Post-CDK4/6 inhibitor treatment landscape in metastatic hormone receptor-positive breast cancer: a narrative review.

[INTRODUCTION] Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) combined with endocrine therapy have markedly improved clinical outcomes and are the preferred first-line treatment for metastatic hormone receptor - positive breast cancer. However, acquired resistance is almost universal, leading to a critical need for effective strategies in the post-CDK4/6i setting.

[AREAS COVERED] This review summarizes therapeutic approaches investigated after progression on CDK4/6i plus endocrine therapy. Key therapeutic approaches in this setting focus on overcoming resistance by inhibiting pathways such as PI3K/AKT/mTOR, altering treatment class through switching CDK4/6 inhibitors or endocrine therapy agents, and incorporating selective estrogen receptor degraders (SERDs). In addition, several novel strategies are under investigation, including targeting CDK7, utilizing antibody - drug conjugates, and exploiting DNA repair vulnerabilities with poly (ADP-ribose) polymerase (PARP) inhibitors. We conducted a literature search in PubMed/MEDLINE, Embase, and Scopus for studies published between January 2018 and June 2025 to identify evidence on efficacy, safety, and patient selection in this setting.

[EXPERT OPINION] Therapeutic development for post-CDK4/6i metastatic HR+ breast cancer is evolving rapidly. Identifying molecular drivers of resistance and matching patients to targeted therapies will be essential to optimize outcomes. Continued efforts toward biomarker-based treatment selection and rational sequencing strategies are expected to refine post-CDK4/6i management.