New drug combinations with elacestrant for advanced hormone receptor-positive, HER2-negative breast cancer

Breast cancer (mammary carcinoma) is a malignant disease of the breast tissue characterized by the uncontrolled proliferation of breast cells. Treatment of the disease depends on numerous factors, such as the patient’s overall health, the stage 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).

The standard treatment for hormone receptor-positive, HER2-negative breast cancer outside of clinical trials is typically hormone therapy (aromatase inhibitors or fulvestrant) plus a CDK4/6 inhibitor. CDK4/6 inhibitors stop cancer cells from dividing by blocking the cell cycle. Some breast cancer tumors also have specific genetic changes (mutations). In these cases, targeted therapies may be used. For example, in the case of a so-called PIK3CA mutation, drugs from the PI3K inhibitor class can slow cancer growth. The mTOR inhibitor everolimus targets a different signaling pathway in the tumor cell, which often becomes active when resistance to anti-hormone therapies develops. The AKT inhibitor capivasertib targets another signaling protein that tumors use to continue growing despite treatment. Elacestrant is a modern, tablet-based anti-hormone therapy that blocks and breaks down the estrogen receptor. The study drug is approved in Germany as monotherapy for postmenopausal women and for men with estrogen receptor-positive, HER2-negative, locally advanced or metastatic breast cancer with an activating ESR1 mutation, if the disease continues to progress after prior therapy.

The goal of this Phase 1b/2 study is to evaluate the optimal dosage, as well as the safety and efficacy, of elacestrant in combination with other targeted therapies: PI3K inhibitors (alpelisib) for PIK3CA mutations, mTOR inhibitors (everolimus), CDK4/6 inhibitors (palbociclib, ribociclib, or abemaciclib), and the AKT inhibitor capivasertib. Premenopausal women and men will receive concomitant hormone suppression (LHRH agonist). The study design is open-label (no blinding, meaning doctors and patients know which drug combination is being administered), with multiple parallel arms (a so-called “umbrella” study). Phase 1b evaluates the recommended dose (safety assessment during the first 28-day cycle). Phase 2 evaluates the efficacy and safety of the combinations. A total of approximately 435 participants are planned.

Eligible participants include women and men aged 18 and older with hormone receptor-positive, HER2-negative breast cancer. The disease must have progressed during or after 1–2 prior anti-hormone therapies (often in combination with CDK4/6 inhibitors). Additional criteria apply to individual arms (e.g., PIK3CA mutation for alpelisib, PIK3CA/AKT1/PTEN alteration for capivasertib; for some arms, prior CDK4/6 therapies are permitted). Patients with active or newly diagnosed brain metastases, those receiving chemotherapy for metastatic disease, or those who have been previously treated with elacestrant or other new estrogen receptor-targeted study drugs are ineligible to participate.