FDA Approves Denosumab for Patients With Cancer

Megan Brooks

September 19, 2011

September 19, 2011 — The osteoporosis drug denosumab (Prolia, Amgen Inc) has received approval from the US Food and Drug Administration for 2 new indications:

  • as a treatment to increase bone mass in women at high risk for fracture who are receiving adjuvant aromatase inhibitor therapy for breast cancer, and

  • as a treatment to increase bone mass in men at high risk for fracture who are receiving androgen deprivation therapy for nonmetastatic prostate cancer.

"Bone loss and fractures are recognized adverse effects of hormone ablation therapies, but we have not had an approved treatment option to prevent these problems for our patients," Matthew Smith, MD, PhD, director of the Genitourinary Malignancies Program at Massachusetts General Hospital Cancer Center, Boston, said in a statement issued by Amgen today. He was lead investigator on a trial of denosumab in men with prostate cancer.

Denosumab: A Brief History

Denosumab is a fully human monoclonal antibody that targets the receptor activator of the nuclear factor-kappa-B ligand (RANKL) protein, which acts as the primary signal to promote bone removal. By inhibiting the development and activity of osteoclasts, denosumab decreases bone resorption and increases bone density. It is administered as a single subcutaneous injection of 60 mg once every 6 months.

Denosumab received US Food and Drug Administration approval in June 2010 for treatment of osteoporosis. In some countries, it is already approved as a therapy for bone loss associated with hormone ablation therapy.

The drug has also been approved in all 27 member states of the European Union for use in adult patients with solid tumors and bone metastases. The indication is for preventing skeletal-related events, including pathological fracture, radiation to bone, spinal cord compression, or surgery to bone.

The same indication was approved in the United States in November 2010 after a 6-month priority review.

The expanded indications granted today for denosumab in the United States are based on 2 phase 3 clinical trials funded by Amgen: a 3-year, randomized, double-blind, placebo-controlled study of 1468 men with nonmetastatic prostate cancer undergoing androgen deprivation therapy, and a 2-year, double-blind, placebo-controlled study of 252 postmenopausal women with breast cancer receiving aromatase inhibitor therapy.

In men, bone mineral density (BMD) was significantly higher at the lumbar spine in those treated with denosumab (+5.6%) for 2 years compared with those treated with placebo (−1.0%). The treatment difference was 6.7% (95% confidence interval [CI], 6.2% - 7.1%; P < .0001).

After 3 years, the differences in BMD favoring denosumab were 7.9% at the lumbar spine, 5.7% at the (total) hip, and 4.9% at the femoral neck. Also at 3 years, the incidence of new vertebral fractures was 3.9% in the placebo group vs 1.5% in the denosumab group, yielding a relative risk reduction of 62% (P = .0125).

In women, BMD was higher at 1 year at the lumbar spine in those treated with denosumab (+4.8%) compared with placebo (−0.7%). The treatment difference was 5.5% (95% CI, 4.8% - 6.3%; P < .0001).

After 2 years, differences in BMD favoring denosumab were 7.6% at the lumbar spine, 4.7% at the (total) hip, and 3.6% at the femoral neck.

In March 2011, the American Society of Clinical Oncology issued an updated guideline on the use of bone-modifying agents in patients with metastatic breast cancer.

As reported by Medscape Medical News at that time, the update recommends denosumab, in addition to the bisphosphonates zoledronic acid and pamidronate, to combat bone loss in this patient population.

In studies of denosumab in patients with bone loss receiving androgen deprivation therapy for prostate cancer or adjuvant aromatase inhibitor therapy for breast cancer, the most common adverse reactions (per patient incidence 10% or greater) reported were arthralgia and back pain. Pain in extremity and musculoskeletal pain have also been reported in clinical trials.

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