ABSTRACT

BACKGROUND
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 with Hormone Receptor-positive, Human Epidermal growth factor Receptor 2-negative advanced
Breast Cancer (HR+/HER2- aBC). However, no large head-to-head comparisons of the three
CDK4/6i have been conducted so far.
PATIENTS AND METHODS
We performed a multicenter, observational, population-based study to compare the effectiveness of
first-line palbociclib, ribociclib and abemaciclib in combination with ET in consecutive HR+/HER2-aBC patients who initiated the treatment between January 2016 and September 2023 in 18 Italian cancer centers. The primary study endpoint was real-world progression-free survival (rwPFS). Multivariable Cox regression models were used to adjust the association between individual CDK4/6i and rwPFS for clinically relevant variables.
RESULTS
Of 1982 patients enrolled in the PALMARES-2 study, 789, 736 and 457 patients received palbociclib, ribociclib and abemaciclib, respectively. Median rwPFS was 34.1 months. 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). In patients with endocrine-sensitive disease, only abemaciclib was associated with better rwPFS when compared to palbociclib. On the other hand, abemaciclib and ribociclib were more effective than palbociclib in patients who were premenopausal or had endocrine-resistant or luminal B-like disease, while abemaciclib was more effective than ribociclib and palbociclib in patients with de novo metastatic disease, and more effective than palbociclib in patients with poorer ECOG PS. The three CDK4/6i were similarly effective in patients who were older or had bone-only disease.
CONCLUSION
Palbociclib, ribociclib and abemaciclib have different real-world effectiveness in HR+/HER2- aBC
patients. Our findings can support clinicians in choosing the most appropriate CDK4/6i in specific
clinical contexts.

KEYWORDS: HR+/HER2- Advanced Breast Cancer; Real-World Evidence; Progression-free
survival; Palbociclib; Ribociclib; Abemaciclib.