Vadhan-Raj, S., von Moos, R., Fallowfield, L.J., Patrick, D.L., Goldwasser, F., Cleeland, C.S., . . . Chung, K. (2012). Clinical benefit in patients with metastatic bone disease: Results of a phase 3 study of denosumab versus zoledronic acid. Annals of Oncology, 23, 3045–3051.

To compare the efficacy and safety of subcutaneous denosumab versus IV zoledronic acid for the treatment of established bone metastases

Patients were allocated to one of two treatment arms using a computer-generated randomization schedule with a permuted block size of 4. Randomization was stratified by tumor type, previous skeletal-related event (SRE), and systemic anti-cancer therapy. Daily calcium and vitamin D supplements were strongly recommended. Patients received either subcutaneous denosumab (120 mg) every four weeks or IV zoledronic acid (4 mg, dose adjusted for renal function) every four weeks for the treatment of established bone metastases.

• N = 1,776
• AGE = 18 years or older
• MALES: 64%, FEMALES: 36%
• KEY DISEASE CHARACTERISTICS: Eligible patients were diagnosed with solid tumors (except breast or prostate) or multiple myeloma with radiographic evidence of one or more bone metastases or bone disease.
• OTHER KEY SAMPLE CHARACTERISTICS: Eastern Cooperative Oncology Group score of 0, 1, or 2; adequate organ function; and a life expectancy of six months or longer

• SITE: Multi-site, international    
• SETTING TYPE: Outpatient    
• LOCATION: Multi-country

• PHASE OF CARE: Palliative
• APPLICATIONS: Palliative care

• International, randomized, double-blind, double-dummy phase 3 trial

• Radiographic evaluation every 12 weeks and as needed
• Brief Pain Inventory (BPI)-Short Form
• Health-related quality of life measured by the Functional Assessment of Cancer Therapy-Generated instrument (FACT-G)

Denosumab delayed time to first SRE or hypercalcemia of malignancy (19 months for denosumab versus 14.4 months for zoledronic acid) and reduced the risk of radiation to bone by 22%. Denosumab reduced the risk of a two-point increase (i.e., worsening) for the BPI worst pain rating by 15% relative to denosumab. Some evidence showed delay in the time to increased pain interference (6.5 months for denosumab versus 5.8 months for zoledronic acid). Both treatments were associated with the maintenance of health-related quality of life. For patients with an analgesic score of 2 or less (no or weak opioid use), fewer patients in the denosumab group than in the zoledronic acid group shifted to strong opioid analgesic use. On average, there was a 27% relative increase in the proportion of zoledronic acid-treated patients who initiated strong opioid analgesics compared with the denosumab-treated group.

The use of denosumab was associated with better prevention of SREs secondary to solid tumors or multiple myeloma compared to zoledronic acid. Denosumab also delayed pain progression and worsening of pain interference.

Skeletal pain is one of the most difficult to treat components of metastatic bone disease. In this study, differences were noted in pain, pain interference, and analgesic use between the treatment groups. Denosumab significantly delayed the worsening of pain and pain interference, as measured by the BPI.