Adjuvant denosumab in early breast cancer: First results from the international multicenter randomized phase III placebo controlled D-CARE study.

Abstract

501 Background: Denosumab (Dmab) is a potent RANK ligand inhibitor approved for the management of treatment induced bone loss in early breast (EBC) and prevention of skeletal morbidity associated with metastatic bone disease. Preclinical data suggested that Dmab could prevent development of bone metastases. This trial evaluated the addition of Dmab to standard (neo)adjuvant therapy for high-risk EBC patients (pts). Methods: 4509 pts with EBC (93.5% node+) from 407 centers were randomized to standard loco-regional and (neo)adjuvant therapy plus either Dmab 120mg sc or matching placebo (P) monthly x 6 then 3 monthly for up to 5 years. In addition to routine clinical follow-up, pts underwent annual CT and bone scan imaging to screen for recurrence. Primary endpoint was bone metastasis free survival (BMFS) defined as first bone metastatic event confirmed by central imaging review or death from any cause. Secondary endpoints included disease free survival (DFS), DFS in the postmenopausal (PM) subgroup, overall survival (OS) and safety. Results: Patient groups were balanced for baseline characteristics with median age 51y, 77% ER+, 20% Her2+ and use of anthracycline and/or taxane chemotherapy in 95.9%. No benefits for the addition of Dmab were seen at a time-driven analysis performed after a median follow-up of 67 months that allowed for the full 5 years of treatment in all pts. Hazard ratio (HR) for BMFS (597 events) was 0.97, 95%CI 0.82-1.14, p = 0.70 and 1.04, 95%CI 0.91-1.19, p = 0.57 for DFS (875 events). OS (412 events) was similar in both groups (HR = 1.03, 95%CI 0.85-1.25). Dmab did not improve BMFS, DFS or OS in the PM subset (n = 2149). Exploratory analysis of time to bone metastases as first recurrence suggested benefit for Dmab (HR = 0.76, 95%CI 0.59-0.97) for this endpoint. Time to on-study fracture prior to bone recurrence was reduced with Dmab (HR = 0.76, 95%CI 0.63-0.92). 122 (5.4%) pts on Dmab and 4 (0.2%) on P developed osteonecrosis of the jaw. 9 (0.4%) pts on Dmab experienced an atypical femoral fracture. Conclusions: Adjuvant Dmab does not reduce breast cancer recurrences or deaths in EBC pts receiving optimal loco-regional and standard of care systemic adjuvant therapy. Clinical trial information: NCT01077154.