Adjuvant denosumab in high-risk early breast cancer does not appear to reduce recurrences or deaths in patients with early breast cancer receiving optimal loco-regional and standard of care systemic adjuvant therapy. That is the conclusion of investigators participating in D-CARE, an international, multicenter, phase III study. Researchers presented the first results from this randomized, placebo-controlled trial at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting, held June 1–5 in Chicago.
Professor Robert E. Coleman, MBBS, MD, of the University of Sheffield and colleagues evaluated the addition of this potent RANK ligand inhibitor to standard neoadjuvant therapy for patients with high-risk early breast cancer. Currently, denosumab is approved for treatment of aromatase inhibitor–induced bone loss in early breast cancer and preventing skeletal morbidity associated with metastatic bone disease. Coleman and coinvestigators noted that preclinical data indicate denosumab could prevent the development of bone metastases.
In the D-CARE study, 4,509 patients were enrolled at 407 centers and randomized to standard locoregional and neoadjuvant therapy plus denosumab at 120 mg subcutaneously or matching placebo. All participants received routine clinical follow-up and underwent annual CT and bone scans. The primary endpoint was bone metastasis–free survival (BMFS), which the researchers defined as the first bone metastatic event confirmed by central imaging review or death from any cause. Secondary endpoints were disease-free survival (DFS), DFS in the postmenopausal (PM) subgroup, overall survival (OS), and safety.
The two patient groups were balanced for baseline characteristics, and the median age was 51 years. In the overall cohort, 77% of patients were ER+, 20% were HER2+, and 95.9% received anthracycline and/or taxane chemotherapy. At a median follow-up of 67 months, there were no benefits for the addition of denosumab. This analysis allowed for a full 5 years of treatment in all patients.
The study showed that the hazard ratio (HR) for BMFS (597 events) was 0.97, and was 1.04 for DFS (875 events). In addition, OS rates were similar in both arms (412 events; HR, 1.03). The researchers found denosumab did not improve BMFS, DFS, or OS in the PM subset of 2,149 women. When the investigators did an exploratory analysis of time to bone metastases as first recurrence, there did appear to be a benefit with denosumab (HR, 0.76). The study showed that with denosumab, the time to on-study fracture prior to bone recurrence was reduced (HR, 0.76).
The side effects were noteworthy, although not surprising, in that 122 patients (5.4%) on denosumab and 4 on placebo (0.2%) developed osteonecrosis of the jaw. In addition, 9 patients (0.4%) patients on denosumab experienced an atypical femoral fracture.