Updated efficacy and safety of CDK4/6 inhibitors plus endocrine therapy in elderly women with HR+/HER-2 metastatic or advanced breast cancer: patient-level network meta-analysis.

Background: Breast cancer (BC) is the most common cancer in women worldwide. More than 80% of new cases of invasive BC are diagnosed among women aged 50 years or older, and they mainly comprise estrogen receptor (ER)-positive and HER2-negative subtypes of the disease. About 91% of deaths occur in this age demographic. Treatment with cyclin-dependent kinase 4/6 inhibitors has resulted in significantly increased survival benefits in terms of progression-free survival and overall survival (OS), but evidence for their use in treating older women with metastatic BC is limited. Therefore, we evaluated the efficacy and safety of cyclin-dependent kinase 4/6 (CDK4/6) inhibitors combined with endocrine therapy in older women with HR+/HER-2 metastatic or advanced BC.

Methods: We conducted a comprehensive search of the PubMed and EMBASE databases between January 2018 and December 2024 for phase II or III randomized controlled trials (RCTs) investigating treatment modalities in HR+/HER-2 metastatic or advanced BC. Kaplan-Meier curves for progression-free survival (PFS) and overall survival (OS) were reconstructed to retrieve individual patient-level data to strengthen the comparison of the benefits of all treatment modalities of interest. In this network meta-analysis (NMA), each study was pooled in a fixed-effects or randomized-effects model based on the individual study quality. We also performed a subgroup analysis and reported the incidence of ≧grade 3 adverse events in elderly patients (≧65 years). The primary endpoints were the pooled PFS, OS, and comparable safety rankings. The treatment modalities were ranked using SUCRA scores.

Results: We identified 15 phase II and III randomized controlled trials with seven treatment modalities that met the inclusion criteria. From these trials, rates of PFS and OS for 1799 and 1568 patients, respectively, were included in the analysis. In terms of PFS, Palbociclib + Letrozole (Let) ranked highest among all treatment modalities, followed by Ribociclib + Fulvestrant (Ful). Meanwhile, Palbociclib plus Ful showed superior OS ranking compared to other treatments in older women with mBC. Regarding safety, Palbociclib plus Endocrine (letrozole or fulvestrant) (79.3%), Ribociclib plus Let (87%), and Abemaciclib + ET (letrozole or anastrozole) were associated with a relatively high incidence of ≧grade 3 adverse events (AEs) compared to placebo plus endocrine therapy.

Conclusions: In this network meta-analysis, the combination of Palbociclib with Letrozole or Fulvestrant was found to have an effect on PFS and OS, and Ribociclib + Let was found to be a relatively safe treatment option for elderly women with HR+/HER2 metastatic or advanced BC. However, given the limited evidence in older populations, comprehensive, well-designed, large-scale randomized controlled trials are needed to address this issue.