PD01-01: Randomized Phase II Trial of Fulvestrant with or without Dasatinib in Postmenopausal Patients with Hormone Receptor-Positive Metastatic Breast Cancer Previously Treated with an Aromatase Inhibitor.

Introduction: Fulvestrant is an effective endocrine therapy in patients with ER+ metastatic breast cancer (MBC) that has become resistant to non-steroidal aromatase inhibitors (NSAI). Dasatinib is a potent, broad spectrum ATP-competitive inhibitor of SRC tyrosine kinase activity that can lead to endocrine therapy resistance and late bone metastases. Dasatinib inhibits proliferation of cancer cell lines that express activated SRC. Inhibition of SRC signaling may overcome the endocrine resistance of HR+ MBC. We sought to determine whether addition of dasatinib to fulvestrant would increase progression-free survival (PFS) over fulvestrant alone in MBC. Methods: This is a randomized phase II study including patients with evaluable or measurable ER+ MBC whose disease had progressed while on adjuvant or metastatic NSAI. Patients were stratified to ≤ 2 yrs vs > 2 yrs from initial breast cancer diagnosis to first diagnosis of metastatic disease and randomly assigned 1:1 to Arm 1 (loading dose of fulvestrant 500 mg followed by 250 mg IM and dasatinib 100 mg PO QD) or Arm 2 (single-agent fulvestrant 250 mg IM). Following FDA approval in 2010 of the 500 mg dose, a loading dose (500 mg) of fulvestrant on Day 1 was followed by 500 mg on Day 15 of Cycle 1 and on Day 1 of each subsequent cycle (n=40 patients received the higher dose). Arm 2 patients who progressed while on fulvestrant could cross over to receive fulvestrant plus dasatinib. The primary objective was median PFS. Secondary objectives included overall survival (OS), overall response rate (ORR), and safety. Results: The study included 99 patients, 50 in Arm 1 (combination) and 49 in Arm 2 (fulvestrant alone). Results for Arm 1 and Arm 2, respectively, were: median PFS 6.0 and 5.3 months; median OS 17.0 and 21.7 months; and clinical benefit rates (CBR) (PR+SD ≥6 months) were 14 (28.0%, 95%CI=16.2%-42.5%) and 16 (32.7%, 95%CI=19.9%-47.5%) months. In Arm 1 and Arm 2, 24% and 8% developed grade 1/2 pleural effusion; 34% and 10% developed grade 1/2 diarrhea, 40% and 6% developed grade 1/2 nausea, and 30% and 18% developed grade 1/2 fatigue. Six patients on Arm 1 stopped dasatinib due to AEs, mainly pleural effusion and dyspnea. Eighteen (37%) Arm 2 patients crossed over to receive combined fulvestrant/dasatinib at disease progression on fulvestrant. Median PFS for crossover patients was 3.8 months, with the longest duration of treatment being 12 and 15 months in 2 patients. Conclusions: The addition of dasatinib to fulvestrant in ER+ postmenopausal MBC patients whose disease had progressed through an NSAI did not improve PFS, CBR, or OS. The combination of fulvestrant and dasatinib in patients with ER+ MBC was well tolerated. Formalin-fixed paraffin-embedded archival BC tissue is being analyzed for SRC-related signature to determine whether a subset of patients benefit from dasatinib. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr PD01-01.