ABCSG-18 is a placebo controlled double blind randomised phase III trial of adjuvant denosumab at the dose of 60mg twice yearly for postmenopausal patients on aromatase inhibitor therapy. We have previously reported the primary endpoint results of this trial demonstrating that clinical fractures are cut in half, basically, with this adjuvant antibody treatment. However, at least as important a question is does denosumab also affect outcome because, as it was shown previously with adjuvant bisphosphonates in postmenopausal women, the adjuvant implication of bone targeted therapy reduces recurrence and improves survival in breast cancer patients. So we looked at disease free survival as a secondary endpoint of the trial and we were able to demonstrate that there is approximately an 18-19% relative improvement in disease free survival which is of borderline statistical significance because the analysis is somewhat premature because we are going to unblind the trial, at least for some patients, in the future because of the dramatic benefit that was demonstrated. In absolute terms this means that patients who get the antibody twice a year will have about 1% improvement in PFS at three years, about 2.1% at five years and approximately 3% at seven years.

Is the benefit significant over bisphosphonates?

It is a trial, a placebo controlled trial, of denosumab versus placebo. There is no trial with a direct comparison of bisphosphonates and denosumab. When you look at the bisphosphonate meta-analysis then you can see that numerically these differences are, let’s say, comparable. In the bisphosphonate meta-analysis it takes ten years to achieve a 3% absolute benefit for patients, in our trial this was happening in five years so I think it’s fair to say that adjuvant denosumab is at least as good as adjuvant bisphosphonates in these patients.

Is there a problem with the cost differences between the two drugs?

Cost and other health economy issues obviously depend on the healthcare environment. Bisphosphonates are basically generic in countries where they are available so they are very cheap. Denosumab is more expensive in the US; in my country, for example, it’s actually quite reasonable. So I’m not sure but definitely all these bone targeted treatments are considerably cheaper than what we nowadays develop in terms of targeted therapies in oncology.

Would you speculate on the action of denosumab in increasing overall survival?

We still have to wait for overall survival. So now we observe disease free survival benefit. I believe that we are now in agreement in the scientific community that the mechanism of action of bone targeted agents in the adjuvant therapy of breast cancer, and prostate cancer for that matter, is coming from an indirect impact on the bone marrow microenvironment. We silence the bone marrow microenvironment by inhibiting osteoclasts and by doing so we make it more difficult for dormant tumour cells to settle or to wake up in the long-term follow-up of these patients. So I believe most scientists and physicians would agree that this is the putative mechanism of action.

Would you suggest that clinicians seeing new patients should give denosumab?

I believe that these data are impressive. It is a small but considerable benefit at almost no tolerability cost and essentially the application in clinical practice will depend on whether reimbursement is available, whether it’s licensed in a given country or not. When it comes down to how would I treat my mother, next week, yes I would give it to her.