Novel Agent Denosumab Effective in Cancer Patients With Bone Metastases, But Will it Challenge Bisphosphonates?

Zosia Chustecka

September 30, 2009

September 30, 2009 (Berlin, Germany) — Denosumab, a novel biologic product that targets bone, has shown efficacy in cancer patients with bone metastases, with results that rival those seen with the bisphosphonate zoledronic acid (Zometa), which is currently used in this patient population.

A large trial in breast cancer patients with bone metastases found the efficacy of denosumab to be superior to zoledronic acid, and a large trial in patients with multiple myeloma and solid tumors (excluding breast and prostate cancers) found the efficacy to be "not inferior." The results were presented here at the 15th Congress of the European CanCer Organization and the 34th European Society for Medical Oncology Multidisciplinary Congress.

Both studies were funded by Amgen, which has developed and is set to launch denosumab soon, with hopes of "blockbuster" sales. It is a biologic product — a monoclonal antibody directed against RANKL, a key mediator in bone turnover — and, as a "first in its class" product, is expected to command a premium price.

At a large press conference in Berlin sponsored by the company, the principal investigators of these 2 trials in cancer patients with bone metastases were enthusiastic about the product, and said they would use denosumab — when it become available — instead of zoledronic acid in this patient population, because of convenience (subcutaneous rather than intravenous administration) and because there was a lower incidence of renal toxicity and acute-phase reactions.

Alison Stopeck, MD, from the Arizona Cancer Center in Tucson, who headed the breast cancer study, noted that in this population, the novel drug was "better."

Denosumab was superior to zoledronic acid in preventing skeletal-related events.

"Denosumab was superior to zoledronic acid in preventing skeletal-related events and delayed worsening of bone pain," Dr. Stopeck said. It also offers potential tolerability advantages for many patients, and so would be "a welcome new treatment option for advanced breast cancer patients." About 80% of such patients develop bone metastases, and these are often accompanied by severe and painful bone complications, she added.

However, another breast cancer expert approached by Medscape Oncology, Joanne Mortimer, MD, from the City of Hope in Duarte, California, said she was "not overwhelmed by the new data." She pointed out that the bisphosphonates have had a huge impact on the natural history of this complication, so there is little room for further improvement. As well as zoledronic acid, pamidronate (Aredia) is often used in this patient population; both of these are administered by intravenous infusion. In Europe, oral ibandronate (Boniva) is often used. "Twenty-five years ago, we were seeing hips that needed replacement and spinal compressions, but we don't see these serious complications when we use bisphosphonates," she said.

Concerns Raised by Data From Other Trials

Dr. Mortimer also noted that some concerns were raised about denosumab at a recent US Food and Drug Administration (FDA) advisory committee meeting that she attended.

That meeting, held on August 13, considered data from clinical trials in which denosumab was being used to prevent bone loss in breast cancer patients receiving aromatase inhibitors and in prostate cancer patients receiving androgen-deprivation therapy (the latter trial was published recently [N Engl J Med 2009;361:745-755]).

That meeting also considered data for denosumab use in the treatment and prevention of postmenopausal osteoporosis, which would be the major indication for the product and the largest and most lucrative potential market for the drug.

The FDA advisory committee voted to recommend approval for denosumab in the treatment of postmenopausal osteoporosis, but not for its prevention, and voted to recommend its use in prostate cancer patients receiving androgen-deprivation therapy but not for its use in breast cancer patients receiving aromatase inhibitors. The FDA usually, but not always, follows the advice of its committees; a decision on denosumab is expected on October 19.

Dr. Mortimer said the clinical trial data presented at that meeting showed a slight increase in infections in patients who were taking denosumab, compared with placebo. "Some of the infections were deep seated," she explained. They included endocarditis, cellulitis, and some unusual infections with abscesses. It raised the concern that the product, a monoclonal antibody known to have an effect on both T and B cells, is interfering with the immune system in such as way that patients become more vulnerable to infection, she said.

In addition, there were more cases of cancer in patients receiving denosumab than in those receiving placebo in the trials of postmenopausal osteoporosis and in the breast and prostate cancer studies. This signal raises the possibility that denosumab is affecting the immune system in a way that would encourage cancer progression, Dr. Mortimer suggested. "If there is any suspicion that there is an increased cancer recurrence, it is not worth it," she said at the meeting.

However, the latest clinical trial data, from cancer patients with bone metastases, do not have any such cancer signal. There was no evidence to suggest that denosumab had any effect on cancer, and there was no difference from zoledronic acid, which was the comparator used, Dr. Stopeck told Medscape Oncology.

Efficacy in Cancer Patients With Bone Metastases

The new trials in cancer patients with bone metastases assessed efficacy by measuring the median time to the first on-study skeletal-related event (defined as fracture, radiation to bone, surgery to bone, or spinal cord compression).

The study conducted in breast cancer patients with bone metastases involved 2064 patients and lasted 34 months. The primary end point, the median time to the first on-study skeletal-related event, was 26.5 months for zoledronic acid but was not reached for denosumab and "could not be estimated." A secondary end point, the median time to first on-study skeletal-related events or hypercalcemia, was 25.2 months for zoledronic acid but again was not reached for denosumab. In addition, worsening of pain was reported earlier with zoledronic acid (at 64 days) than with denosumab (at 88 days).

All of these differences were statistically significant. The researchers, headed by Dr. Stopeck, concluded that denosumab was "superior" to zoledronic acid.

The overall incidence of adverse events was similar in the 2 groups (reported by 96% of patients receiving denosumab and 97% receiving zoledronic acid); serious adverse events were reported by 44% and 46%, respectively. The researchers noted that renal toxicity was seen in 4.9% of patients receiving denosumab and in 8.5% receiving zoledronic acid. Osteonecrosis of the jaw was seen in 2% receiving denosumab and in 1.4% receiving zoledronic acid; this difference was not statistically significant. The overall survival and the time to cancer progression were balanced in the 2 treatment groups.

"The incidence of adverse events and serious adverse events was consistent with what has been previously reported for these 2 agents," Dr. Stopeck told the meeting.

The study conducted in patients with solid tumors (except for breast and prostate cancer) and multiple myeloma with bone metastases involved 1776 patients, and was reported at the meeting by David Henry, MD, clinical professor of medicine at Pennsylvania Hospital in Philadelphia.

In this study, the median time to first on-study skeletal-related event was 20.6 months for denosumab and 16.3 months for zoledronic acid, which, although numerically different, was not statistically significant. However, this difference was "statistically significant for noninferiority," Dr. Henry said. The 2 secondary end points — time to first on-study skeletal-related events or hypercalcemia of malignancy — were statistically significant (19 months for denosumab vs 14.4 months for zoledronic acid). Worsening of pain was reported at 36 days with zoledronic acid and at 57 days with denosumab.

The incidence of adverse effects was similar in the 2 groups, with an overall incidence of 96% in both groups, and serious adverse events were reported by 63% receiving denosumab and 66% receiving zoledronic acid. Rates of osteonecrosis of the jaw and infectious events were also balanced between the 2 treatment groups, as was overall survival and the time to cancer progression.

A third trial, in patients with prostate cancer and bone metastases, is still underway. Amgen said that it will wait for those results before filing for an indication for denosumab use in cancer patients with bone metastases.

All of the studies with denosumab were funded by Amgen, which is developing the drug.

15th Congress of the European CanCer Organization (ECCO 15) and the 34th European Society for Medical Oncology (34th ESMO) Multidisciplinary Congress: Abstracts 2LBA and 20LBA. Presented September 22 and September 21, 2009.

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