OBJECTIVES: Abiraterone (ABI) and enzalutamide (ENZ) have been recently approved for the treatment of docetaxel (DOC)-naïve metastatic castration-resistant prostate cancer (mCRPC) but the cost-effectiveness associated with sequencing of these agents remains unclear. The objective of this study was to compare the efficacy and drug costs of different treatment sequences considering the loss of efficacy associated to subsequent treatments in mCRPC patients. METHODS: Median overall survival (OS) and costs were estimated for the following sequences: (A) ABI-DOC-CBZ; (B) ABI-DOC-ENZ; (C) ENZ-DOC-CBZ and (D) ENZ-DOC-ABI. OS and duration of treatment (DoT) estimates were based on data from clinical trials and adjusted according to literature review and expert clinical opinion, to account for potential efficacy loss after ABI or ENZ exposure as follows: DOC -10%; CBZ -10%; ENZ -40%; ABI -50%. The cost analysis included only drug costs and was undertaken from the perspective of the Spanish National Healthcare System. Incremental cost-effectiveness ratios (ICERs) were calculated in terms of cost per life year gained (LYG) for the following comparisons: A-vs-B and C-vs-D. Uncertainties around efficacy and DoT assumptions were explored in a sensitivity analysis. RESULTS: In the base case scenario, median OS estimates for patients treated with sequences A, B, C and D were 40.1, 37.5, 34.8 and 29.1 months, with respective costs of €68,967, €62,228, €60,766 and €50,952. The ICERs were €31,712/LYG for A vs B and €20,697/LYG for C vs D. When reduction rates were applied only to OS but were not considered their influence on DoT, treatment sequences containing third-line CBZ were dominant vs sequences containing ENZ or ABI.   CONCLUSIONS: Sequences containing third-line CBZ were more effective than sequences containing third-line ABI or ENZ. Third-line CBZ after ABI-DOC or after ENZ-DOC could be considered as cost-effective compared to third-line ABI or ENZ.