FDA Panel Rejects Denosumab Against Bone Metastasis in Prostate Cancer

SILVER SPRING, MD. – A Food and Drug Administration advisory panel voted 12 to 1 on Feb. 8 that denosumab did not have a favorable risk-benefit profile as a treatment to reduce the risk of bone metastases in men who are at high risk for developing them with castrate-resistant prostate cancer.

Concern over the possibility of increased toxicity, especially osteonecrosis of the jaw, with longer drug exposure weighed heavily in the Oncologic Drugs Advisory Committee decision (ODAC). The patient representative was the only panelist to vote in favor.

Denosumab (Xgeva) was approved in 2010 for the prevention of skeletal-related events in patients with bone metastases from solid tumors. The new indication, proposed by manufacturer Amgen, would start treatment earlier to avert bone metastases before they develop in men with castrate-resistant prostate cancer (CRPC).

Amgen said that denosumab "prolongs bone metastasis-free survival by reducing the risk of developing bone metastases."

The application is based on the results of a phase III international study of 1,432 men with CRPC at high risk of developing bone metastases (defined as a prostate-specific antigen level of 8.0 ng/mL or higher or a PSA level that had doubled within 10 months or less).

The study found that survival free of bone metastases, the primary end point, was prolonged by a median of about 4 months in patients randomized to denosumab (120 mg subcutaneously every 4 weeks) compared with those on placebo – a statistically significant difference that represented a 15% reduction in risk.

But ODAC was nearly unanimous in finding that this difference in bone metastasis–free survival was modest and did not outweigh the risks of treatment, namely osteonecrosis of the jaw. In the study, almost 5% of those on denosumab developed osteonecrosis of the jaw, a known effect of treatment, compared with none of those on placebo. Panelists were concerned that this risk could increase with longer exposure to the drug.

The panel was not asked specifically whether it recommended approval for this expanded indication. The FDA must make a decision by the Prescription Drug User Fee Act (PDUFA) action date of April 26, 2012.

Amgen issued the following statement after the ODAC vote: "We look forward to further discussions with the FDA as they continue to review our application," it said. "The development of bone metastases in men with castration-resistant prostate cancer is a clinically significant event, and delaying bone metastases in these men is a clear unmet need with no approved therapies."

In the study under consideration, bone metastasis–free survival was determined by time to first occurrence of bone metastasis (symptomatic or asymptomatic at detection) or death, which was a median of 29.5 months among those on denosumab vs. 25.2 months among those on placebo.

There were no significant differences in overall survival, progression-free survival, or patient-reported outcomes between the two groups. In about two-thirds of cases, bone metastases were asymptomatic.

Denosumab, a monoclonal antibody that inhibits the RANK ligand (RANKL), is marketed as Xgeva at the same dose and schedule used in this study for prevention of skeletal events such as fractures from bone metastases. It is not indicated for the prevention of skeletal-related events in patients with multiple myeloma. By binding to RANKL, denosumab "prevents activation of RANK, thereby inhibiting osteoclast formation, activation, and survival," according to Amgen.

Denosumab is also approved as Prolia, at a lower dose administered once a year, to treat postmenopausal women with osteoporosis who are at high risk of fracture; to increase bone mass in men who are at high risk of fracture while receiving androgen deprivation therapy for nonmetastatic prostate cancer; and to increase bone mass in women at high risk of fracture while receiving adjuvant aromatase inhibitor therapy for breast cancer.

If the new indication is granted, Xgeva would be the first treatment approved to prevent or delay bone metastases in men with nonmetastatic CRPC, according to Amgen. But that appears unlikely, since the FDA usually follows the recommendations of its advisory panels.

Panelists were cleared of potential conflicts before voting on denosumab.

SILVER SPRING, MD. – A Food and Drug Administration advisory panel voted 12 to 1 on Feb. 8 that denosumab did not have a favorable risk-benefit profile as a treatment to reduce the risk of bone metastases in men who are at high risk for developing them with castrate-resistant prostate cancer.

Concern over the possibility of increased toxicity, especially osteonecrosis of the jaw, with longer drug exposure weighed heavily in the Oncologic Drugs Advisory Committee decision (ODAC). The patient representative was the only panelist to vote in favor.

Denosumab (Xgeva) was approved in 2010 for the prevention of skeletal-related events in patients with bone metastases from solid tumors. The new indication, proposed by manufacturer Amgen, would start treatment earlier to avert bone metastases before they develop in men with castrate-resistant prostate cancer (CRPC).

Amgen said that denosumab "prolongs bone metastasis-free survival by reducing the risk of developing bone metastases."

The application is based on the results of a phase III international study of 1,432 men with CRPC at high risk of developing bone metastases (defined as a prostate-specific antigen level of 8.0 ng/mL or higher or a PSA level that had doubled within 10 months or less).

The study found that survival free of bone metastases, the primary end point, was prolonged by a median of about 4 months in patients randomized to denosumab (120 mg subcutaneously every 4 weeks) compared with those on placebo – a statistically significant difference that represented a 15% reduction in risk.

But ODAC was nearly unanimous in finding that this difference in bone metastasis–free survival was modest and did not outweigh the risks of treatment, namely osteonecrosis of the jaw. In the study, almost 5% of those on denosumab developed osteonecrosis of the jaw, a known effect of treatment, compared with none of those on placebo. Panelists were concerned that this risk could increase with longer exposure to the drug.

The panel was not asked specifically whether it recommended approval for this expanded indication. The FDA must make a decision by the Prescription Drug User Fee Act (PDUFA) action date of April 26, 2012.

Amgen issued the following statement after the ODAC vote: "We look forward to further discussions with the FDA as they continue to review our application," it said. "The development of bone metastases in men with castration-resistant prostate cancer is a clinically significant event, and delaying bone metastases in these men is a clear unmet need with no approved therapies."

In the study under consideration, bone metastasis–free survival was determined by time to first occurrence of bone metastasis (symptomatic or asymptomatic at detection) or death, which was a median of 29.5 months among those on denosumab vs. 25.2 months among those on placebo.

There were no significant differences in overall survival, progression-free survival, or patient-reported outcomes between the two groups. In about two-thirds of cases, bone metastases were asymptomatic.

Denosumab, a monoclonal antibody that inhibits the RANK ligand (RANKL), is marketed as Xgeva at the same dose and schedule used in this study for prevention of skeletal events such as fractures from bone metastases. It is not indicated for the prevention of skeletal-related events in patients with multiple myeloma. By binding to RANKL, denosumab "prevents activation of RANK, thereby inhibiting osteoclast formation, activation, and survival," according to Amgen.

Denosumab is also approved as Prolia, at a lower dose administered once a year, to treat postmenopausal women with osteoporosis who are at high risk of fracture; to increase bone mass in men who are at high risk of fracture while receiving androgen deprivation therapy for nonmetastatic prostate cancer; and to increase bone mass in women at high risk of fracture while receiving adjuvant aromatase inhibitor therapy for breast cancer.

If the new indication is granted, Xgeva would be the first treatment approved to prevent or delay bone metastases in men with nonmetastatic CRPC, according to Amgen. But that appears unlikely, since the FDA usually follows the recommendations of its advisory panels.

Panelists were cleared of potential conflicts before voting on denosumab.

SILVER SPRING, MD. – A Food and Drug Administration advisory panel voted 12 to 1 on Feb. 8 that denosumab did not have a favorable risk-benefit profile as a treatment to reduce the risk of bone metastases in men who are at high risk for developing them with castrate-resistant prostate cancer.

Concern over the possibility of increased toxicity, especially osteonecrosis of the jaw, with longer drug exposure weighed heavily in the Oncologic Drugs Advisory Committee decision (ODAC). The patient representative was the only panelist to vote in favor.

Denosumab (Xgeva) was approved in 2010 for the prevention of skeletal-related events in patients with bone metastases from solid tumors. The new indication, proposed by manufacturer Amgen, would start treatment earlier to avert bone metastases before they develop in men with castrate-resistant prostate cancer (CRPC).

Amgen said that denosumab "prolongs bone metastasis-free survival by reducing the risk of developing bone metastases."

The application is based on the results of a phase III international study of 1,432 men with CRPC at high risk of developing bone metastases (defined as a prostate-specific antigen level of 8.0 ng/mL or higher or a PSA level that had doubled within 10 months or less).

The study found that survival free of bone metastases, the primary end point, was prolonged by a median of about 4 months in patients randomized to denosumab (120 mg subcutaneously every 4 weeks) compared with those on placebo – a statistically significant difference that represented a 15% reduction in risk.

But ODAC was nearly unanimous in finding that this difference in bone metastasis–free survival was modest and did not outweigh the risks of treatment, namely osteonecrosis of the jaw. In the study, almost 5% of those on denosumab developed osteonecrosis of the jaw, a known effect of treatment, compared with none of those on placebo. Panelists were concerned that this risk could increase with longer exposure to the drug.

The panel was not asked specifically whether it recommended approval for this expanded indication. The FDA must make a decision by the Prescription Drug User Fee Act (PDUFA) action date of April 26, 2012.

Amgen issued the following statement after the ODAC vote: "We look forward to further discussions with the FDA as they continue to review our application," it said. "The development of bone metastases in men with castration-resistant prostate cancer is a clinically significant event, and delaying bone metastases in these men is a clear unmet need with no approved therapies."

In the study under consideration, bone metastasis–free survival was determined by time to first occurrence of bone metastasis (symptomatic or asymptomatic at detection) or death, which was a median of 29.5 months among those on denosumab vs. 25.2 months among those on placebo.

There were no significant differences in overall survival, progression-free survival, or patient-reported outcomes between the two groups. In about two-thirds of cases, bone metastases were asymptomatic.

Denosumab, a monoclonal antibody that inhibits the RANK ligand (RANKL), is marketed as Xgeva at the same dose and schedule used in this study for prevention of skeletal events such as fractures from bone metastases. It is not indicated for the prevention of skeletal-related events in patients with multiple myeloma. By binding to RANKL, denosumab "prevents activation of RANK, thereby inhibiting osteoclast formation, activation, and survival," according to Amgen.

Denosumab is also approved as Prolia, at a lower dose administered once a year, to treat postmenopausal women with osteoporosis who are at high risk of fracture; to increase bone mass in men who are at high risk of fracture while receiving androgen deprivation therapy for nonmetastatic prostate cancer; and to increase bone mass in women at high risk of fracture while receiving adjuvant aromatase inhibitor therapy for breast cancer.

If the new indication is granted, Xgeva would be the first treatment approved to prevent or delay bone metastases in men with nonmetastatic CRPC, according to Amgen. But that appears unlikely, since the FDA usually follows the recommendations of its advisory panels.

Panelists were cleared of potential conflicts before voting on denosumab.