Abstract PS1-12-24: Optimal sequencing after progression with CDK4/6 inhibitors in hormone receptor-positive metastatic breast cancer: a real-world analysis

Abstract Introduction: CDK4/6 inhibitors combined with endocrine therapy have transformed the management of hormone-positive/HER2-negative metastatic disease, consolidating their position as the standard of care in first-line therapy. However, there is still a significant gap in the literature regarding the best therapeutic strategy after progression and the prognostic factors that impact treatment sequencing in clinical practice. Methods: We conducted a retrospective study of patients with HR+/HER2- metastatic breast cancer treated with CDK4/6 inhibitors (palbociclib, ribociclib, or abemaciclib) between 2016 and 2025 at a referral cancer center. Clinical, pathological, and molecular variables were analyzed, focusing on progression-free survival after second-line therapy (PFS2), overall survival (OS), and progression-free survival after first-line therapy (PFS1). Statistical analyses included Kaplan-Meier curves, univariate and multivariate Cox models, and multiple imputation to address missing data. Results: Of the 377 patients, 177 experienced a second progression event, and 318 were included in the overall survival analysis. We observed that the type of second-line treatment significantly impacted PFS2. Strategies based on endocrine therapy, especially fulvestrant, demonstrated superior PFS2 compared to CDK4/6i rechallenge (median 11.3 vs. 5.4 months; HR 0.41, 95% CI 0.23-0.75, p = 0.004). Regimens containing capecitabine demonstrated inferior performance, with a median time of 6.9 months. In multivariate analysis with multiple imputation, factors such as visceral metastasis (HR 1.64, 95% CI 1.12-2.42, p = 0.01) and late use of CDK4/6i (HR 1.25, 95% CI 1.13-1.39, p 0.001) predicted worse overall survival. Interestingly, early discontinuation of CDKi due to toxicity appeared as a protective factor (HR 0.41; p = 0.004), and 27% of patients maintained response without requiring second-line therapy at last follow-up, a hypothesis that raises discussions about early response and biological sensitivity. Conversely, 13% presented rapid progression leading to death before the initiation of second-line therapy. Regarding overall survival, a trend toward a negative impact of visceral metastasis (HR 1.64; p = 0.01) and elevated Ki-67 (HR 1.44; p = 0.01) was observed. In contrast, patients who received fulvestrant or everolimus after progression had better survival rates (median PFS2 of 12.1 months), outperforming chemotherapy-based regimens. The proportion of patients who did not receive second-line treatment included both individuals with rapidly fatal clinical progression (13%) and patients without documented progression at the end of follow-up (27%). Conclusion: This demonstrates that second-line therapeutic choices significantly impact post-progression outcomes. Endocrine strategies, particularly combinations of everolimus and fulvestrant, were associated with superior progression-free survival and overall survival compared with chemotherapy or CDK4/6 inhibitor reintroduction. Citation Format: V. Primo Basilio de Souza, N. Soldi, A. Cicilini, T. Saruwatari, L. De Mattos, M. Camandaroba, M. Tariki, C. Machado, S. Sanches, A. Da Costa, V. De Lima, E. Dos Santos. Optimal sequencing after progression with CDK4/6 inhibitors in hormone receptor-positive metastatic breast cancer: a real-world analysis abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS1-12-24.