European Multidisciplinary Cancer Congress (EMCC) 2011, 23-27 September, Stockholm

Denosumab delays metastases for prostate cancer

Professor Stephane Oudard – Georges Pompidou European Hospital, France

Good morning. It’s a pleasure for me to share with you some data on denosumab in prostate cancer. The subject of my talk is to speak about denosumab and bone metastasis free survival in men with castration resistant prostate cancer. It’s a subgroup analysis from an international double blind randomised phase III trial.

So why is it important to look at bone metastasis in prostate cancer? Bone metastasis develops in nearly all men with castration resistant prostate cancer and last week I had one patient in my institution who had pain in the back due to bone metastasis, suffering, having a bad quality of life which has repercussions around social activity and so on. Really it’s really difficult to handle this kind of patient because they’re having to be stuck at home, you’re having to give morphine and so on, so really if you can avoid the appearance of metastasis, I think it’s really good for the patient.

And these bone mets induce, of course, pain but also skeletal related events and also is associated with mortality. Also it causes significant health and economic problems. The development of bone metastases in CRPC patients is dependent upon disease-related criteria and we know very nicely two prognostic factors, which are PSA value and also the PSA doubling time, which allow you to predict whether or not this patient is going to have bone mets.

So far we have a new drug, denosumab, it’s a fully human anti-rank ligand monoclonal antibody and it’s going to target a very specific receptor and this is the only agent to significantly increase bone metastasis free survival in non-metastatic CRPC patients and this is for the first time that we presented data in Europe. Here I would like to share you with the consistency of effect of denosumab in this population across both demographic and disease related subgroups.

So this is the phase III study, it’s a very robust phase III study, international randomised double blind placebo controlled trial looking at either denosumab 120mg subcutaneous every month with calcium and vitamin D supplementation or placebo. This is addressed to patients having castration resistant prostate cancer, low level of testosterone, high risk of bone metastasis, in other words either a patient with a high PSA level or a short PSA doubling time. Of course those patients need to have no bone metastasis and no IV bisphosphonates. The primary endpoint of this study was bone metastasis free survival, which means time to first bone metastasis, either asymptomatic or symptomatic, or death on study, and the second endpoint was time to first bone metastasis, meaning that time to first bone metastasis, either asymptomatic or symptomatic, and also overall survival. So this is the primary endpoint, bone metastasis free survival, which is in favour of denosumab compared to a placebo, 29.5 months compared to 25.2 months, leading to a gain of 4.2 months in delaying the appearance of metastasis. This corresponds to a reduction of 50% of the risk of the appearance of these bone mets with a hazard ratio of 0.85 and the p-value, which is highly significant. When you look at this subgroup analysis of these patients, whatever are the age, region, race, histology, defined by Gleason score and PSA stratum, whatever the patient characteristic, all the patients will benefit from using denosumab.

Again, if you look at time to symptomatic bone metastasis, again it’s in favour of denosumab. Less events, 10% of events compared to 30% in the placebo arm, leading to a 33% reduction of risk with a hazard ratio which is very good, 0.67, and of course a p-value which is highly significant. And again whatever the patient is, according to age and so on, the patient benefits from using denosumab.

In terms of toxicity this drug is very well tolerated, no more side effects in the denosumab arm compared to the placebo arm. I just want to focus that those patients in the denosumab arm could have more frequent osteoporosis of the jaw, 5% compared to 0%, and it is a cumulative incidence from year 1 to year 3 and then those patients receive around 20 cycles of denosumab so maybe this could explain that.

So to conclude, this is in Europe the first time that we present this large phase III randomised study, robust study, which demonstrates targeting of bone significantly delays bone metastasis in men with prostate cancer and patients having a high risk of metastasis defined by either PSA level of above 8 or a short PSA doubling time; whatever the patient is, they will benefit from having denosumab. Again, similar results were obtained looking at symptomatic bone metastasis. So therefore it’s really a new drug and it’s hope for the patient in order to delay the occurrence of bone mets in this patient population.

Thank you for your attention.