OT1-01-03: A Phase 3 Randomized, Double-Blind, Placebo-Controlled Multicenter Study Comparing Denosumab with Placebo as Adjuvant Treatment for Women with Early-Stage Breast Cancer Who Are at High Risk of Disease Recurrence (D-CARE).

Abstract

Abstract Background Bone is a common site of distant recurrence in women with early-stage breast cancer. Cancer cells are thought to stimulate osteoclast-mediated bone resorption, which releases growth factors and cytokines that promote tumor growth. RANK Ligand (RANKL) is the key mediator of osteoclast-induced bone destruction. In preclinical studies, RANKL inhibition reduced the incidence of bone and lung metastases, suppressed tumor progression, and prolonged survival of tumor-bearing mice. Effects were additive with hormonal, chemotherapy, or targeted therapies. Denosumab is a fully human monoclonal antibody against RANKL, approved in the U.S. for the prevention of skeletal-related events in patients with bone metastases from solid tumors. In patients with castrate-resistant prostate cancer, denosumab significantly improved bone metastasis-free survival (BMFS) compared to placebo. The D-CARE trial evaluates BMFS effects of denosumab in women with stage II or III breast cancer. Methods: Women with node-positive or locally advanced (T3 or T4) disease, and known hormone and HER-2 receptor status are eligible. Standard-of-care adjuvant or neoadjuvant chemo-, endocrine, or HER-2 targeted therapy, alone or in combination must be planned with curative intent. Women with a prior history of breast cancer (other than ductal carcinoma in situ [DCIS] or lobular carcinoma in situ [LCIS]) or distant metastasis, oral bisphosphonate (BP) use within 1 year or any intravenous BP use are excluded. Patients are randomized 1:1 to receive denosumab 120 mg or placebo subcutaneously monthly for 6 mos, then every 3 mos, for a total of 5 yrs treatment. All patients receive vitamin D (≥ 400 IU) and calcium (≥ 500 mg) supplements. Primary endpoint of this event-driven trial is BMFS. Secondary endpoints include disease-free (DFS) and overall survival. The study is powered for both, BMFS and DFS. Safety, quality of life assessments and biomarkers are additional endpoints. The trial, sponsored by Amgen Inc. and registered with the ClinicalTrials.gov identifier NCT01077154 began enrolling patients in June 2010. PG and DF are supported in part by the Avon Foundation, NY. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr OT1-01-03.