Upfront Versus Deferred CDK4/6 Inhibitor Use in Hormone Receptor-Positive, HER2-Negative Metastatic Breast Cancer: A Real-World Study

Background/Objectives: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) are commonly used as first-line treatment for hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer. However, the optimal timing of CDK4/6i initiation remains uncertain. This study compared overall survival (OS) between upfront first-line and deferred second-line CDK4/6i use in routine clinical practice. Methods: This retrospective, two-center cohort study included 403 patients with hormone receptor-positive, HER2-negative metastatic breast cancer who received a CDK4/6i between January 2019 and December 2024. Patients were categorized into upfront-use and deferred-use groups according to whether CDK4/6i treatment was initiated in the first or second metastatic treatment line. Overall survival was estimated using the Kaplan–Meier method. An exploratory analysis of progression-free survival (PFS) from CDK4/6i initiation was also performed. Cox proportional hazards regression, inverse probability of treatment weighting (IPTW), and a 12-month landmark analysis were performed. Results: Of 403 patients, 311 received upfront treatment and 92 received deferred treatment. At a median follow-up of 63.0 months, the deferred-use group had higher rates of visceral metastasis and endocrine-resistant disease. Median PFS from CDK4/6i initiation was longer in the upfront-use group than in the deferred-use group (27.0 vs. 14.0 months; log-rank p < 0.001). Median OS was 61.0 months in the upfront-use group and 76.0 months in the deferred-use group, without a statistically significant difference (log-rank p = 0.059). After adjustment for clinical factors and year of metastatic diagnosis, deferred use was not independently associated with OS (adjusted hazard ratio [HR] 1.167, 95% confidence interval [CI] 0.772–1.765, p = 0.463). Similar results were obtained in the IPTW analysis (HR 0.925, 95% CI 0.552–1.549; p = 0.766) and the 12-month landmark analysis. Conclusions: Deferred second-line CDK4/6i use was not independently associated with inferior overall survival compared with upfront use. These findings support an individualized, risk-adapted sequencing approach in carefully selected patients but do not establish equivalence or justify routine deferral.