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FDA Approval for Denosumab

Brand name(s):  Prolia®, Xgeva®

Full prescribing information is available, including clinical trial information, safety, dosing, drug-drug-interactions, and contraindications.

Approved for unresectable giant cell tumor of bone in adults and skeletally mature adolescents

On June 13, 2013, the Food and Drug Administration (FDA) approved denosumab (Xgeva®  injection, Amgen Inc., for subcutaneous use) for the treatment of adults and skeletally mature adolescents with giant cell tumor of bone that is unresectable or where surgical resection is likely to result in severe morbidity. 

Denosumab's approval was based on observation of durable objective responses in two multicenter open-label trials enrolling adult and skeletally mature adolescents with histologically confirmed, measurable giant cell tumor of bone. These tumors were recurrent, unresectable, or located where planned surgery was likely to result in severe morbidity. Patients received 120 mg denosumab subcutaneously every 4 weeks, with additional doses on days 8 and 15 of the first month.

A total of 304 patients received denosumab. The median age was 33 years (range: 13-83 years) and a total of 10 patients were skeletally mature adolescents (13-17 years). Radiographic assessments at baseline and following denosumab treatment were available for 187 patients (61 percent). A retrospective determination of objective response was performed by an independent review committee using modified Response Evaluation Criteria in Solid Tumors (RECIST 1.1). 

An objective response was identified in 47 of 187 patients, for an overall response rate of 25 percent (95 percent confidence interval: 19, 32).  All responses were partial responses. The estimated median time to response was 3 months.  In the 47 patients with an objective response, the median duration of follow-up was 20 months (range: 2-44 months), and 51 percent (24 of 47) had responses lasting at least 8 months.  Three patients experienced disease progression following an objective response. 

Safety data were evaluated for 304 patients with giant cell tumor of bone who received at least one dose of denosumab. Of these patients, 145 were treated for at least 1 year. The most common adverse reactions were arthralgia, headache, nausea, back pain, fatigue, and pain in the extremity. The most common serious adverse reactions were osteonecrosis of the jaw and osteomyelitis

The recommended dose and schedule of denosumab for the treatment of giant cell tumor of bone is 120 mg administered subcutaneously every 4 weeks, with additional 120 mg doses on days 8 and 15 of the first month.

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Approved to increase bone mass in patients at high risk for fracture including androgen deprivation therapy (ADT) for nonmetastatic prostate cancer or adjuvant aromatase inhibitor (AI) therapy for breast cancer

On September 16, 2011, the FDA granted approval for denosumab (Prolia®, made by Amgen, Inc.) as a treatment to increase bone mass in patients who are at high risk of fracture from receiving androgen deprivation therapy (ADT) for nonmetastatic prostate cancer or adjuvant aromatase inhibitor (AI) therapy for breast cancer. In men with nonmetastatic prostate cancer, denosumab also reduced the incidence of vertebral fracture. 

Denosumab is a monoclonal antibody that binds to RANKL, a protein involved in the formation, function, and survival of osteoclasts, the cells responsible for bone resorption. 

The approvals were based on results from two international randomized (1:1), double-blind, placebo-controlled trials in patients receiving ADT for nonmetastatic prostate cancer or adjuvant AI 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 (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 (median age 59 years). Women 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 age 25. 

Patients were randomly assigned to receive subcutaneous injections of 60 mg denosumab or a placebo, once every 6 months, for a total of 6 doses in Trial 20040138 and for a total of 4 doses in Trial 20040135. 

The primary outcome measure in each trial was the percent change in lumbar spine BMD, from baseline to month 24 in Trial 20040138 and baseline to month 12 in Trial 20040135. A secondary outcome measure in Trial 20040138 was the incidence of new vertebral fractures through month 36. 

In Trial 20040138, the randomization was stratified by age (younger than 70 years vs. 70 years or older) and duration of ADT at trial entry (6 months or less vs. more than 6 months). Seventy nine percent received ADT for more than 6 months at trial entry.

In Trial 20040135, the randomization was stratified by duration of adjuvant AI therapy at trial entry (6 months or less vs. more than 6 months). Sixty-two percent received adjuvant AI therapy for more than 6 months at trial entry. 

Denosumab resulted in a statistically significant effect on BMD compared with placebo in patients with nonmetastatic prostate or breast cancer, at 24 and 12 months respectively. In men with prostate cancer, denosumab also significantly reduced the incidence of new vertebral fractures at 36 months. At 36 months, the proportion of men with new vertebral fracture was 1.5 percent in men treated with denosumab compared with 3.9 percent in men treated with placebo [Absolute Risk Reduction (ARR) 2.4%, 95% CI (0.7, 4.1); Relative Risk Reduction (RRR) 62% (22, 81); p=0.0125]. 

Efficacy Results for Prolia in Patients at High Risk for Fracture Receiving ADT for Nonmetastatic Prostate Cancer or Adjuvant AI Therapy for Breast Cancer 
 Trial 20040138 Non-metastatic Prostate CancerTrial 20040135 Non-metastatic Breast Cancer
 ProliaPlaceboProliaPlacebo
Change in lumbar spine BMD from baseline to end of study period*+5.6%-1.0%+4.8%-0.7%
Treatment difference (95% CI)6.7% (6.2, 7.1)5.5% (4.8, 6.3)
p-value< 0.0001< 0.0001

* at 24 months in Trial 20040138; at 12 months in Trial 20040135

Adverse reactions reported in at least ten percent of patients treated with denosumab and more frequently than in patients treated with placebo were arthralgia and back pain. Extremity pain and musculoskeletal pain were also noted. Hypocalcemia (serum calcium less than 8.4 mg/dL) was observed only in patients treated with denusomab (2.4 percent) at the first monthly follow-up visit. The recommended dose and schedule for denosumab as a treatment to increase bone mass in patients at high risk for fracture receiving ADT for nonmetastatic prostate cancer or adjuvant AI therapy for breast cancer is 60 mg subcutaneously every 6 months.

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Approved for prevention of skeletal-related events (SREs) in patients with bone metastases from solid tumors

On November 18, 2010, the FDA approved denosumab (Xgeva, made by Amgen Inc.) for the prevention of skeletal-related events (SREs) in patients with bone metastases from solid tumors. Denosumab is not indicated for the prevention of SREs in patients with multiple myeloma.

Denosumab is a monoclonal antibody that binds to RANKL, a protein involved in the formation, function, and survival of osteoclasts. Increased osteoclast activity, stimulated by RANKL, is a mediator of bone pathology in bone metastases from solid tumors.

The approval is based on results from three international randomized (1:1) double-blind double-dummy trials in patients with bone metastases comparing denosumab to zoledronic acid. Trial 20050103 enrolled 1,901 patients with hormone-refractory prostate cancer, Trial 20050136 enrolled 2,046 patients with breast cancer, and Trial 20050244 enrolled 1,776 patients with advanced multiple myeloma or solid tumors other than breast or prostate cancer.

In all three trials, patients were randomly assigned to receive either 120 mg denosumab subcutaneously every 4 weeks or 4 mg zoledronic acid intravenously every 4 weeks (dose-adjusted for reduced renal function). Patients with creatinine clearances less than 30 mL/min were excluded, and prior intravenous bisphosphonate therapy was not permitted.

The primary outcome measure in each trial was the detemination of non-inferiority in time-to-first SRE in patients treated with denosumab as compared to patients treated with zoledronic acid. An SRE was defined as a pathologic fracture, radiation therapy to bone, surgery to bone, or spinal cord compression due to cancer. Other outcome measures included superiority of time-to-first SRE and superiority of time-to-first and subsequent SRE.

In Trial 20050244, 40 percent of patients had non-small cell lung cancer, 10 percent had multiple myeloma, 9 percent had renal cell carcinoma, and 6 percent had small cell lung cancer.Other tumor types individually comprised less than 5 percent of the enrolled population.

Denosumab therapy resulted in a statistically significant delay in the time-to-first SRE and in the time-to-first and subsequent SRE compared with zoledronic acid in patients with breast cancer (Trial 20050136) or hormone-refractory prostate cancer (Trial 20050103). In Trial 20050244, denosumab wasnot less effective than zoledronic acid in delaying the time-to-first SRE and did not demonstrate superiority.

Efficacy Results for Xgeva Compared to Zoledronic Acid

 Trial 1
Metastatic Breast Cancer
Trial 2
Metastatic Solid Tumors or Multiple Myeloma
Trial 3
Metastatic Hormone-Refractory Prostate Cancer
XgevaZoledronic AcidXgevaZoledronic AcidXgevaZoledronic Acid
N10261020886890950951
First On-study SRE
Number of Patients who had SREs (%)315 (30.7)372 (36.5)278 (31.4)323 (36.3)341 (35.9)386 (40.6)
Components of First SRE
Radiation to Bone82 (8.0)119 (11.7)119 (13.4)144 (16.2)177 (18.6)203 (21.3)
Pathological Fracture212 (20.7)238 (23.3)122 (13.8)139 (15.6)137 (14.4)143 (15.0)
Surgery to Bone12 (1.2)8 (0.8)13 (1.5)19 (2.1)1 (0.1)4 (0.4)
Spinal Cord Compression9 (0.9)7 (0.7)24 (2.7)21 (2.4)26 (2.7)36 (3.8)
Median Time to SRE (months)NRb26.420.516.320.717.1
Hazard Ratio (95% CI)0.82 (0.71, 0.95)0.84 (0.71, 0.98)0.82 (0.71, 0.95)
Noninferiority p-value< 0.001< 0.001< 0.001
Superiority p-valuec0.0100.0600.008
First and Subsequent SREd
Mean Number/Patient0.460.600.440.490.520.61
Rate Ratio (95% CI)0.77 (0.66, 0.89)0.90 (0.77, 1.04)0.82 (0.71, 0.94)
Superiority p-valuee0.0010.1450.009

bNR = not reached.
cSuperiority testing performed only after denosumab demonstrated to be noninferior to zoledronic acid within trial.
dAll skeletal events postrandomization; new events defined by occurrence ≥ 21 days after preceding event.
eAdjusted p-values are presented.

No apparent differences in overall survival were observed between treatment groups in any of the three trials. In a subgroup analysis of patients with multiple myeloma in Trial 20050244, mortality appeared to be higher for patients treated with denosumab compared with those treated with zoledronic acid (hazard ratio [95 percent CI] of 2.26 [1.13, 4.50]; n = 180).The limited number of patients in this subgroup precludes a definitive conclusion.

The most common adverse reactions in patients receiving denosumab (in at least 25 percent of patients) were fatigue or asthenia, hypophosphatemia, and nausea. The most common serious adverse reaction in patients receiving denosumab was dyspnea. The most common adverse reactions resulting in denosumab discontinuation were osteonecrosis and hypocalcemia.

Severe hypocalcemia (corrected serum calcium less than 7 mg/dL or less than 1.75 mmol/L) occurred in 3.1 percent of patients treated with denosumab and 1.3 percent of those treated with zoledronic acid. Osteonecrosis of the jaw was confirmed in 1.8 percent of patients treated with denosumab and 1.3 percent of those  treated with zoledronic acid.

The recommended dose and schedule for denosumab for the prevention of SREs in patients with bone metastases from solid tumors is 120 mg administered subcutaneously every 4 weeks.

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Full prescribing information for Prolia is available, including clinical trial information, safety, dosing, drug-drug-interactions, and contraindications.

Approved for treatment of postmenopausal women with osteoporosis at high risk for fracture

On June 1, 2010, denosumab was approved for the treatment of postmenopausal women with osteoporosis at high risk for fracture and is marketed under the trade name Prolia. The dose for this indication is 60 mg administered subcutaneously every 6 months.

This summary was provided by Richard Pazdur, M.D., director of the FDA's Division of Oncology Drug Products.

The FDA is the division of the U.S. Department of Health and Human Services charged with ensuring the safety and effectiveness of new drugs and other products. (See "Learn How Drugs and Devices Get Approved.") The FDA's mission is to promote and protect the public health by helping safe and effective products to reach the market in a timely way, and monitoring products for continued safety after they are in use.

  • Updated: July 2, 2013