# CDK4/6 Inhibitors Plus Endocrine Therapy in Early-Stage HR+/HER2− Breast Cancer: Updated Meta-Analysis of Phase III Trials

## TL;DR

Adding CDK4/6 inhibitors to endocrine therapy improves survival outcomes in early-stage HR+/HER2− breast cancer, but long-term benefits need more study.

## Contribution

An updated meta-analysis of phase III trials provides new insights into the efficacy and safety of CDK4/6 inhibitors in early-stage breast cancer.

## Key findings

- CDK4/6 inhibitors improved invasive disease-free survival compared to endocrine therapy alone.
- A strong trend toward improved distant recurrence-free survival was observed but not statistically significant.
- Adverse events like neutropenia and diarrhea were more common with CDK4/6 inhibitors.

## Abstract

HR+/HER2− breast cancer is a common type of early-stage breast cancer. Although endocrine therapy is the standard treatment, some patients still experience recurrence. This study updates previous analyses on adding CDK4/6 inhibitors (CDK4/6i) to endocrine therapy (ΕΤ) using the latest clinical trial data. The analysis includes data from randomized phase III studies with different patient risk profiles and treatment durations, providing a comprehensive overview of recent data. The findings contribute to the ongoing discussion about optimizing adjuvant therapy and may help refine treatment strategies and inform future research in early breast cancer.

Background/Objectives: This meta-analysis aimed to evaluate the efficacy of combining CDK4/6i with ET, compared with ET alone, in improving invasive disease-free survival (iDFS), distant recurrence-free survival (DRFS), and overall survival (OS) in early-stage hormone receptor-positive (HR+), human epidermal growth factor 2-negative (HER2−) breast cancer. Given the inconclusive findings of previous meta-analyses, an updated synthesis of the latest phase III trial data was performed. Methods: A systematic review and meta-analysis were conducted following PRISMA guidelines. Randomized Controlled Trials (RCTs) comparing CDK4/6i plus ET versus ET alone were identified through PubMed, Scopus, and ClinicalTrials.gov. Hazard ratios and adverse events were analyzed using appropriate statistical models. Results: Four RCTs (monarchE, NATALEE, PENELOPE-B, PALLAS) including 17,749 patients were analyzed. CDK4/6 inhibitors improved iDFS (HR 0.80; 95% CI: 0.67–0.96; p = 0.01), while a strong trend toward improved DRFS was observed (HR 0.79; 95% CI: 0.61–1.02; p = 0.07), suggesting a potential clinically relevant benefit that requires longer follow-up to confirm. The effect on OS (HR 0.95; 95% CI: 0.79–1.16; p = 0.63) remains inconclusive. Adverse events, including neutropenia and diarrhea, were more frequent with CDK4/6i. Conclusions: The addition of CDK4/6i to ET improves iDFS and shows a favorable trend in DRFS in early-stage HR+/HER2− breast cancer, highlighting the need for longer follow-up to clarify their long-term benefit.