Background: The treatment paradigm for advanced HR+/HER2- breast cancer has been rapidly evolving since the approval of the first CDK4/6 inhibitor in the U.S. in 2015. Available literature on real-world utilization of various treatment options available to these patients remains limited. The objective of this study was to describe how advanced HR+/HER2- breast cancer treatment patterns have changed over time since the approval of novel CDK4/6 inhibitors. Methods: IBM MarketScan Research Databases, a nationally representative source of U.S. insurance claims data, was used to identify women diagnosed with advanced breast cancer between January 2015 and December 2019 via ICD-9/10 codes. Algorithms were applied to capture patients with HR+/HER2- subtype and advanced disease diagnosis. Patients were indexed on their advanced breast cancer diagnosis date and were required to have six months continuous enrollment in the insurance claims database prior to and after the index date to ensure patients included in the cohort were alive and contributed at least 12 months of data for analysis. Lines of therapy (LOTs) were constructed and treatment patterns were reported over time. Descriptive analyses were conducted using Instant Health Data software. Results: A total of 4,128 women (mean age: 58 years, IQR: 50-64 years) had received at least one systemic breast cancer treatment and were included in the analysis. During a mean follow-up time of two years, nearly 29% of patients received at least four LOTs for advanced disease. A high number of unique regimens were reported in each LOT (30 in 1L, 48 in 2L, 53 in 3L and 50 in 4L+). The distribution of the top 1L regimens changed significantly over time (Table). CDK4/6 inhibitor use in the 2L setting also increased substantially from 43% in 2015 to 68% in early 2019, while chemotherapy and endocrine monotherapy utilization decreased. Conclusions: These data reflect a significant shift in the treatment landscape for HR+/HER2- advanced breast cancer patients in real-world practice since the availability of CDK4/6 inhibitors. However, there remains significant heterogeneity in the use of other treatments in these patients and in treatment sequencing, suggesting potential unmet need with current therapies. Further insight into patient, clinical and community-level factors guiding treatment decisions in the real world is needed.