OBJECTIVES: Prostate cancer is the second leading cause of cancer death in American men and has a high economic burden. Enzalutamide received FDA approval for an expanded indication based on significant improvement in overall survival and radiographic progression-free survival in chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC) patients. Our objective was to estimate the 1-year budget impact (BI) of adopting enzalutamide’s expanded indication. METHODS: Epidemiologic data, including SEER incidence rates, were used to estimate total number of chemotherapy-naïve mCRPC patients in a hypothetical 1-million member U.S. health plan. Treatment options included abiraterone acetate, sipuleucel-T, radium-223 dichloride, and docetaxel. Dosing, administration, mean duration of therapy and adverse event (AE) rates were based on package inserts and pivotal studies. Drug costs (including pre- and concomitant medications) were obtained from RedBook and CMS ASP pricing files, administration and monitoring from CMS Physician Fee Schedule, and AEs from AHRQ H-CUP and published literature. Drug utilization was estimated for each comparator before and after adoption of enzalutamide. Incremental aggregate budget, per patient per year (PPPY), per patient per month (PPPM), and per member per month (PMPM) impact were calculated. One-way sensitivity analyses were performed.  RESULTS: In an estimated population of 115 mCRPC patients, adopting the new enzalutamide indication had modest annual plan impact ($510,641 incremental aggregate BI, $4,426 PPPY, $368.83 PPPM and $0.04 PMPM). Enzalutamide acquisition cost was partially offset by moderate AEs and no additional monitoring costs. Results were most sensitive to enzalutamide drug cost, size of chemotherapy-naïve mCRPC patient population and enzalutamide adoption rate.  CONCLUSIONS: Results indicate a modest 1-year BI to adopt enzalutamide for chemotherapy-naïve mCRPC patients, partly due to the cost offset of moderate incidence of AEs and lack of additional required monitoring. Further analysis to understand cost per clinical outcome may complement the BI model to understand relative costs and benefits.