Denosumab Delays Onset of Bone Metastases in Prostate Cancer

Zosia Chustecka

September 25, 2011

September 25, 2011 (Stockholm, Sweden) — The novel bone agent denosumab (Xvega, Amgen) is the only product to date that has been shown to delay the onset of bone metastases in men with castration-resistant prostate cancer (CRPC) who are at high risk for this complication.

In a phase 3 trial, men with CRPC who were treated with denosumab developed their first detectable bone metastasis about 4 months later than those on placebo, Stephane Oudard, MD, head of the Department of Oncology at the Georges Pompidou Hospital, Paris, France, reported here at the 2011 European Multidisciplinary Cancer Congress.

Dr. Stephane Oudard

Nearly 90% of men with CRPC will develop bone metastases. The development of this complication signals that the cancer is entering a chronic and then terminal phase, with major physical and psychological implications for the patient, he said.

"Being able to delay this turning point is therefore very significant," he said. "We have shown that the use of denosumab in this group of patients can impede the onset of bone metastases by just over 4 months," he added.

"Delaying the development of bone metastases in these men is an unmet medical need," said Joaquim Bellmunt, MD, from the Valle d'Hebron University Hospital, Barcelona, Spain, who acted as a discussant for this paper.

However, he was uncertain about how to screen for men who could benefit from this therapy.

He pointed out that although the trial showed a delay in the development of bone metastases, it did not show any effect on overall survival. However, previous studies have shown that men with prostate cancer and bone metastases have 5 times the risk for death as men without this complication, he noted.

"This will require further investigation," he added.

Nevertheless, Dr. Bellmunt was enthusiastic about the finding. As the first agent shown to delay the onset of bone metastasis in CRPC, denosumab "represents a paradigm shift in our beliefs about the limited efficacy of presently available antimetastatic strategies," he explained in a statement.

The results from this study were presented earlier this year, by Matthew Smith, MD, from the Massachusetts General Hospital and Harvard Medical School in Boston, at the American Urological Association annual meeting, and they were highlighted in a manufacturer's press release at that time.

This use of denosumab in men with CRPC who do not have bone metastases, where it would be used to delay the onset of bone metastases, is a potential new indication for the drug. The product is already approved in the United States for use in patients with solid tumors (including prostate cancer) and bone metastases, where it is used to prevent skeletal-related events.

The bisphosphonate zoledronic acid (Zometa, Novartis) has a similar indication. It is being studied in the setting of cancer without bone metastases to see if it can also delay the onset of this complication, but these results are not expected until 2014.

At the moment, "there is a gap in the treatment plan for this group of patients who are hormone-resistant but have not yet developed metastatic disease," said Dr. Oudard.

"Our trial has shown that denosumab prolongs the period before metastasis, where the patients' quality of life has not yet suffered to a great extent," he added.

Delaying Onset of Bone Metastasis

The trial was conducted in 1432 men with CRPC who did not have radiologically detectable bone metastases but were considered to be at high risk for bone metastases because of prostate-specific antigen (PSA) findings (i.e., PSA value of 8 ng/mL or more and/or a PSA doubling time of 10 months or more). They were randomized to receive denosumab 120 mg subcutaneously or placebo.

Denosumab significantly increased the median bone-metastasis-free survival (i.e., the time to first bone metastasis or death from any cause), the primary end point of the study. This was 29.5 months with denosumab and 25.2 months with placebo (hazard ratio, 0.85; 95% confidence interval, 90.73 to 0.98; P = .03).

"These results were consistent among different subgroups of the disease and demographic variables such as age, ethnicity, and geographical location," Dr. Oudard explained.

Adverse events were similar in the 2 groups, with the exception of osteonecrosis of the jaw, which developed in 33 patients in the denosumab group (4.6%) and in none in the placebo group.

"Bone is one of the most common places for cancer to spread, and we believe that it is a very fertile environment for tumor cells," Dr. Oudard said in a statement. "When cancer spreads to bone, the tumor cells settle in their new microenvironment and continue to grow. Once established, they increase the breakdown of bone, which releases an excess of growth factors back into the bloodstream, which then further stimulates bone."

Denosumab has a novel mechanism of action; it inhibits the RANKL protein to stop osteoclast-mediated bone destruction, and appears to hold back this cycle of bone destruction and tumor proliferation.

"This is the first large clinical trial to demonstrate that targeting of the bone microenvironment significantly delays the onset of bone metastases in hormone-resistant prostate cancer patients with high risk for development of bone metastases," said Michael Baumann, MD, president of the European CanCer Organisation, and professor of radiation oncology at the University of Technology is Dresden, Germany.

"What is really striking here is that the effect holds true for all subgroups of patients evaluated," Dr. Baumann noted in a statement. "This offers new options for a considerable group of patients, and will also stimulate important further research in this field."

This trial was supported by Amgen, the manufacturer of denosumab.

2011 European Multidisciplinary Cancer Congress (EMCC): Abstract 7003. Presented September 25, 2011.