PROteolysis TArgeting Chimera (PROTAC) Estrogen Receptor Degraders for Treatment of Estrogen Receptor–Positive Advanced Breast Cancer

Abstract

The estrogen receptor (ER) signaling pathway is a key driver of breast cancer, primarily through the activation of genes that promote tumor cell survival and growth. The recommended first-line treatment for ER-positive (ER+)/human epidermal growth factor receptor 2–negative (HER2−) advanced or metastatic breast cancer is endocrine therapy plus a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor. However, most patients experience disease progression, and there is no clear standard of care in the second-line setting. Thus, novel treatments in the advanced setting are needed. In this narrative review, we describe the unique mechanisms of action of a new class of drugs called PROteolysis TArgeting Chimera (PROTAC) ER degraders. Unlike other ER-targeted therapies, these small molecules harness the body’s primary intracellular natural protein disposal machinery, the ubiquitin-proteasome system, to directly induce ER degradation. Vepdegestrant (ARV-471) is the furthest advanced PROTAC ER degrader currently in clinical development. Preclinical data demonstrate increased tumor growth inhibition with vepdegestrant alone or in combination with CDK4/6 inhibitors compared with the selective ER degrader fulvestrant. In a first-in-human phase 1/2 clinical study, vepdegestrant administered orally as monotherapy or in combination with palbociclib showed promising clinical activity and a favorable safety profile in patients with heavily pretreated ER+/HER2− advanced breast cancer. Several other PROTAC ER degraders (AC699, ERD-3111, ERD-4001, and HP568) are in early development and have demonstrated activity in preclinical breast cancer models, with some recently entering clinical trials. The data highlight the potential for PROTAC ER degraders to be a new backbone therapy in breast cancer. The most common subtype of breast cancer, estrogen receptor (ER)-positive (ER+)/human epidermal growth factor receptor 2–negative (HER2−), grows in response to the hormone estrogen. The primary treatment for ER+/HER2− advanced breast cancer is typically hormone therapy, also known as endocrine therapy, combined with medications called cyclin-dependent kinase 4/6 (CDK4/6) inhibitors. Hormone therapies block the body’s ability to produce estrogen or block estrogen activity in cancer cells, which may slow or stop cancer growth. CDK4/6 inhibitors block the CDK4 and CDK6 proteins that cause cancer cell growth. However, most cancers eventually stop responding to treatment and start to grow again; therefore, new therapies are needed. This review describes how new medicines called PROteolysis TArgeting Chimera (PROTAC) ER degraders work. These degraders directly eliminate ER, blocking estrogen activity and potentially shrinking or stopping ER+ breast cancer tumors from growing. The furthest advanced PROTAC ER degrader in development is called vepdegestrant. In animal studies, vepdegestrant, either alone or combined with CDK4/6 inhibitors, was better at stopping tumor growth than a selective estrogen degrader called fulvestrant. In a clinical trial involving people with advanced breast cancer who had already received several treatments, vepdegestrant taken as pills by mouth either alone or with a CDK4/6 inhibitor called palbociclib showed promising results with manageable side effects. Animal studies investigating several other PROTAC ER degraders in early-stage development also indicate potential for these therapies. Overall, PROTAC ER degraders may become an important part of breast cancer treatment in the future.

Topics & Concepts