Background: CDK4/6i and endocrine therapy (ET) are an international gold standard therapy in estrogen receptor (ER) positive and HER2-negative advanced breast cancer (aBC). Individual trials of abemaciclib, palbociclib and ribociclib show similar impact on progression-free survival yet differing statistical significance for OS. A robust comparative evaluation of the efficacy, safety, and tolerability of the three drugs is warranted. Methods: We searched PubMed, ASCO, ESMO and SABCS proceedings to identify phase 3 randomized clinical trials reporting OS of CDK4/6i in combination with ET in ER-positive aBC in first or second line. A network meta-analysis using WinBUGS was performed to evaluate comparative efficacy, based on the ET partner, in the absence of direct comparisons. Trial level data on common and serious adverse events (AE) were extracted for each drug. The odds ratio (OR) for each AE was calculated comparing each CDK4/6i to the respective endocrine therapy backbone (aromatase inhibitor (AI) or fulvestrant) alone. Results: Seven studies comprising 4087 patients met the inclusion criteria. Median follow up was 70.2 months. Four studies paired a CDK4/6i with an AI or tamoxifen, 3 studies were paired with fulvestrant. There were no statistically significant differences in OS between any of the CDK4/6i with any ET backbone. Compared to palbociclib, ribociclib and abemaciclib showed significantly lower grade 1-2 fatigue/asthenia (ribociclib OR 0.69 [95% CI 0.58, 0.83]; abemaciclib OR 0.6 [95% CI 0.49, 0.74]) and abemaciclib showed significantly lower grade 1-2 alopecia (abemaciclib 0.76 [95% CI 0.6, 0.97]). Compared to palbociclib, ribociclib and abemaciclib showed significantly higher GI toxicity (ribociclib any grade vomiting OR 1.71 [95% CI 1.36, 2.15]; abemaciclib any grade vomiting OR 2.1 [95% CI 1.61, 2.62], any grade diarrhea 13.2 [95% CI 10.31, 16.78]). Treatment discontinuation was highest with abemaciclib. Conclusions: In this network meta-analysis, there was no statistically significant difference in OS between CDK4/6i despite differences in individual trials. Real-world data analyses may help to identify if a there is a meaningful inter-drug difference in efficacy. Significant differences between CDK4/6i are observed for safety and tolerability outcomes.

HR (95% CI), p value.