ASCO 2010 Annual Meeting, 4—8 June 2010, ChicagoInterview with Professor Robert Coleman (Weston Park Hospital, Sheffield, UK)

Targeted therapy for bone metastases

The process of metastasis, especially when cancer goes to the bone, is utterly fascinating.  You’ve been targeting it for a long time.  First of all, why is it a good target to go for the bone, in terms of the overall health of the patient and not just controlling disease in the bone?

Well, I think we’ve learned over recent years that there’s a very important relationship between cancer cells, bone cells, and the stem cells, the normal stem cells that reside in the bone marrow.  They talk to each other, and as you’ll be aware, you know, sometimes cancer comes back many years after diagnosis.  What we believe is that the cancer cells live in the bone marrow.  They just sit there, supported by the bone cells, supported by the stem cells, in this dormant state and then, for reasons we don’t understand, they become active.  Now, if we interrupt that interaction between those three cell types with a bone-targeted drug, we change the environment, then that seems to have an effect on the ability of a cancer to metastasize.

In myeloma for instance, bone is crucially involved.  Also in breast cancer and prostate cancer, metastases go to the bone quite frequently.  What happens and why do they go there?

Well, there are a number of factors.  One is, if you’re talking about breast and prostate cancer, their initial genetic makeup is programmed to take into bone, so they express molecules that make them sort of friendly to the bone environment.  They also adapt to the bone environment, and they start taking on some of the characteristics of bone cells, and then they presumably have this ability to talk to the stem cells as well.  Myeloma’s a little different.  I mean, it is a bone marrow disease per se, and it may be that  there is more of a direct anti-cancer effect of bisphosphonates.  That’s something that a number of groups have been looking at.

They mention bisphosphonate, the first of the agents.  Could you tell me what benefits they have achieved so far?  Because now, you’re starting from a certain platform of achievement against bone disease, and you’re going above that with some newer agents, aren’t you?

I think there are a number of important developments.  Firstly, of course, in preventing complications of advanced cancer, the bisphosphonates – and particularly, more recently zoledronic acid – have become very well-established in routine practice.  But, they’re not perfect, and patients still get fractures and pain and need regular therapy.  So, there has been a drive over recent years to improve on that with a very specific antibody which is targeted to RANK ligand, which is a key regulator of bone cell function, which we call denosumab.  Denosumab has been compared now, in three very large randomised trials, to zoledronic acid.  Head-to-head trials, over 6,000 patients in total, and in each of those trials, whether it be breast cancer, prostate cancer, or a mixture of other solid tumours, denosumab has outperformed zoledronic acid.  By that, we mean that the time to the complication is extended, and the total number of complications is reduced by about 15, 20%.

What have been the achievements already of the bisphosphonates and zoledronic acid over and above which the new antibody is trying to do better?

It is really important to appreciate that zoledronic acid and the bisphosphonates are already good drugs, and if we look back to the pre-bisphosphonate era... you know how wards used to be full of poor patients with fractures and hypercalcaemia.  That’s largely disappeared, so bisphosphonates have gotten rid of maybe half of the complications we used to see, and denosumab is chipping away at that residual morbidity.  And then, of course, the other really exciting development comes back to some of the things we were talking about earlier, which is in earlier disease, can we make patients live longer?  Can we prevent the cancer coming back?  That’s where there’s been some very exciting new data.

One of the ways you measure how the disease is progressing and the success against the disease is by looking at skeletal-related events.  Another is by survival.  What’s happened so far?

In terms of skeletal-related events, we’ve reduced the vast majority of them with modern bisphosphonates and now, even better, with denosumab.  In advanced cancer, we probably don’t greatly influence survival.  We improve quality of life and mobility and probably reduce health care costs as well.  It’s in early disease that we’re seeing effects on survival.  So, for instance, in multiple myeloma,  a very interesting trial from the MRC took patients who are starting their chemotherapy for the first time for myeloma, with different cytotoxic combinations, but randomised them to one of two different bisphosphonates: clodronate, an old drug, relatively weak, without probably the anti-tumour activity against zoledronic acid, which is much more powerful and is said to have some anti-cancer activity.  And in that head-to-head comparison, there was a five month, statistically significant improvement in survival in the large number of patients treated with zoledronic acid.  We’ve never seen that in myeloma with a bisphosphonate, and that incremental benefit is at least as large as we would see with a new cytotoxic or a new biological treatment.

Now, because the bone is intimately involved in the disease process in myeloma, perhaps from the start, were you in a privileged position with myeloma whereas with breast and prostate cancer, maybe it’s a more difficult problem.

It’s certainly a very different problem, and I think one might feel that it’s a more speculative approach, but again, we’ve seen some very interesting data from the Austrian breast cancer study group – data previously published but updated at this year’s ASCO meeting – where they took 1,800 young women who started off their disease in a pre-menopausal state, pushed them into a menopausal endocrine treatment, and randomised them again, either to zoledronic acid or no bisphosphonate treatment.  What they have shown and confirmed in their updated analysis is about a 35% improvement in disease-free survival, or a 35% reduction in the risk of recurrence, which is quite a significant increment.  Now, it’s a very specific group of patients.  They’re all young.  They all had a hormone-sensitive disease.  So, one can’t necessarily apply this to every woman with breast cancer, but for that particular subset of women, this is a really exciting result.

Do you think that will also translate to overall survival?

Probably, I mean, at the moment there aren’t enough events to know whether that’s going to happen, but generally, adjuvant treatments that improve disease-free survival with the passage of time and sufficient number of events do translate to overall survival benefits.

Also at the Chicago meeting of ASCO data have been presented on prostate cancer.  Could you tell me about that study?

This was a study of the use of denosumab compared to zoledronic acid in men with hormone refractory prostate cancer and bone metastasis.  It was a large study of over 1,800 patients and it was very much a head-to-head, which is the best bone drug type of study, looking at time to first skeletal event and the overall skeletal morbidity.  What we saw was that denosumab was more effective at inhibiting the skeletal complications.  It was also in most regards better tolerated, so you didn’t see any need for renal function monitoring, which you have to do with bisphosphonates.  Patients didn’t get the fever and that sort of feeling horrible after the first one or two treatments, what we call the acute phase reaction.  That didn’t occur with denosumab.  The only downside was that there were at least as many, if not numerically more, cases of osteonecrosis of the jaw, which is a relatively rare but well-recognised complication associated with bone-targeted therapy.  So, that’s still a problem that we have to deal with, but otherwise, it was a very positive result.