Abstract P1-10-07: Efficacy and Safety Results from a Randomized, Phase II Study of CC-486 in Combination with Fulvestrant in Postmenopausal Women with Estrogen Receptor–positive (ER+), Human Epidermal Growth Factor Receptor 2–negative (HER2−) Metastatic Breast Cancer (MBC)

Abstract Background: Most patients diagnosed with breast cancer have ER+ tumors. Treatment of ER+ MBC typically involves endocrine therapy, including aromatase inhibitors and selective ER modulators such as tamoxifen; however, many patients develop resistance. Fulvestrant, an ER antagonist, is a commonly prescribed second- or third-line therapy for postmenopausal patients who have progressed on endocrine therapy; although, most patients will eventually develop resistance to this drug as well. It was hypothesized that CC-486, an oral formulation of azacitidine, may resensitize patients to endocrine therapy and possibly delay resistance to fulvestrant through the epigenetic regulation of certain genes. Methods: 97 postmenopausal female patients aged ≥ 18 years with ER+, HER2− MBC refractory to an aromatase inhibitor were randomized 1:1 to receive CC-486 300 mg on days 1 through 21 and fulvestrant 500 mg on days 1 and 15 of cycle 1 and day 1 of subsequent 28-day cycles or the same fulvestrant regimen alone. The primary endpoint was progression-free survival (PFS) based on investigator's assessment using RECIST version 1.1 and summarized by the Kaplan-Meier method. A Cox proportional hazards model was used to estimate the hazard ratio (HR; including a 2-sided 95% CI), and a log-rank test was used to calculate P values for comparisons between treatment arms. Key secondary endpoints included objective response rate (ORR), overall survival (OS), and safety. Results: 48 patients were included in the CC-486 + fulvestrant arm and 49 in the fulvestrant-alone arm. Median age was 63 years. Baseline characteristics were generally balanced between treatment groups, with some exceptions. The CC-486 + fulvestrant treatment cohort had fewer patients aged ≥ 65 years (40% vs 49%), with an ECOG PS of 1 (25% vs 57%), or with liver metastases (29% vs 43%) than did the fulvestrant-alone cohort. At the time of this analysis, 36 patients (75%) in the CC-486 + fulvestrant arm and 40 patients (82%) in the fulvestrant-alone arm had discontinued treatment, mostly due to progressive disease (81% and 90%, respectively). Median PFS was 5.5 months in both treatment groups (HR 0.87; 95% CI, 0.54 - 1.42; P = 0.599). ORR was 8.3% vs 2.0% in patients receiving CC-486 + fulvestrant vs fulvestrant alone, respectively. Median OS has not been reached. In patients who received CC-486 + fulvestrant, the most common any-grade nonhematologic treatment-emergent adverse events (TEAEs) were nausea (78%), vomiting (78%), diarrhea (44%), and constipation (41%), and the most frequent any-grade hematologic TEAE was neutropenia (26%). Of patients who discontinued due to AEs, most patients receiving CC-486 + fulvestrant treatment discontinued due to gastrointestinal (GI) TEAEs. Conclusion: The addition of CC-486 to fulvestrant did not improve PFS in patients with ER+, HER2− MBC compared with fulvestrant alone, and GI TEAEs were reported in a majority of patients. These results do not support further evaluation of this combination in this setting. Citation Format: Campone M, Sachdev J, Bianchi GV, Beck JT, Martínez-Jáñez N, Cortes J, Schmidt M, Zamagni C, Chen P, Miller J, Fandi A, Gianni L. Efficacy and safety results from a randomized, phase II study of CC-486 in combination with fulvestrant in postmenopausal women with estrogen receptor–positive (ER+), human epidermal growth factor receptor 2–negative (HER2−) metastatic breast cancer (MBC) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-10-07.