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Denosumab vs Zoledronic Acid for Patients with Prostatic Bone Metastases
Abstract & Commentary
By Jerome W. Yates, MD, Hematology/Immunology Unit, National Institute on Aging, NIH. Dr. Yates reports on financial relationships relevant to this field of study.
Synopsis: In a Phase 3 trial comparing the recently introduced monoclonal antibody denosumab with zoledronic acid for the treatment of patients with prostate cancer metastatic to bone, the incidence of skeletal events including pathological fracture, radiation, skeletal surgery, or cord compression was delayed on average by more than 3 months for those treated with denosumab. Adverse events were comparable. Denosumab is administered subcutaneously and can be given to patients with renal insufficiency. Clinicians have become familiar with zoledronic acid in this setting, and it remains unclear whether its role as the standard approach will be supplanted.
Source: Fizazi K, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: A randomized, double blind trial. Lancet 2011;377:813-822.
For men with prostate cancer, the presence of metastatic foci within bone remains a major source of pain and disability. There have been improvements over the years, most notably the use of zoledronic acid, which has proven to delay the progression of bone disease in patients with hormone independent metastatic prostate cancer.1,2 More recently, Amgen Inc. has developed and introduced denosumab for this purpose as well, and the drug recently was approved by the FDA for use in this setting.
Denosumab is a full-length human monoclonal IgG2 that targets receptor activator of nuclear factor kappa B ligand (RANKL). The antibody blocks the binding of RANKL to its receptor (RANK) and thus inhibits its downstream signaling. Of the myriad of consequences of RANKL-RANK signaling are the formation, function, and survival of mature osteoclasts, the cells responsible for bone resorption.3 The resulting decrease in bone resorption theoretically would counter destructive bone metastases and thereby reduce or delay subsequent skeletal events such as fracture or cord compression.
To compare whether denosumab is comparable (i.e., not inferior) to zoledronic acid for patients with metastatic prostate cancer, Fizazi and colleagues from 42 centers in 39 countries conducted an Amgen-sponsored Phase 3 clinical trial in which approximately 2000 patients were randomized to receive 120 mg subcutaneous denosumab plus intravenous placebo, or 4 mg intravenous zoledronic acid plus subcutaneous placebo, every 4 weeks until the primary analysis cutoff date (median, approximately 1 year; IQR approximately 6-18 months for both groups). Randomization was stratified by previous skeletal- related event, PSA, and prior prostate cancer chemotherapy. The primary endpoint was time to first on-study skeletal-related event (pathological fracture, radiation therapy, surgery to bone, or spinal cord compression), and was assessed for non-inferiority. The data were further assessed to determine superiority as a secondary outcome. Efficacy analysis was by intention to treat.
The median time to first on-study skeletal-related event was 20.7 months (95% confidence interval [CI] 18.8–24.9) with denosumab compared with 17.1 months (15.0–19.4) with zoledronic acid (hazard ratio 0.82, 95% CI 0.71–0.95; P = 0.0002 for non-inferiority; P = 0.008 for superiority). Adverse events were recorded in 916 patients (97%) on denosumab and 918 patients (97%) on zoledronic acid, and serious adverse events were recorded in 594 patients (63%) on denosumab and 568 patients (60%) on zoledronic acid. More events of hypocalcaemia occurred in the denosumab group (121 [13%]) than in the zoledronic acid group (55 [6%]; P < 0.0001). Osteonecrosis of the jaw occur-red infrequently in both groups; 2% vs 1% for denosumab and zoledronic acid, respectively (P = 0.09).
The primary objective of this trial was to demonstrate that denosumab was not inferior to zoledronic acid for prevention of skeletal-related events, and as it turns out it appears that it might even be slightly better, in that events occurred on average 3.5 months later. From the Kaplan-Meier graphs presented, it seems the cumulative number of events will be the same for both groups, although at the time of publication the data were not sufficiently mature to make that conclusion. However, despite the delay in skeletal events, progression-free and overall survival were virtually superimposable between the two groups.
This study is one of three virtually identical trials comparing denosumab with zoledronic acid. In the other two, the comparison was made in patients with bone involvement from either breast cancer4 or from other cancers, excluding breast and prostate but including multiple myeloma5 and the results were similar to the current report; skeletal events including fracture, radiation, skeletal surgery, or cord compression were delayed to a greater extent by denosumab.
In summary, it is likely that denosumab delays for a few months the occurrence of adverse skeletal events for patients with prostatic bone metastases beyond that achieved by zoledronic acid. Furthermore, the drug has the advantage of subcutaneous rather than intravenous administration and it can be administered safely in patients with renal insufficiency. On the other hand, zoledronic acid has the advantage of greater accumulated clinical experience. Neither drug appears to provide survival advantage compared to the other. Both drugs are expensive and both are associated with a spectrum of adverse events, including the infrequent but important occurrence of osteonecrosis of the jaw. As clinicians become comfortable with the use of denosumab, it may become a new standard for treatment of patients with bone metastases, but it is early to make that conclusion. The question also arises whether its use in patients at risk for bone metastases, such as those with high-grade or locally extensive prostate cancer, may benefit from adjuvant use of either of these two agents. Hopefully, this approach would be shown to reduce the frequency of bone involvement and greatly reduce the occurrence of skeletal events.
1. Lee RJ, et al. Treatment and prevention of bone complications from prostate cancer. Bone 2011;48:88-95.
2. Saad F, et al. Long-term efficacy of zoledronic acid for the prevention of skeletal complications in patients with metastatic hormone-refractory prostate cancer. J Natl Cancer Inst 2004;96:879-882.
3. Lacey DL, et al. Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 1998;93:165-176.
4. Stopeck AT, et al. Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: A randomized, double-blind study. J Clin Oncol 2010;28:5132-5139.
5. Henry DH, et al. Randomized, double-blind study of denosumab versus zoledronic acid in the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma. J Clin Oncol 2011;29:1125-1132.