AIM: CDK4/6 inhibitors in the first and second treatment line in patients with HR+/HER2- metastatic breast cancer (mBC) in combination with hormonal therapy improve progression-free survival. Role of CDK4/6 inhibitors in further treatment lines remains unclear. METHODS: Retrospective analysis of 24 HR+/HER2- heavily pretreated mBC patients is presented. RESULTS: A total of 58.3% patients achieved stable disease. No objective response was observed. Median progression-free survival was 4.8 months; median overall survival was 11 months. Treatment was well tolerated. CONCLUSION: Favorable toxicity profile and efficacy of palbociclib/aromatase inhibitors combination in heavily pretreated luminal mBC patients in this study emphasize the need for further investigation of such drugs in this population.