Abstract Background: Randomized clinical trials and a growing body of real-world evidence have demonstrated clinical benefit of cyclin dependent kinase 4/6 inhibitors (CDK4/6i) in combination with endocrine therapy for HR+/HER2- (MBC). In the National Comprehensive Cancer Network (NCCN) guidelines, CDK4/6i + AI or Fulvestrant is recognized as a preferred regimen for HR+/HER2- MBC. Disparities in survival and clinical outcomes between AA and white breast cancer patients are well documented, but AA patients were not well represented in CDK4/6i randomized clinical trials. We compared real-world progression free survival (rwPFS) and overall survival (OS) of palbociclib plus AI (PB+AI) vs AI alone in AA patients with HR+/HER2- MBC in US clinical practices. Methods: The Flatiron Health longitudinal database contains electronic health records from >280 cancer clinics representing > 2.4 million actively treated cancer patients in the US. We conducted a retrospective analysis of 270 AA patients from the Flatiron database with HR+/HER2- MBC who started PB+AI or AI as first-line therapy between February 2015 and March 2020, Patients were evaluated from start of PB+AI or AI to September 30, 2020 (Data cutoff date), death, or last visit, whichever came first. OS was defined as months from start of PB+AI or AI to death. Patients were censored at the end of the study if they were living. rwPFS was defined as months from start of PB+AI or AI to death or disease progression, evaluated based on clinical assessment or radiographic scan/tissue biopsy. Cox proportional-hazards models were used to estimate the relative effectiveness of PB+AI vs AI without and with adjustment of baseline demographics and clinical characteristics. Results: Of the 270 eligible patients, 127 (47.0%) were treated with PB+AI and 143 (53.0%) were treated with AI. Median age was 64.0 years in PB+AI patients and 68.0 years in AI patients, respectively. Median follow-up was 24.0 months for PB+AI and 18.2 months for AI treated patients. Compared with AI patients, those treated with PB+AI were more likely to have de novo MBC (48.6% vs 30.8%) and to have ≥2 metastatic sites (41.7% vs 29.4%). Of the PB+AI patients, 82.7% started PB at 125mg/day and 30.7% experienced dose adjustment. Median OS was not reached (NR, 95%CI=(38.2-NR)) in PB+AI patients vs 28.2 months (95%CI=19.2-52.8) in AI patients (HR=0.46, 95%CI=0.31-0.68, p =< 0.001; adjusted HR=0.56, 95%CI=0.36-0.89, p=0.013). Median rwPFS was 18.0 months (95%CI = 12.4 – 26.7) in PB+AI patients and 10.5 months (95%CI=7.0-13.4) in AI patients (HR=0.63, 95%CI=0.44-0.88, p < 0.007; Adjusted HR=0.74, 95%CI=0.47-1.17, p =0.199). Conclusions: This comparative analysis of palbociclib plus AI vs AI alone provides evidence that first-line palbociclib in combination with endocrine is associated with improved effectiveness for AA patients with HR+/HER2- MBC in the real-world setting. Additonal studies with larger cohorts are needed to provide additional evidence of outcomes and safety for AA patients in routine clinical practice. Table. Patient characteristics and effectiveness outcomes Citation Format: Hope Rugo, Xianchen Liu, Benjamin Li, Lynn McRoy, Connie Chen, Rachel M. Layman, Adam M. Brufsky. Real-world effectiveness of palbociclib plus aromatase inhibitors (AI) in African American (AA) patients with metastatic breast cancer (MBC) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-01-15.