ASCO 2015

Adjuvant denosumab may preserve bone health in postmenopausal breast cancer patients: results of the ABCSG-18 trial

Prof Michael Gnant - Medical University of Vienna, Vienna, Austria

Bone targeted therapies are increasingly important in breast cancer, especially in the era of aromatase inhibition as a therapy. So what have you been trying to do in this study, the ABCSG-18 study?

You’re quite right. We have made great progress in the adjuvant treatment of hormone receptor positive breast cancer. Virtually all patients nowadays receive aromatase inhibitors and this has helped in increasing the cure rates so it’s a big success story. However, there is no free lunch and the main side effects of these otherwise very successful treatments are deterioration of bone health, treatment induced osteopenia, osteoporosis and even fractures.

One of the approaches to tackling that difficulty is to use bisphosphonates. However, you actually used denosumab in this particular issue.

That’s correct. Several clinical practice guidelines nowadays advocate the use of bisphosphonates but only for patients at high risk of fracture. I think this is right where our trial results kick in and probably change a little bit how we view the whole issue. First, this is a trial which focussed on bone health and what we saw is that the actual fracture rate is much higher than observed so far because usually in the large adjuvant AI trials fractures are reported as side effects. We are pretty sure that we have severely under-reported fractures so far so in this trial, which is really focussed on bone health, fractures as a primary endpoint, we see that almost 10% of women in this situation will suffer a treatment-induced fracture at three years and almost 20% at six years and that’s quite significant.

Can you describe what you did? You had nearly 3,500 patients, didn’t you?

Yes, 3425 patients recruited to this placebo controlled, double blind adjuvant study of denosumab versus placebo. Denosumab at the dose of 60mg every six months, so that’s same dose used in osteoporosis. These patients, the result in this trial is that basically denosumab cuts fractures in half so the hazard ratio is 0.5, that’s obviously statistically highly significant. We have also measured a number of secondary endpoints, including bone marrow density which is dramatically improved by the antibody, vertebral fractures again cut in half so significantly reduced, and what is most important – this treatment is safe. So it’s a double blind placebo controlled trial and we were unable to record any differences in adverse events or serious adverse events.

Based on your knowledge from other studies, what was basically the difference between using this bone targeted monoclonal antibody as compared with bisphosphonates?

The first issue is that denosumab is easy to use, it’s two sub-cue injections per year. I’m not suspicious that I would be against bisphosphonates because I have studied them for the majority of my professional life but they are kind of cumbersome to use. The oral bisphosphonates are not well tolerated for gastrointestinal side effects; the IV bisphosphonates, they use chair time, they can have renal problems and all of that. So they’re good but the better is the enemy of the good so I think that denosumab will basically develop into a new standard of care.

So what are the clinical implications, in your opinion, coming out of this paper you’ve just reported, then, here at ASCO?

I believe that we have demonstrated a benefit of a magnitude that you cannot ignore in clinical practice, particularly because this treatment is so safe and is so easy to use. Now obviously in different countries there are different access and reimbursement issues, they may be resolved or not in the coming months, but I believe this is going to be a new standard of care pretty quickly.

So what do you think cancer doctors should take home from this right now?

Right now I think it’s just a pivotal clinical trial with interesting results, by the way published online in The Lancet this morning. Then we will have to see how the community takes it up. We are still waiting for the effect of the antibody on recurrence which is a secondary endpoint that we will report when data are mature but for fracture prevention I think the situation is pretty clear.