Denosumab inhibits RANKL, a protein involved in bone metabolism, and appears to delay bone metastases onset in patients with prostate cancer, researchers from the Georges Pompidou Hospital, Paris, France, reported at the European Multidisciplinary Cancer Congress 2011, Stockholm, Sweden. The scientists say theirs is the first large-scale human study to show such an effect from denosumab (Xgeva).
Professor Stéphane Oudard, head of the hospital’s Oncology Department, explained that 9 in every 10 patients with prostate cancer that does not respond to hormone treatment will have their primary tumor spread (metastasize) to the bone. When the cancer establishes itself in the bone, it becomes chronic and eventually terminal, resulting in “major physical and psychological consequences for the patient.”
Prof Oudard said:
“Being able to delay this turning point is therefore very significant. We have shown that the use of denosumab in this group of patients can impede the onset of bone metastases by just over four months.”
RANKL, a protein, is closely involved in the formation of osteoclasts – cells that nibble at and break down bone, and are responsible for bone resorption. Osteoblasts do the opposite; they form bone. If the formation of osteoclasts can be blocked, the bone will be stronger and will be able to hold out against the development of metastases.
In this study, 1,432 men were randomly selected into two groups – one was given the active medication while the other got a placebo. The were advised to take vitamin D and calcium supplements for their bones. By July 2010, 660 of them had either developed bone metastases or had died. They then unblinded the trial and analyzed the results.
Prof Oudard said:
“We found that denosumab prolonged bone metastasis-free survival significantly as compared with placebo, and that these results were consistent among different sub-groups of the disease and demographic variables such as age, ethnicity, and geographical location. From this we can conclude that, whatever the patient characteristics (initially based on a high prostate specific antigen (PSA) value and/or a short PSA doubling time), denosumab can delay the appearance of bone metastasis. In a condition where there is currently no effective treatment, this is a highly significant finding.”
The risk of premature death for a patient with bone metastases is nearly five times higher, compared to those whose cancer has not spread to the bone.
Professor Oudard said:
“Effective therapies are already in place for both early (hormone-sensitive) and advanced (hormone-resistant) prostate cancer, but until now there was a gap in the treatment plan for this group of patients, who are hormone-resistant but have not yet developed metastatic disease.”
Adverse effects were found to be similar in both groups, the denosumab and placebo groups. Those in the denosumab group experienced slightly higher rates of jawbone deterioration, lower calcium levels, and osteonecrosis of the jaw. The most commonly reported adverse effect was back pain.
Professor Oudard said:
“Bone is one of the most common places for cancer to spread, and we believe that it is a very fertile environment for tumour cells. When cancer spreads to bone, the tumour cells settle in their new micro-environment and continue to grow. Once established, they increase the breakdown of bone, which releases an excess of growth factors back into the blood stream, which then further stimulate tumour growth.”
Bone metastases in patients will usually lead to serious complications. Patients commonly experience pain initially, which can be very debilitating. As the tumor grows, the bone weakens and the patient is at higher risk of SREs (skeletal-related events), such as spinal cord compression or fractures. SREs can seriously disrupt a patient’s life; they can undermine cancer delay or prevention strategies.
If the bone destruction caused by osteoclasts can be blocked by inhibiting the RANKL protein, the cycle of bone decay and tumor growth can be held in check. The vast majority of patients with advanced prostate cancer eventually have bone metastases. Inhibiting RANKL activity could help these patients enormously, the scientists added.
Professor Oudard said:
“In this group of patients with castrate resistant prostate cancer, once they have developed bone metastases they are only likely to survive for around two years. 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. For the first time, we have shown that targeting the bone micro-environment can work in this way. We believe that in future we may be able to do even better by combining denosumab with other targeted treatments.”
Professor Michael Baumann, president of ECCO (European CanCer Organization) said:
“This is the first large clinical trial to demonstrate that targeting of the bone micro-environment significantly delays onset of bone metastases in hormone resistant prostate cancer patients with high risk for development of bone metastases. What is really striking here is that the effect holds true for all sub-groups of patients evaluated. This offers new options for a considerable group of patients and also will stimulate important further research in this field.”
ESMO (European Society for Medical Oncology) spokesperson, Dr. Joaquim Belmunt, from the Medical Oncology Service, Hospital del Mar, Barcelona, said:
“Denosumab, being the first agent able to delay the onset of bone metastasis in castrate-resistant prostate cancer, represents a paradigm shift in our beliefs about the limited efficacy of the presently available anti-metastatic strategies. The way this activity will translate into survival benefit will require future investigation.”
Written by Christian Nordqvist