Post-CDK 4/6 Inhibitor Therapy: Current Agents and Novel Targets

SIMPLE SUMMARY: CDK4/6 inhibitors (CDK4/6i) with endocrine therapy are the established first-line treatment for metastatic and advanced hormone receptor-positive breast cancer (mBC). Recently, there has been an expansion in available next lines of therapy; however, optimal sequencing remains unclear. This paper reviews data on the efficacy and response rates of approved therapeutic options, and when possible, discusses their efficacy in the setting of prior exposure to CDK4/6i. This paper also seeks to review emerging targets and therapeutics that may be approved in the future for this patient population. ABSTRACT: Front-line therapy for advanced and metastatic hormone receptor positive (HR+), HER2 negative (HER−) advanced or metastatic breast cancer (mBC) is endocrine therapy with a CDK4/6 inhibitor (CDK4/6i). The introduction of CDK4/6i has dramatically improved progression-free survival and, in some cases, overall survival. The optimal sequencing of post-front-line therapy must be personalized to patients’ overall health and tumor biology. This paper reviews approved next lines of therapy for mBC and available data on efficacy post-progression on CDK4/6i. Given the success of endocrine front-line therapy, there has been an expansion in therapies under clinical investigation targeting the estrogen receptor in novel ways. There are also clinical trials ongoing attempting to overcome CDK4/6i resistance. This paper will review these drugs under investigation, review efficacy data when possible, and provide descriptions of the adverse events reported.