Abstract PS1-12-29: Real-world outcomes of second-line therapies in HR+/HER2- metastatic breast cancer after progression on CDK4/6 inhibitor

Abstract Introduction: Metastatic HR+/HER2- breast cancer (MBC) remains incurable. Following progression on CDK4/6 inhibitors and endocrine therapy, treatment options include further lines of endocrine-based regimens alone or in combination with targeted therapies such as PI3K inhibitors or everolimus, and chemotherapy. To date, no reliable predictive markers for response to second-line (2L) therapy have been established. Methods: We performed a single center cohort study of all patients with HR+/HER2- MBC who initiated 2L therapy following progression on first-line (1L) treatment with CDK4/6 inhibitors and endocrine therapy. The primary objective was to describe progression-free survival (PFS) and overall survival (OS) according to the type of 2L treatment and to identify prognostic factors associated with PFS and OS according to the type of therapy. Outcomes were assessed using the Kaplan-Meier method alongside multivariable cause-specific Cox regression models, which included factors such as the type of 2L treatment, duration of 1L CDK4/6 inhibitors therapy, metastatic sites, and HER2 expression. A prognostic model was developed for patients treated in the 2L and used to provide corrected comparisons of different treatments. Results: Between January 1, 2018, and December 31, 2023, 281 women were included. Median age was 67 years and 80% were postmenopausal. 30% had de novo MBC and 20% had bone-only metastasis. Additionally, 78% of patients had an ECOG Performance Status (PS) of 0 or 1. In the 2L, 149 patients were treated with chemotherapy alone or combined with maintenance endocrine therapy, 84 received everolimus plus endocrine therapy, and 48 were given other treatment. Median follow-up was 26.1 months (95% CI: 22.7 - 29.2). For patients treated with everolimus, the median PFS and OS were 4.9 months (95% CI: 3.9–6.5) and 23.4 months (95% CI: 19.4–36.7), respectively. In comparison, patients treated with chemotherapy had a median PFS of 4.4 months (95% CI: 3.4–5.7) and a median OS of 14.9 months (95% CI: 10.7–18.7) in the overall population. Among patients who received 1L CDK4/6 inhibitors for more than 12 months, those treated with everolimus had a median PFS of 4.5 months (95% CI: 3.7–6.5) and OS of 27.8 months (95% CI: 20.0–41.4). In contrast, patients treated with chemotherapy in this subgroup experienced had a median PFS of 6.7 months (95% CI: 4.6–8.9) and OS of 18.7 months (95% CI: 15.3–27.6). The multivariable Cox model incorporated ECOG-PS score, metastatic sites, 2L treatment category, duration of CDK4/6 inhibitors in 1L and HER2 expression. None of the interaction terms tested between the 2L treatment and the duration of CDK4/6 in 1L, the metastatic site and the HER2 expression were significant. We observed a significant increase in the risk of death for patients treated with chemotherapy alone versus everolimus HR = 1.80, (95% CI: 1.07-3.04), p = 0.0269. This risk also increases for patients with an ECOG-PS score 2 HR = 5.20, (95% CI: 2.71-9.96), p 0.0001, patients with 12 months or less of CDK4/6 inhibitors in 1L HR = 1.59, (95% CI: 1.07-2.35), p = 0.0215 and patients with brain or liver metastasis compared to bone only metastasis HR = 2.58, (95% CI: 0.35-.94), p = 0.0042. Conclusion: These preliminary results suggest everolimus with endocrine therapy is an option for patients with HR+/HER2- metastatic breast cancer in 2L who received more than 12 months of CDK4/6 inhibitors in 1L, have an ECOG-PS score 2, and present with bone-only metastasis. Chemotherapy may be considered otherwise. This database enabled the development of a prognostic model that identifies different patient profiles and helps clinicians choose the best treatment option. Prospective studies must be conducted to confirm the prognostic model. Citation Format: A. PEINOIT, F. LE BORGNE, J. FRENEL, L. MATHIOT, F. BOCQUET, A. PATSOURIS, M. ROBERT, E. BULTOT, J. QUINTIN, V. SIMMET, M. CAMPONE. Real-world outcomes of second-line therapies in HR+/HER2- metastatic breast cancer after progression on CDK4/6 inhibitor 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 PS1-12-29.