Abstract PS1-10-13: Fulvestrant Post-CDK Inhibitor in Hormone Receptor-Positive Breast Cancer: A Pooled FDA Analysis

Abstract Background: Fulvestrant monotherapy has served as a control arm option in many later-line clinical trials enrolling patients with metastatic hormone receptor-positive (HR+) breast cancer. Since CDK4/6 inhibitors (CDKi) have become a standard initial therapy in the United States, such trials now enroll patients with disease progression on or after CDKi-based therapy. Moreover, recent trials have identified biomarkers that may affect the choice of therapy and disease prognosis in this treatment space. These developments call for a close reevaluation of the role of fulvestrant monotherapy in the treatment of patients with HR+ breast cancer, after progression on initial therapy. Methods: We pooled patient-level data from four randomized phase 3 trials: SOLAR-1, EMERALD, CAPItello-291, and EMBER-3. For patients in the control arm who received single-agent fulvestrant, we descriptively compared objective response rate (ORR) in patients who had received prior CDKi versus patients with no prior CDKi, and evaluated progression-free survival (PFS) and overall survival (OS) in the patients with prior CDKi. In the post-CDKi population with ESR1/PI3K-pathway alterations, we assessed OS with fulvestrant against biomarker-informed therapy on the trial comparator arm. Last, we developed multivariate Cox regression models adjusting for baseline characteristics to explore the impact of ESR1 and PI3K pathway alterations on the prognosis of patients treated with fulvestrant post-CDKi. Results: Among 1099 patients receiving fulvestrant, the ORR in 603 patients with prior CDKi was 5.1% (95% CI: 3.5, 7.2) compared to 12.7% (95% CI: 9.9, 16.0) in the 496 patients without prior CDKi. In patients with prior CDKi, median PFS was 2.8 months (95% CI: 2.0, 3.6), with 11.2% (95% CI: 8.5, 14.2) progression-free at 1 year. Median OS in these patients was 26.8 months (95% CI: 20.8, NE). Among 572 patients with a treatment-eligible biomarker and prior CDKi, randomization to biomarker-informed therapy (N=303) was associated with favorable OS, compared to fulvestrant (N=269), with hazard ratio (HR) 0.61 (95% CI: 0.46, 0.82). Among the 603 patients treated with fulvestrant post-CDKi, we observed inferior outcomes in patients with an ESR1 mutation or a PI3K-pathway alteration. In multivariate Cox regression analyses, PI3K pathway alterations were associated with shortened OS (HR = 1.66; 95% CI: 1.18-2.33), while ESR1 mutations were associated with shortened PFS (HR = 1.31; 95% CI: 1.01-1.70). Discussion: In this exploratory pooled analysis of patient-level data, the activity of fulvestrant as reflected by ORR was reduced in patients with prior CDKi treatment. Patients with prior CDKi also experienced a generally short progression-free interval on fulvestrant, suggesting limited treatment benefit. Tumor-based metrics such as ORR and PFS can underestimate the value of a less toxic therapy, so we evaluated the pooled OS comparison against biomarker-directed management among eligible patients, showing favorable OS for biomarker-directed management over fulvestrant. To evaluate the importance of ESR1 and PI3K-pathway alterations in defining the post-CDKi patient population, we assessed whether they had prognostic impact in this setting, in patients receiving fulvestrant. The presence of either biomarker was independently associated with worse outcomes. Given its diminished activity, short intervals to progression, and unfavorable survival comparison in recent trials, single agent fulvestrant is not a reasonable option for biomarker-positive or biomarker-unselected populations post-CDK4/6 inhibitor-based therapy. The current data are not well suited to evaluate its role in selected biomarker-negative populations, which appear distinct prognostically. Citation Format: J. Buturla, Y. Zhang, E. Chang, P. Narayan, M. Shah, C. Osgood, M. Fiero, A. De Claro, R. Pazdur, L. Amiri-Kordestani. Fulvestrant Post-CDK Inhibitor in Hormone Receptor-Positive Breast Cancer: A Pooled FDA 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 PS1-10-13.