A study comparing combination therapy with lasofoxifene and abemaciclib to standard treatment in patients with hormone receptor-positive breast cancer and acquired resistance due to an ESR1 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, including the stage of the disease. There are a total of four stages that describe how extensive the tumor is and whether certain risk factors are present. As a standard practice, an initial course of chemotherapy (neoadjuvant) is administered before surgery to remove the breast or, if necessary, the lymph nodes. Depending on the risk factors, further treatment (adjuvant) is then administered. In a locally advanced stage (Stage 3B) or if breast cancer has already spread to other parts of the body (metastases), the disease is often no longer curable. In such cases, the goal is to “keep the disease in check” for as long as possible.

A particularly important factor for treatment is whether the cancer cells express elevated levels of hormone receptors (estrogen receptor-positive, progesterone receptor-positive) or the HER2 protein. Hormone receptor-positive breast cancer is treated with anti-hormone therapy, for which various classes of medications are available. These include aromatase inhibitors (e.g., letrozole), drugs that break down the estrogen receptor (SERD, e.g., fulvestrant), or modulate it (SERM, e.g., tamoxifen). In addition, this hormone therapy can be combined with CDK4/6 inhibitors (e.g., abemaciclib), as this combination can increase the effectiveness of anti-hormone therapy. As the disease progresses, a change in the estrogen receptor may develop (ESR1 mutation). In rare cases, this mutation may already be present at the onset of the disease. In such cases, standard anti-hormone therapy is often less effective. The drug lasofoxifene belongs to the SERM class. It is already approved but has not yet been adopted as standard therapy. However, there is evidence that lasofoxifene may be more effective than fulvestrant—another standard anti-hormonal therapy—in cases of an ESR1 mutation.

The goal of the ELAINEIII study is to investigate lasofoxifene in combination with abemaciclib compared to standard therapy with fulvestrant in patients with a known ESR1 mutation. The study will assess whether this new combination is more effective than standard therapy. Assignment to the two study groups is random. Both the medical staff and the patient know which medication is being taken. Treatment and follow-up are scheduled to last for approximately three years.

Women and men aged 18 and older with hormone receptor-positive (estrogen receptor-positive), HER2-negative breast cancer at the locally advanced (Stage 3B) or metastatic (Stage 4) whose breast cancer has progressed during their initial treatment with anti-hormone therapy using an aromatase inhibitor in combination with either palbociclib or ribociclib. This progression must be due to a genetic mutation in the estrogen receptor 1 (ESR1). Patients whose cancer has progressed while on fulvestrant or abemaciclib are not eligible for the study. Whether patients are premenopausal or postmenopausal is not an inclusion or exclusion criterion. Patients may have previously undergone chemotherapy; however, they must not have any ongoing symptoms resulting from the prior treatment and should generally be in good physical condition. Brain metastases are not a general exclusion criterion but may lead to exclusion under certain circumstances (e.g., active, untreated).