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The phase III MONALEESA trials tested the efficacy and safety of the cyclin-dependent kinase (CDK)4/6 inhibitor ribociclib with different endocrine therapy partners as first- or second-line treatment of hormone receptor–positive/human epidermal growth factor receptor 2–negative advanced breast cancer (ABC). Using the largest pooled biomarker dataset of the CDK4/6 inhibitor ribociclib in ABC to date, we identified potential biomarkers of response to ribociclib. Baseline circulating tumour DNA from patients in the MONALEESA trials was assessed using next-generation sequencing. An analysis of correlation between gene alteration status and progression-free survival (PFS) was carried out to identify potential biomarkers of response to ribociclib. Multiple frequently altered genes were identified. Alterations in ERBB2 , FAT3 , FRS2 , MDM2 , SFRP1 , and ZNF217 were associated with a greater PFS benefit with ribociclib versus placebo. Patients with high tumour mutational burden (TMB) and with ANO1 , CDKN2A/2B/2C , and RB1 alterations exhibited decreased sensitivity to ribociclib versus placebo. Although exploratory, these results provide insight into alterations associated with the improved response to ribociclib treatment and may inform treatment sequencing in patients with actionable alterations following progression on CDK4/6 inhibitors. Validation of potential biomarkers identified here and development of prospective trials testing their clinical utility are warranted. NCT01958021, NCT02422615, NCT02278120. • We report an exploratory analysis of the association of gene alteration status and PFS across MONALEESA-2, -3, and -7. • This analysis used the largest pooled biomarker dataset of the CDK4/6 inhibitor ribociclib in ABC to date. • ERBB2 , FAT3 , FRS2 , MDM2 , SFRP1 , and ZNF217 alterations were associated with increased sensitivity to ribociclib. • ANO1 , CDKN2A/2B/2C , and RB1 alterations and high TMB were associated with decreased sensitivity to ribociclib. [ABSTRACT FROM AUTHOR]