Real-world effectiveness of CDK4/6 inhibitors in older patients with HR+/HER2- advanced breast cancer: a sub-analysis of the multicenter, PALMARES-2 study

Background: Older patients with Hormone Receptor–positive, HER2-negative advanced breast cancer (HR+/HER2− aBC) are often frailer than younger patients. Endocrine therapy (ET) plus CDK4/6 inhibitors (CDK4/6i) is the standard first-line treatment regardless of age; however, CDK4/6i real-world effectiveness in older patients is unknown. Patients and methods: PALMARES-2 (NCT06805812) is a large real-world study investigating first-line ET plus CDK4/6i effectiveness in HR+/HER2− aBC patients. We compared real-world progression-free survival (rwPFS) between older (>75 years) and younger (≤75 years) patients in the whole study cohort, as well as in palbociclib, ribociclib, or abemaciclib sub-cohorts. Cox regression models and inverse probability of treatment weighting (IPTW) were used to adjust for prognostic covariates. Results: Older patients accounted for 302 (15.2%) of the PALMARES-2 study cohort (n = 1982). Compared with younger patients, older patients were less likely to have ECOG PS 0 or bone-only disease, and more likely to receive palbociclib. At multivariable analysis, older patients had better rwPFS when compared to younger patients (aHR 0.77; 95% CI 0.67–0.90, p = 0.001). In younger patients, ribociclib and abemaciclib were more effective than palbociclib, whereas in older patients palbociclib showed similar effectiveness to abemaciclib and superior effectiveness to ribociclib (p for interaction <0.001). Among patients treated with palbociclib, older patients had improved rwPFS compared with younger patients (aHR 0.69; 95% CI 0.57–0.84, p < 0.001). Conclusion: First-line ET plus CDK4/6i is highly effective in older patients with HR+/HER2− aBC. Based on effectiveness and clinical manageability, palbociclib represents a particularly suitable option in this population.