Background: Abiraterone and enzalutamide are increasingly being used to treat advanced prostate cancer. Understanding barriers to adhering to treatment is of paramount importance in ensuring continued access to these important therapies. Patients with limited resources or insufficient access to mechanisms that lower their out-of-pocket cost are likely to suffer from significant financial toxicity and may engage in coping mechanisms such as rationing or abandoning their medication. Methods: To address the variability in measures of financial hardship, we performed a retrospective cohort study on a 20% sample of patients eligible for Medicare Part D who received their first fill of abiraterone or enzalutamide between July 2013 and June 2015. Patients were assigned to a provider based on their first prescription, and a hospital referral region (HRR) based on their ZIP code. The primary outcomes were to determine the proportion of days covered (PDC), overall prescription adherence, and average monthly out-of-pocket cost to patients prescribed abiraterone or enzalutamide, all within the first six months of treatment. Results: From mid-2013 to mid-2015, 4529 patients filled abiraterone or enzalutamide through Medicare Part D, within 305 HRRs. There was substantial variability in PDC, adherence, and out-of-pocket cost to patients among HRRs. The mean PDC was 84% with mean adherence of 73%, which included the 393 (8.7%) of patients who abandoned oral therapy after 1-2 fills. The median standard monthly out-of-pocket cost was $707, ranging between $0 and $3505. Among patients with low-income subsidies, median out-of-pocket cost by HRR ranged from $0 to $2815. We observed that PDC tracked closely with socioeconomic status – HRRs that included a higher proportion of patients eligible for Medicaid had lower PDCs and adherence, but lower standard out-of-pocket cost. Conclusions: This investigation demonstrated significant variation in PDC, adherence, and out-of-pocket cost among different HRRs for patients prescribed abiraterone and enzalutamide and that much of the variability in financial hardship measures among HRRs may be due to socioeconomic variables and regional variability.