FDA Approves Denosumab to Increase Bone Mass in Patients with Cancer


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Denosumab (Prolia) recently received FDA approval as a treatment to increase bone mass in patients at high risk for fracture receiving androgen deprivation therapy for nonmetastatic prostate cancer or adjuvant aromatase inhibitor therapy for breast cancer. 

Pivotal Trials

The approvals were based on results from two international, randomized, double-blind, placebo-controlled trials in patients receiving androgen deprivation therapy for nonmetastatic prostate cancer or adjuvant aromatase inhibitor therapy for breast cancer. Trial 20040138 was a 3-year trial that enrolled 1,468 men with prostate cancer (median age 76 years). Men less than 70 years of age were required to have either a baseline bone mineral density 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 (median age 59 years). Women had a baseline bone mineral density T-score at the lumbar spine, total hip, or femoral neck between –1.0 and –2.5 and had not experienced fracture after age 25.

Patients were randomized to receive subcutaneous injections of either placebo or 60 mg denosumab, once every 6 months, for a total of 6 doses in the prostate cancer trial and for a total of 4 doses in the breast cancer trial.

Study Design and Outcomes

The primary outcome measure in each trial was the percent change in lumbar spine bone mineral density, from baseline to month 24 in men with prostate cancer and from baseline to month 12 in women with breast cancer. A secondary outcome measure in the prostate cancer trial was the incidence of new vertebral fractures through month 36. 

In Trial 20040138, randomization was stratified by age (< 70 years vs ≥ 70 years) and duration of androgen deprivation therapy at trial entry (≤ 6 months vs > 6 months). At trial entry 79% of patients received androgen deprivation therapy for more than 6 months.

In Trial 20040135, randomization was stratified by duration of adjuvant aromatase inhibitor therapy at trial entry (≤ 6 months vs > 6 months). At trial entry 62% received adjuvant aromatase inhibitor therapy for more than 6 months.

Denosumab resulted in a statistically significant effect on bone mineral density as compared to placebo at 24 months in patients with nonmetastatic prostate (P < .0001) and at 12 months in patients with breast cancer (P < .0001). In men with prostate cancer, denosumab also significantly reduced the incidence of new vertebral fractures at 36 months. The proportion of men with new vertebral fracture at 36 months was 1.5% in men treated with denosumab compared to 3.9% in men on the placebo arm ( P = .0125).

Safety and Administration

Adverse reactions reported in ≥ 10% of denosumab-treated patients and more frequently than in placebo-treated patients were arthralgia and back pain. Pain in extremity and musculoskeletal pain were also noted. Hypocalcemia was observed only in denosumab-treated patients (2.4%) at the month 1 visit.

The recommended dose and schedule for denosumab as a treatment to increase bone mass in patients at high risk for fracture receiving androgen deprivation therapy for nonmetastatic prostate cancer or adjuvant aromatase inhibitor therapy for breast cancer is 60 mg subcutaneously every 6 months.

On June 1, 2010, denosumab (Prolia) at the same dose and schedule was approved for the treatment of postmenopausal women with osteoporosis at high risk for fracture. On November 18, 2010, denosumab (marketed under the tradename 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.

Denosumab is a monoclonal antibody that binds to RANKL, a protein involved in the formation, function, and survival of osteoclasts. ■



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