OBJECTIVES: A key challenge for successful introduction of new drugs in metastatic breast cancer (MBC) is a positive health technology assessment (HTA) outcome across Europe. Thus, understanding of the MBC HTA landscape is essential. This study aims to identify key decision drivers and challenges for HTA in MBC. METHODS: An in-depth analysis of published HTA submissions in MBC over the last 5 years was conducted. In total, 96 HTA reports in MBC from 9 agencies were identified. Based on submission type and approval status, 38 HTA assessments for 8 drugs were selected for further analysis. The analysis focussed on the submitted data and valuation by the different agencies. Outcomes were validated in an HTA expert meeting. RESULTS: Of 38 HTA assessments, 11 received a negative recommendation, 8 a positive recommendation, and 13 a positive recommendation with restrictions. The remaining 6 assessments were ongoing/did not provide a recommendation as yet. The majority of submissions included RCTs with PFS as primary endpoint and OS as secondary endpoint. HRQoL was not provided in 13/38 cases, with criticism in 8/38 cases. Some criticism was expressed regarding the logistics of HRQoL collection. The weight assigned to significance and incremental PFS and OS differed between countries. Twenty-eight of 38 submissions included a PE evaluation. The key uncertainties in economic modelling related to validation of OS and PFS modelling (9/28) and the incorporation of safety data (11/28). Unfavourable ICERs and uncertainty in economic modelling were key drivers for negative decisions. CONCLUSIONS: Gaining favourable HTA recommendation for new MBC drugs is challenging. In order to improve probability of successful introduction of a new MBC drug, demonstrating significant and clinically meaningful incremental OS and/or PFS is key, as is providing strong HRQoL data. Moreover, well-validated PE model and acceptable ICERs are important to gain favourable HTA opinion.