OBJECTIVES: To compare the efficacy of two treatments in mCRPC using alternative approaches to indirect treatment comparisons (ITCs). METHODS: The TROPIC and COU-AA-301 trials demonstrated that cabazitaxel+prednisone (CbzP) and abiraterone+prednisone (AbP) improve overall survival (OS) in patients with mCRPC vs. mitoxantrone+P (MP) or P alone, respectively. Examination of patient and disease characteristics noted differences in the exposure to docetaxel and discontinuation of docetaxel due to progressive disease. The current study: 1) conducted systematic literature reviews of second-line treatment studies; 2) reviewed NICE and IQWIG submissions; 3) reviewed the initial and updated OS data from the TROPIC and COU-AA-301 studies; 4) interviewed clinical experts; and 5) performed a meta-analysis of two first-line (1L) mCRPC studies to inform the ITC on the OS for the two treatments and connect the network. Three comparisons were performed using hazard ratios (HRs) for the MP vs. P: 1.0 (clinical expert opinion), 0.97 (1L studies meta-analysis), and 0.90 (survival curve extraction). The Bucher ITC was used with a HR (CbzP vs. AbP)<1 favoring CbzP.  RESULTS:  Results based on updated OS data were consistent across methodologies, with HR(OS, clinical)=0.97 (95%CI: 0.78-1.21), HR(OS, meta-analysis)=0.95 (95%CI: 0.69-1.30) and HR(OS, extraction)=0.88 (95%CI: 0.63-1.21), but all HRs were not significantly different. This was observed in the docetaxel-resistant subgroup as well; with HR(OS, clinical) =0.95 (95%CI: 0.70-1.28), HR(OS, meta-analysis) =0.92 (95%CI: 0.63-1.34) and HR(OS, extraction)=0.85 (95%CI: 0.59-1.24). These are different from the results presented in the IQWIG submission assuming that MP has the same effect as P alone based on initial OS data. CONCLUSIONS: Differences in results highlight the dependency of ITCs on efficacy assumptions. Lack of equivalence in disease, comparators or patient characteristics contribute to uncertainty regarding conclusions, which further emphasizes the fact that randomized prospective clinical trials are best suited to fully evaluate the efficacy and safety of cancer treatments.