does not. All participants are aware of their assignment (open-label). Standard therapy consists of HER2 inhibitors and anti-hormone therapy. Patients receive a fixed combination of pertuzumab and trastuzumab (PH-FDC SC) as a HER2 inhibitor, administered via subcutaneous injection every three weeks. For antihormonal therapy, either tamoxifen or an aromatase inhibitor plus a GnRH analog is used, depending on the treating physician’s choice.

Treatment lasts 18 weeks, followed by surgery or a biopsy. Three weeks after the end of treatment, the rate of patients who are completely disease-free (= complete remission) is assessed using a tissue sample or as part of the standard follow-up breast surgery. Eligible participants include women and men aged 18 and older with untreated early-stage HER2-positive, hormone receptor-positive breast cancer. The disease must also have a PIK3CA mutation, and the tumor must be at least 1 cm in size.