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FDA approves denosumab to increase bone mass
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The monoclonal antibody denosumab has received FDA approval to improve bone mass among patients at high risk for fracture who receive androgen deprivation therapy for nonmetastatic prostate cancer or adjuvant aromatase inhibitor therapy for breast cancer. According to the agency, the drug was also associated with a decrease in vertebral fracture incidence among men with nonmetastatic prostate cancer.
In these patient populations, the recommended dose and schedule for denosumab is 60 mg subcutaneously every 6 months.
Approvals were based on results from two international, randomized, double blind, placebo-controlled trials in patients receiving androgen deprivation therapy (ADT) for nonmetastatic prostate cancer (Trial 20040138) or adjuvant aromatase inhibitor therapy for breast cancer (Trial 20040135).
Trial 20040138 enrolled 1,468 men with prostate cancer at a median age of 76 years. Those aged younger than 70 years required a baseline BMD T-score at the lumbar spine, total hip or femoral neck between -1.0 and -4.0 or history of osteoporotic fracture.
Trial 20040135 was a 2-year trial that enrolled 252 women with breast cancer at a median age of 59 years. Patients had a baseline BMD T-score at the lumbar spine, total hip or femoral neck between -1.0 and -2.5 and had not experienced fracture after 25 years of age.
Patients were randomly assigned to subcutaneous injections of placebo or 60 mg denosumab (Prolia, Amgen), once every 6 months, for a total of six doses in Trial 20040138 and a total of four doses in Trial 20040135.
The primary endpoint was the percent change in lumbar spine BMD, from baseline to month 24 in Trial 20040138 and baseline to month 12 in Trial 20040135. The secondary endpoint in Trial 20040138 was the incidence of new vertebral fractures through month 36, according to an agency press release.
Patients were randomly assigned according to age (<70 years vs. ≥70 years) and duration of ADT at trial entry (≤6 months vs. .6 months) in Trial 20040138. Seventy-nine percent received ADT for more than 6 months at trial entry.
In Trial 20040135, randomization was stratified by duration of adjuvant aromatase inhibitor therapy at trial entry (≤6 months vs. .6 months). Sixty-two percent received adjuvant aromatase inhibitor therapy for more than 6 months at trial entry.
Denosumab was associated with a statistically significant effect on BMD compared with placebo in both cohorts of patients at 24 and 12 months. In addition, men with prostate cancer had a significantly reduced incidence of new vertebral fractures at 36 months, 1.5% in denosumab arm vs. 3.9% in placebo arm (absolute risk reduction=2.4%; 95% CI, 0.7-4.1 and relative risk reduction=62%; 95% CI, 22-81).
Arthralgia and back pain were reported in at least 10% of patients in the treatment arm and occurred more frequently than in the placebo arm. Pain in extremity and musculoskeletal pain were also noted. Hypocalcemia was observed only in the treatment arm (2.4%) at the 1-month visit.
On June 1, 2010, the same dose and schedule of denosumab was approved for the treatment of postmenopausal women with osteoporosis at high risk for fracture. On Nov. 18, 2010, denosumab (marketed under the trade name Xgeva) was approved for the prevention of skeletal-related events in patients with bone metastases from solid tumors. The dose for this indication is 120 mg subcutaneously every 4 weeks, according to the FDA.
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