CDK4/6 inhibitors, PI3K/mTOR inhibitors, and HDAC inhibitors as second-line treatments for hormone receptor-positive, HER2-negative advanced breast cancer: a network meta-analysis

Background: This study sought to compare the benefits and safety of agents including Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors, phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitors, and histone deacetylase (HDAC) inhibitors as second-line treatments for these patients by conducting a comprehensive systematic review and network meta-analysis. Methods: The Medline, Embase and Cochrane Library databases were searched for randomized trials comparing CDK4/6 inhibitors, PI3K/mTOR inhibitors, or HDAC inhibitors vs. placebo with the addition of exemestane or fulvestrant as second-line treatments in patients with HR + advanced breast cancer up to December 16, 2021. Outcomes of interest were progression-free survival (PFS), overall response rate (ORR), overall survival (OS), clinical benefit rate (CBR), and grade 3–4 adverse drug events (ADEs). The present study was conducted according to the Cochrane Collaboration and PRISMA statements. The overall effect was pooled using the random effects model. Results: Seventeen studies with a total of 9,100 participants were included in the current study. Compared with placebo plus fulvestrant, PFS was significantly improved by CDK4/6 inhibitor plus fulvestrant, mTOR inhibitor plus fulvestrant, mTOR inhibitor plus exemestane, and PI3K inhibitor plus fulvestrant, but not HDAC inhibitor plus exemestane. While mTOR inhibitor plus exemestane was the best regimen (SUCRA value 89.5%), the mTOR inhibitor plus exemestane regimen induced more severe adverse events (SAEs) than the HDAC inhibitor plus exemestane regimen [OR, 95% CI: 2.40 (1.40–4.10)]. Conclusion: mTOR inhibitor and CDK4/6 inhibitor-based regimens demonstrated superior clinical efficacy and comparable safety profiles as second-line treatment in patients with HR-positive, HER2-negative advanced breast cancer.