Background: Prostate cancer (PC) is the most common male cancer in the United States and the second leading cause of cancer-related death. Our group previously reported that men from Appalachian Kentucky had worse survival outcomes compared to non-Appalachian Kentucky and general population. This survival difference could be mainly due to socio-economic disparities. However, several new treatments have been approved for metastatic PC (mPC) in the last decade and these current standard of care (SOC) therapies have significantly improved survival outcomes in mPC. Therefore, we aim to investigate whether the recent change in SOC treatments have improved overall survival (OS) in patients with Appalachian (App) Kentucky vs. Non-Appalachian (Non-App) Kentucky from 2004–2019. Methods: All male patients who were > 20 years old with primary diagnoses of prostate adenocarcinoma, listed in Kentucky cancer Registry (KCR), diagnosed between 2004 and 2019, were included in the study. Basic demographics and survival outcomes were compared for all stages of PC and between App and Non-App Kentucky. We also compared the survival difference between two time periods 2004- 2011 vs. 2012-2019. Kaplan Meir and multivariate Cox Regression were performed to compare patients’ overall survival (OS). Results: A total of 36,695 patients were included in this retrospective analysis, of which 74.3% were Non-App and 15.7% were App. Caucasians predominated in both groups (N-App 85% vs. App 97%). The majority of Kentucky patients were aged between 50-74 years (79%). App Kentucky was noted to have more poorly differentiated histology (44.4% vs 40.1%), high Gleason score (26.4% vs 20%), more distant disease at the time of diagnosis (8.3 vs 6.7%), and higher percentage of patients with smoking history (40.1% vs 34.9%) compared to Non-App, respectively. A higher proportion of Non-App Kentucky had private insurance (35%) at the time of cancer diagnosis compared to more patients enrolled in Medicare (56.6%) or Medicaid (4.7%) in App. There was a survival difference between App and Non-App Kentucky by univariate analysis (p<0.001). In multivariate Cox regression showed that Non-App patients had better OS (p<0.001; HR=0.92, 95%CI 0.87-0.96). Patients diagnosed in the years 2012- 2019 had better survival compared to patients in 2004 – 2011 group (p=0.01; HR=0.94, 95%CI 0.9-0.99). Other factors that contributed to better survival include younger age, lived in the metro area, had private insurance, being a nonsmoker, being lower stage, and receiving treatment. We got similar result for stage IV patients, but the App variable was not significant in the COX regression (p=0.2). Conclusions: Our study shows that Appalachian has worse outcomes compared than Non-Appalachian Kentucky based on population-based analysis from 2004-2019. Additional research is needed to understand the health care disparities in App Kentucky.