Bone Drug in Limbo

The FDA decides to wait on reviewing Prolia (denosumab) for reducing treatment-related bone loss in breast and prostate cancer patients, but a new study may shed light on the drug’s importance.

An advisory panel recently recommended to the Food and Drug Administration to approve Prolia (denosumab)—a drug that shows promise in treating bone loss in certain patient populations—for postmenopausal women with osteoporosis and for prostate cancer patients, but not for breast cancer patients. However, the Advisory Committee for Reproductive Health Drugs made their decision mid-August, before the September release of a large new study that shows the safety and efficacy of the drug, at a higher dose and given more frequently, in another patient population—breast cancer patients with bone metastases.

After reviewing data from 30 clinical studies involving more than 12,000 patients, the ACRHD recommended approval of Prolia for the treatment of bone loss in prostate cancer patients undergoing hormone ablation therapy. However, the committee did not recommend approval of Prolia for treatment of bone loss associated with ablation therapy in women with early-stage breast cancer receiving aromatase inhibitors (AI), a class of drugs that block estrogen production. Approved AIs include Arimidex (anastrozole), Femara (letrozole), and Aromasin (exemestane).

Noting that there is already an effective, time-tested treatment available in a class of drugs called bisphosphonates, the panel was concerned that there was not enough information on the long-term safety of the drug, mainly the risk progression of the primary tumor and recurrence. Bisphosphonates attach to the surface of bone and inhibit bone resorption, thereby promoting an increase in bone mineral density. Prolia, on the other hand, slows the breakdown of bone by blocking the receptor activator of NF-kB ligand (RANKL)—a protein that activates osteoclasts, the cells responsible for bone resorption. (You can read more on bone health drugs in “Good to the Bone”) from the Winter 2007 issue.


Succinctly, the ACRHD panel concluded the risks of the new drug may outweigh the benefits in breast cancer patients The trial, which the ACRHD based its decision upon, was a phase II study and did not have the large number of patients the osteoporosis or prostate cancer trials had, which may have led the panel to feel the study was too small to make a recommendation for approval, especially with the availability of bisphosphonates.

But for breast cancer patients with bone metastases, the drug may be very helpful. Instead of administered every six months, as Prolia was in the early-stage breast cancer trial, patients with metastatic cancer were given monthly denosumab at twice the dosage. (Because the two breast cancer trials administered the drug in different frequencies and doses, denosumab may have two different trade names).

Given the timing of the panel’s decision, it is unlikely they were aware of the findings of the new study that demonstrated denosumab’s safety and efficacy in preventing skeletal-related events (SRE)—pathologic fracture, radiation or surgery to bone, or spinal cord compression—in patients with bone metastases.

The phase III trial randomized two groups of about 1,020 breast cancer patients each to receive either the intravenous bisphosphonate Zometa (zoledronic acid), the standard of care for this population, or denosumab injections on a monthly schedule. During the 34-month study, a median for first SRE was not yet reached for the patients treated with denosumab, while the median time to first SRE for Zometa was 806 days.

“I was pleasantly surprised how positive a study it was,” says lead author Alison Stopeck, MD, associate professor of medicine and director of the Clinical Breast Cancer Program at the Arizona Cancer Center in Tucson. “We have a drug that’s not only more effective, but less toxic. It doesn’t need any monitoring, it doesn’t cause renal dysfunction, and it doesn’t cause any of the flu-like symptoms or bony pain that are common with ZA [Zometa],” Stopeck says. “It’s very uncommon to see that in oncology (an agent that is more efficacious and less toxic).”

Rates of renal toxicity were lower in the denosumab group, and rates of adverse events, overall survival, and time to cancer progression were comparable between the two groups. Osteonecrosis of the jaw—a rare side effect where the bone in the jaw dies—occurred infrequently in both groups, affecting 2 percent of the denosumab group and 1.4 percent of the Zometa group, which was not considered statistically different. (You can read more on this side effect in “Bisphosphonates May Increase the Risk of Jaw Disease in Cancer Patients” from our Winter 2007 issue).

“This is actually a very important finding from this trial,” Stopeck says. “What this tells us is that osteonecrosis of the jaw is not specifically related to bisphosphonates, but to the mechanism or action of bisphosphonates, which is osteoclast inhibition.” Bone loss and bone remodeling are highly regulated, coordinated processes, she explained. “When you remodel bone, which we do all the time, every day, we are resorbing bone. When you stop one, you stop the other.”

A recent study of patients with prostate cancer without bone metastases receiving androgen-deprivation therapy also showed positive results with Prolia. In the double-blind, multicenter trial of 1,468 patients, half received Prolia and half received a placebo. The Prolia group experienced a significant increase in bone mineral density and decreased incidence of new vertebral fractures compared with the placebo group.

Neither of the studies investigated whether or not Prolia might have an anti-tumor effect. “Bisphosphonates have hypothetical-only—not proven—anti-tumor effects,” Stopeck says. “One could make several similar assumptions about Prolia that would suggest it would also have anti-tumor effects.” Proving this would require studying Prolia in an adjuvant setting; trials testing the drug in the adjuvant setting are currently being planned.

Regardless of the ACRHD’s recommendation of Prolia for the two patient groups, the FDA delayed approval of the drug in October citing a need for more data. Specifically, the FDA wants results from further trials demonstrating that Prolia has no detrimental effects on time-to-disease progression or overall survival. Amgen, the makers of the drug, are working with the FDA to determine the appropriate next steps.

Sundeep Khosla, MD,an endocrinologist and research professor of the Departments of Medicine and Physiology College of Medicine at the Mayo Clinic in Rochester, Minnesota, speculates that FDA approval of Prolia in cancer patients could take a while. “If it happens, it may be after the drug has been out and used in post-menopausal women [with osteoporosis] for some time and there’s more data,” he says.

Whether and when the drug receives clearance, pricing may be a substantial stumbling block. “Amgen hasn’t really given people a clue as to what the cost may be,” Khosla says. Alendronate, a generic oral bisphosphonate, costs patients about $500 yearly; other oral and IV drugs, including Zometa, cost between $1,000 and $1,500 a year. And Prolia will have to compete with those anti-resorptive drugs.

“If it’s priced much above $1,500 a year, it will run into some trouble,” Khosla says.