A new combination therapy using two drugs not yet approved (saruparib and camizestrant) for locally advanced or metastatic breast cancer with a confirmed BRCA1, BRCA2, or PALB2 gene alteration (mutation)

Breast cancer (mammary carcinoma) is a malignant disease of the breast gland tissue characterized by uncontrolled cell proliferation. Treatment depends on various factors, including the patient’s overall health, the tumor stage, the tumor’s growth rate (Ki-67 index), and the expression of hormone receptors (estrogen and progesterone receptors) or the HER2 protein on the cell surface. In a locally advanced stage (Stage 3B) or when metastases are already present (Stage 4), the disease is often no longer curable. In such cases, the goal is to delay the progression of the disease for as long as possible. Genetic factors can influence the risk of breast cancer. Mutations in the BRCA1, BRCA2, and PALB2 genes increase the lifetime risk of developing breast or ovarian cancer.

Hormone receptor-positive breast cancer is treated with anti-hormone therapy. Various classes of drugs are used, including aromatase inhibitors (e.g., letrozole) or medications that break down the estrogen receptor (SERD, e.g., fulvestrant) or modify it (SERM, e.g., tamoxifen). This therapy is often combined with CDK4/6 inhibitors (e.g., abemaciclib), as this combination enhances the effectiveness of anti-hormone therapy. Another class of drugs consists of poly-ADP-ribose polymerase 1 (PARP1) inhibitors. PARP1 is an enzyme that plays a central role in repairing DNA damage in cells. Inhibiting PARP1 blocks the repair of DNA damage in cancer cells, which can lead to their death—particularly in tumors with BRCA1, BRCA2, or PALB2 mutations. Saruparib belongs to the group of PARP inhibitors and is currently still in the approval phase. Other members of this class of drugs are already approved for the treatment of BRCA1/2-mutated breast cancer, though usually only after prior therapy. Camizestrant is a selective estrogen receptor degrader (SERD) and has not yet been approved. Unlike fulvestrant, it can be taken as a tablet and may be effective against cancer cell resistance mechanisms.

The goal of the EvoPAR-BR01 study is to investigate whether first-line therapy with saruparib in combination with camizestrant offers advantages over standard therapy. Standard therapy consists of a CDK4/6 inhibitor (selected at the clinician’s discretion) in combination with anti-hormonal therapy (selected at the clinician’s discretion). A third study arm is evaluating the combination of camizestrant and a CDK4/6 inhibitor. Participants are randomly assigned in a 2:2:1 ratio. Treatment lasts for approximately five years, with follow-up lasting about 7.5 years.

Women and men aged 18 and older with hormone receptor-positive, HER2-negative breast cancer at the locally advanced (Stage 3B) or metastatic (Stage 4) stage who have mutations in the BRCA1, BRCA2, or PALB2 and for whom curative treatment is no longer an option. Patients must be in good physical condition (ECOG 0 or 1). Certain pre-existing conditions, such as heart disease, may exclude participation. Brain metastases are not permitted. The disease must not have been treated previously, with the exception of anti-hormone therapy, which, however, must not have begun more than 28 days prior to randomization.