Management of Metastatic Hormone Receptor-Positive Breast Cancer Beyond CDK4/6 Inhibitors.

Purpose of review: Since the introduction of cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) in combination with endocrine therapy (ET) as the first-line treatment for metastatic hormone receptor (HR) positive, human epidermal growth factor receptor 2 (HER2) negative (HR+/HER2-) breast cancer, there has been a significant expansion in the number of therapeutic options for subsequent lines of therapy. Many new agents are being studied, with potential for future regulatory approval. The increased number of therapeutic options raises questions about the optimal selection and sequencing of therapies for individual patients. These advances represent an important clinical challenge in this rapidly evolving field, given the introduction of new therapies targeting various pathways (alone or in combination) and new therapeutic classes being studied.

Recent findings: Recently approved targeted therapies have demonstrated improvements in progression free survival (PFS) for patients whose cancer harbors mutations in the PI3K/AKT pathway, ESR1, BRCA1/2, and/or PALB2. Data to support continuation of CDK4/6 inhibition after progression on a prior CDK4/6i remains mixed, though some studies suggest a subset of patients may benefit from this approach. Several agents with unique mechanisms of action have shown promise in data from early phase trials, and have the potential to enter the treatment lexicon in the coming years. Examples include CDK2- and CDK4-selective inhibitors, complete estrogen receptor antagonists (CERANs), proteolysis targeting chimeras (PROTACs), and next-generation PI3K pathway inhibitors. In this narrative review, we summarize the current and upcoming treatments for metastatic HR+/HER2- breast cancer after progression on a CDK4/6i plus ET, with a focus on the following: an overview of first-line regimens of CDK4/6i plus ET and observed mechanisms of resistance; currently approved second-line therapy options; and upcoming options currently under exploration in clinical trials. We focus primarily on new therapy classes that may offer therapeutic options beyond currently available treatments.