The good, the bad, and the manageable: real-world outcomes with CDK4/6 inhibitors.

Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) in combination with endocrine therapy represent the standard of care for hormone receptor-positive (HR+), HER2-negative metastatic breast cancer (mBC). While clinical trials established their efficacy, real-world evidence on safety, dose adjustments, and outcomes remains limited. We conducted a prospective observational study including patients with HR+/HER2- mBC treated with palbociclib, ribociclib, or abemaciclib across three oncology units between 2019 and 2024. Data on adverse events, dose modifications, progression-free survival (PFS), and overall survival (OS) were collected and analyzed. Adverse events were reported in 77.5% of patients. Neutropenia was the most frequent adverse event with palbociclib and ribociclib, while diarrhea and hepatic toxicity predominated with abemaciclib. Pulmonary toxicity occurred in 19.1% of abemaciclib-treated patients, often in those previously irradiated. Median PFS and OS were 26.4 and 31.1 months, respectively. The occurrence of grade 3-4 adverse events correlated with improved OS (37.1 vs. 23.0 months, P  < 0.001). Dose reductions, required in more than 60% of patients, did not compromise efficacy; instead, they were associated with longer PFS and OS. Conversely, treatment discontinuation predicted worse outcomes. In real-world practice, CDK4/6i toxicities are frequent but manageable. Proactive toxicity management and timely dose adjustments are essential to sustain treatment benefit. Dose reductions may even improve outcomes, underscoring the value of individualized dosing strategies.