Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2025 Jul 25:16:1600892.
doi: 10.3389/fphar.2025.1600892. eCollection 2025.

Comparative long-term outcomes of first-line CDK4/6 inhibitors plus endocrine therapy versus endocrine therapy in patients with HR+/HER2-metastatic or advanced breast cancer: a meta-analysis

Xiaojian Wang #  1 , Xinyi Liang #  1 , Chenchen Li  2 , Mengtian Qin  1 , Jianyu Wu  1 , Yuechen Qin  1 , Yue Zou  1 , Haijian Zeng  1 , Chunlan Li  1 , Xiaomeng Huang  1 , Haiyun Tao  1 , Jieru Quan  3 , Xiao Wang  1
Affiliations

Comparative long-term outcomes of first-line CDK4/6 inhibitors plus endocrine therapy versus endocrine therapy in patients with HR+/HER2-metastatic or advanced breast cancer: a meta-analysis

Xiaojian Wang et al. Front Pharmacol. .

Abstract

Introduction: This meta-analysis was designed to compare the long-term outcomes of first-line cyclin-dependent kinase 4/6 (CDK4/6) inhibitors plus endocrine therapy (ET) versus ET in patients with HR+/HER2-metastatic or advanced breast cancer (BC).

Materials and methods: Four databases (Medline, Embase, Web of Science, and CENTRAL) were searched for literature comparing First-line CDK4/6 inhibitors plus ET to ET in patients with HR+/HER2-metastatic or advanced breast cancer. The search was conducted from the database's establishment to April 3, 2025. Progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and severe treatment-related adverse events (SAEs) were subjected to meta-analyses.

Results: Twelve Randomized controlled trials (RCTs) were included in the meta-analysis. The meta-analysis included a group of 4,957 patients diagnosed with HR+/HER2-metastatic or advanced breast cancer. Within this cohort, 2,877 patients were administered First-line CDK4/6 inhibitors together with ET, while 2080 patients received first-line ET alone. Compared with ET, First-line CDK4/6 inhibitors plus ET yielded superior ORR (RR = 1.39, 95% CI, 1.28 to 1.51, P < 0.01), DCR (RR = 1.09, 95% CI, 1.05 to 1.14, P < 0.01), PFS (HR: 0.57, 95%CI 0.53 to 0.62, P < 0.01) and OS (HR: 0.81, 95%CI 0.73 to 0.89, P < 0.01). Reconstruction of Kaplan-Meier curves for OS and PFS using the IPDformKM program provided a clear and comprehensible representation of oncological outcomes. First-line CDK4/6 inhibitors plus ET was more effective than ET in terms of PFS (median survival time: 27.0 months versus 14.4 months, HR: 0.55, 95%CI 0.51 to 0.59, P < 0.01) and OS (median survival time: 59.6 months versus 50.0 months, HR: 0.79, 95%CI 0.72 to 0.87, P < 0.01). With regards to safety, First-line CDK4/6 inhibitors plus ET exhibited a greater likelihood of encountering SAEs (RR = 1.54, 95% CI: 1.30 to 1.82, P < 0.01) in comparison to ET.

Conclusion: The present meta-analysis reported comparative long-term outcomes of CDK4/6 inhibitors plus ET versus ET as first-line therapy for HR+/HER2-metastatic or advanced breast cancer. Compared with ET alone, CDK4/6 inhibitors plus ET as first-line therapy provided improved ORR, DCR, PFS, and OS. Furthermore, the heightened efficacy of CDK4/6 inhibitors plus ET was accompanied by a rise in SAEs.

Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/view/CRD42024590572, Identifier CRD42024590572.

Keywords: CDK4/6 inhibitors; breast cancer; endocrine therapy; meta-analysis; metastatic; objective response rate; overall survival; progression-free survival.

PubMed Disclaimer

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Flow chart of literature search strategies.
FIGURE 2
FIGURE 2
Risk of bias assessment diagram.
FIGURE 3
FIGURE 3
Forest plot of the meta-analysis for ORR.
FIGURE 4
FIGURE 4
Forest plot of the meta-analysis for DCR.
FIGURE 5
FIGURE 5
Forest plot of the meta-analysis for PFS.
FIGURE 6
FIGURE 6
Kaplan-Meier curves for PFS.
FIGURE 7
FIGURE 7
Forest plot of the meta-analysis for OS.
FIGURE 8
FIGURE 8
Kaplan-Meier curves for OS.
FIGURE 9
FIGURE 9
Forest plot of the meta-analysis for SAEs.
FIGURE 10
FIGURE 10
The quality of the evidence analysis (GRADE approach).
See this image and copyright information in PMC

Similar articles

See all similar articles

References

    1. Adkins D., Ley J., Neupane P., Worden F., Sacco A. G., Palka K., et al. (2019). Palbociclib and cetuximab in platinum-resistant and in cetuximab-resistant human papillomavirus-unrelated head and neck cancer: a multicentre, multigroup, phase 2 trial. Lancet Oncol. 20 (9), 1295–1305. 10.1016/s1470-2045(19)30405-x - DOI - PubMed
    1. Albanell J., Martínez M. T., Ramos M., O'Connor M., de la Cruz-Merino L., Santaballa A., et al. (2022). Randomized phase II study of fulvestrant plus palbociclib or placebo in endocrine-sensitive, hormone receptor-positive/HER2–advanced breast cancer: GEICAM/2014–12 (FLIPPER). Eur. J. Cancer 161, 26–37. 10.1016/j.ejca.2021.11.010 - DOI - PubMed
    1. Altucci L., Addeo R., Cicatiello L., Germano D., Pacilio C., Battista T., et al. (1997). Estrogen induces early and timed activation of cyclin-dependent kinases 4, 5, and 6 and increases cyclin messenger ribonucleic acid expression in rat uterus. Endocrinology 138 (3), 978–984. 10.1210/endo.138.3.5002 - DOI - PubMed
    1. Ana C. G.-C., Noah G., Lestat R. A., Christina H., Jennifer D., Khanh D., et al. (2025). Phase I study of ribociclib (CDK4/6 inhibitor) with spartalizumab (PD-1 inhibitor) with and without fulvestrant in metastatic hormone receptor-positive breast cancer or advanced ovarian cancer. J. Immunother. Cancer 13 (2), e010430. 10.1136/jitc-2024-010430 - DOI - PMC - PubMed
    1. Arnold M., Morgan E., Rumgay H., Mafra A., Singh D., Laversanne M., et al. (2022). Current and future burden of breast cancer: global statistics for 2020 and 2040. Breast 66, 15–23. 10.1016/j.breast.2022.08.010 - DOI - PMC - PubMed

Publication types

LinkOut - more resources