OBJECTIVES: Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors palbociclib, ribociclib, and abemaciclib are widely used for the first-line treatment of locally advanced or metastatic breast cancer (mBC). Direct comparisons of these treatments in randomized controlled trials (RCTs) are lacking. The aim of the study is to gather and analyze published data on the comparative effectiveness of CDK4/6 inhibitors in combination with aromatase inhibitors (AI) in postmenopausal patients with HR+/HER2– mBC.

METHODS: A systematic review of publications on original studies examining the impact of CDK4/6 inhibitor + AI on the survival of patients with HR+ HER2– mBC was performed.

RESULTS: Nineteen studies with data on progression-free survival (PFS) and overall survival (OS) were identified. These included 7 real-world evidence (RWE) studies, 1 naïve comparison, 2 matching-adjusted indirect comparisons (MAIC), and 9 meta-analyses. The hazard ratio (HR) range for PFS was 0.97-1.25 (palbociclib vs. ribociclib), 0.53-1.27 (palbociclib vs. abemaciclib), and 0.56-1.10 (ribociclib vs. abemaciclib). None of the studies established statistically significant differences in PFS between the different CDK4/6 inhibitors. The HR range for OS was 1.06-1.47 (palbociclib vs. ribociclib), 1.08-1.23 (palbociclib vs. abemaciclib), and 1.01-1.06 (ribociclib vs. abemaciclib). A statistically significant superiority of ribociclib over palbociclib in terms of OS was observed in a single MAIC, while seven other studies of various types did not find significant differences between the investigated drugs in terms of this efficacy endpoint. The MAIC methodology remains controversial due to potential hidden differences between studies, especially in early relapse frequency in the underlying RCTs and patient management after treatment failure.

CONCLUSIONS: There is no compelling evidence of the superiority of one CDK4/6 inhibitor over others. A preference for a specific drug within the class can only be made after conducting direct RCTs or accumulating sufficient RWE on the use of such drugs.