DENOSUMAB FOR DELAYING BONE METASTASES NOT RECOMMENDED

February 9, 2012 — An additional indication for the novel bone drug denosumab (Xgeva, Amgen) — that of delaying bone metastases in men with castration-resistant prostate cancer (CRPC) — has not been recommended for approval by the US Food and Drug Administration (FDA) Oncologic Drugs Advisory Committee that met yesterday.

The FDA is expected to make a ruling on this indication by April 26; the agency usually follows the committee's recommendation, but not always.

Denosumab was approved for use in cancer patients who have bone metastases because data showed that it prevents skeletal-related events, such as pathological fracture, spinal cord compression, and radiotherapy or surgery for the bone metastases.

The indication under consideration is use of the drug to delay the onset of bone metastases in patients with CRPC who are at high risk of developing this complication. The data supporting this indication come from a phase 3 clinical trial of 1432 men with CRPC, and show that denosumab significantly delayed the time to a first bone metastasis or death from any cause by about 4 months, compared with placebo (29.5 vs 25.2 months; P = .03). These results were presented last year at the European Multidisciplinary Cancer Congress (EMCC), and were later published in the Lancet.

When the study was presented at the EMCC meeting, prostate cancer experts were enthusiastic about the results, pointing out that this was the first drug shown to delay the onset of bone metastasis and that it represented a "paradigm shift."

There was less enthusiasm at the committee meeting yesterday, however. The panel voted 12 to 1 against recommending the indication for approval, saying that the benefit was not outweighed by the potential risks of treatment (which include jaw osteonecrosis, seen in about 5% of trial participants). The committee also noted that there was no effect on overall survival or on the overall course of the disease in general.

Committee chair Wyndham Wilson, MD, chief of the lymphoma therapeutics section at the National Institutes of Health, explained that the magnitude of the benefit that was seen (delaying the onset of bone metastasis by 4 months) was "quite low." In addition, there was discussion about whether this benefit is clinically meaningful, in light of the lack of effect on overall survival.

Amgen said that it believes that the drug offers a clinically meaningful benefit. "The development of bone metastasis is an irreversible life-changing event for men living with castration-resistant prostate cancer, and is associated with significant and progressive morbidity," said Sean Harper, MD, chief medical officer at Amgen. Denosumab is the first agent shown to prolong the time to this event, and it addresses an important unmet medical need, he said.

Analysts have forecast sales of denosumab of $3 to $4 billion by 2015, and they estimate that this new indication would be worth about $1 billion of that.