Overcoming resistance to endocrine therapy in hormone receptor-positive human epidermal growth factor receptor 2-negative (HR⁺/HER2⁻) advanced breast cancer: a meta-analysis and systemic review of randomized clinical trials

New targeted therapies have been developed to overcome resistance to endocrine therapy (ET) and improve the outcome of HR⁺/HER2⁻ advanced breast cancer (ABC). We conducted a meta-analysis and systemic review on randomized controlled trials evaluating various targeted therapies in combination with ET in HR⁺/HER2⁻ ABC. PUBMED and EMBASE databases were searched for eligible trials. Hazard ratios (HRs) for progression-free survival (PFS), odds ratios (ORs) for objective response rate (ORR), clinical benefit rate (CBR), and toxicity were meta-analyzed. Twenty-six studies with data on 10 347 patients were included and pooled. The addition of cyclin-dependent kinase 4/6 inhibitors to ET significantly improved median PFS (pooled HR = 0.547, P < 0.001), overall survival (pooled HR= 0.755, P < 0.001), and tumor response rates (ORR, pooled OR= 1.478, P < 0.001; CBR, pooled OR= 1.201, P < 0.001) with manageable toxicities (pooled OR= 3.280, P < 0.001). The mammalian targets of rapamycin inhibitors and exemestane were not clinically beneficial for this pooled population including ET-naïve and ET-resistant patients. Moderate improvement in PFS (pooled HR = 0.686, P < 0.001) yet pronounced toxicities (pooled OR = 2.154, P < 0.001) were noted in the combination of phosphatidylinositol-4,5-bisphosphate 3-kinase inhibitors with fulvestrant. Future studies are warranted to optimize the population and the dosing sequence of these available options.