e13047 Background: Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors improve outcomes in metastatic hormone receptor-positive, human epidermal growth factor receptor 2– negative (HR+/HER2–) breast cancer (MBC), but their benefit in early-stage disease and the efficacy-toxicity balance remain uncertain. We conducted a meta-analysis of phase III trials comparing CDK4/6 inhibitors plus endocrine therapy (ET) versus ET alone. Methods: MEDLINE, Embase, and Web of Science were searched through October 1, 2025. Phase III randomized trials comparing CDK4/6 inhibitors plus ET versus ET alone were included. Two reviewers independently extracted data and assessed risk of bias using the Cochrane Risk of Bias 2.0 tool. Random-effects models with Hartung–Knapp adjustment pooled hazard ratios (HRs) for time-to-event outcomes and risk ratios (RRs) for dichotomous outcomes. Statistical heterogeneity was assessed using the I 2 statistic, with values > 50% reported in the results. Primary outcomes were overall survival (OS) and progression-free survival (PFS); secondary outcomes included invasive disease-free survival (iDFS), distant relapse-free survival (DRFS), objective response rate (ORR), clinical benefit rate (CBR), disease control rate (DCR), treatment discontinuation (TDR), dose reduction (DRR), and grade 3–4 adverse events. The study followed PRISMA 2020 guidelines (PROSPERO: CRD420251132302). Results: Twenty-two trials were included (18 MBC, n = 6,364; 4 EBC, n = 17,741; outcomes reported variably). In MBC, CDK4/6 inhibitors improved OS (HR 0.78, 95% CI 0.72–0.85; p < 0.001) and PFS (HR 0.53, 95% CI 0.50–0.56; p < 0.001), with consistent OS benefit in ET-naive (HR 0.80, 95% CI 0.71–0.89; p < 0.001) and previously ET-treated patients (HR 0.75, 95% CI 0.61–0.93; p = 0.009). ORR (RR 2.07, 95% CI 1.26–3.40; p = 0.004; I 2 = 92.5%), CBR (RR 1.25, 95% CI 1.18–1.32; p < 0.001; I 2 = 72.9%), and DCR (RR 1.09, 95% CI 1.04–1.15; p = 0.001; I 2 = 57.1%) were increased. TDR and DRR were increased (RR 2.39, 95% CI 1.54–3.70; and RR 9.51, 95% CI 6.96–13.01; both p < 0.001). Hematologic and non-hematologic adverse events (diarrhea, liver enzymes, infections) were increased. In EBC, iDFS improved (HR 0.81, 95% CI 0.67–0.98; p = 0.029; I 2 = 60%), while OS (HR 0.92, 95% CI 0.75–1.12; p = 0.40) and DRFS (HR 0.81, 95% CI 0.24–2.67; p = 0.73; I 2 = 73.2%) were not significant. TDR and DRR were increased (RR 8.39, 95% CI 2.24–31.42; p = 0.014; I 2 = 95.7%; and RR 26.84, 95% CI 14.85–48.49; p < 0.0001). Hematologic and non-hematologic adverse events (fatigue, liver enzymes) were increased. Conclusions: CDK4/6 inhibitors confer significant OS and PFS benefits in MBC, supporting standard first-line use. In EBC, iDFS improved without demonstrated OS benefit and was accompanied by increased treatment modifications and toxicity, underscoring the need for individualized risk-benefit assessment. Longer follow-up is warranted to clarify immature OS data.
Dhanoa et al. (Thu,) studied this question.