Real-world effectiveness comparison of first-line palbociclib, ribociclib or abemaciclib plus endocrine therapy in advanced HR-positive/HER2-negative BC patients: results from the multicenter PALMARES-2 study

Background: The cyclin-dependent kinase 4/6 inhibitors (CDK4/6is) 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-positive/HER2-negative aBC). However, no large head-to-head comparisons of the three CDK4/6is have been conducted so far. Patients and methods: We carried out a multicenter, observational, population-based study to compare the effectiveness of first-line palbociclib, ribociclib and abemaciclib in combination with ET in consecutive HR-positive/HER2-negative aBC patients who initiated the treatment between January 2016 and September 2023 in 18 Italian cancer centers. The primary endpoint of this analysis 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 with palbociclib [adjusted hazard ratio (aHR) 0.76, 95% confidence interval (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 with palbociclib. On the contrary, 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 Eastern Cooperative Oncology Group performance status. The three CDK4/6i were similarly effective in patients who had bone-only disease. Conclusions: Palbociclib, ribociclib and abemaciclib have different real-world effectiveness in HR-positive/HER2-negative aBC patients. Our findings can support clinicians in choosing the most appropriate CDK4/6i in specific clinical contexts.