PALMARES-2 Study Highlights Variable Efficacy of CDK4/6 Inhibitors in HER2-Negative Advanced Breast Cancer

Results from a study published in the Annals of Oncology revealed that in clinically relevant settings, the use of the cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) palbociclib, ribociclib, and abemaciclib is associated with different outcomes, highlighting the value of patient-centered treatment plans.

The cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) palbociclib, ribociclib, and abemaciclib in combination with endocrine therapy (ET) are the standard-of-care, first-line treatment for patients diagnosed with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer  (HR+/HER2- aBC).

The authors wrote, “The three CDK4/6i have different pharmacology and safety, but no large effectiveness comparisons have been conducted so far.”

The PALMARES-2 study is a multicenter observational study that encompasses both retrospective and prospective data collection to evaluate the effectiveness of the cyclin-dependent kinase 4/6 inhibitors (CDK4/6i), including palbociclib, ribociclib, and abemaciclib for the treatment of HR+/HER2- aBC.

The primary study endpoint was real-world progression-free survival (rwPFS), and multivariable Cox regression models were employed to modify the correlation between individual CDK4/6i and rwPFS for clinically relevant variables.

The study cohort comprised of 1,982 patients who initiated therapy from January 2016 to September 2023.

Results revealed that of 1,982 patients registered in the PALMARES-2 study, 789, 736, and 457 patients received palbociclib, ribociclib, and abemaciclib, respectively.

The average rwPFS was reported as 34.1 months.

The authors noted, “In the whole study cohort, abemaciclib and ribociclib were associated with better rwPFS when compared to palbociclib (adjusted HR [aHR] 0.76, 95% CI 0.63-0.92; P=0.004 and aHR 0.83, 95% CI 0.73-0.95; P=0.007, respectively).”

The results also revealed that, compared to palbociclib, only using abemaciclib was associated with better rwPFS among patients with endocrine-sensitive disease.

On the contrary, among patients who were premenopausal or had endocrine-resistant or luminal B-like disease, the use of abemaciclib and ribociclib was more effective than palbociclib in patients; however, among patients with de novo metastatic disease, the use of abemaciclib was more effective than ribociclib and palbociclib, and more effective than palbociclib in patients with poorer Eastern Cooperative Oncology Group Performance Status [ECOG PS]. Moreover, among patients who were older or had bone-only disease, the use of the three CDK4/6is were equally effective.

Also, in comparison with palbociclib, abemaciclib and ribociclib were associated with better rwPFS, time to next treatment or death (TTNT-D), time to chemotherapy or death (TTC-D), and overall survival (OS).

The authors concluded that the three CDK4/6 inhibitors exhibit varying real-world effectiveness, and their large-scale study offers the first real-world evidence to guide clinicians in selecting the most appropriate CDK4/6i for patients diagnosed with HR+/HER2- aBC, considering patient and tumor-specific factors, as well as efficacy, safety, and cost.

Reference

Provenzano L, et al.  Annals of Oncology.  2025 Apr 7:S0923-7534(25)00134-6. doi: https://doi.org/10.1016/j.annonc.2025.03.023.