Introduction: Palbociclib, a CDK4/6 inhibitor, has significantly improved outcomes in patients with HR+/HER2？ metastatic breast cancer. While its efficacy has been demonstrated in randomized clinical trials, real-world comparative data between first-line (1L) and second-line (2L) use remain limited. Materials and Methods: This single-center retrospective study included 55 patients treated with palbociclib between January 2020 and June 2024. Patients were classified into a first-line group (n = 30; palbociclib plus aromatase inhibitor) and a second-line group (n = 25; palbociclib plus fulvestrant). The primary endpoint was progression-free survival (PFS). Results: The mean age was 52.4 years. Median PFS was significantly longer in the first-line group compared with the second-line group (19 vs. 8 months; p < 0.001). Overall survival was also superior in the first-line group (36.8 vs. 25.5 months; p = 0.001). The objective response rate was higher in first-line treatment (39% vs. 22%; p = 0.03). The safety profile was acceptable and consistent with previously published clinical trials and real-world data. Conclusion: This real-world study supports the superiority of palbociclib when used in the first-line setting, reinforcing the benefit of early CDK4/6 inhibitor integration in the treatment sequence.
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