ASCO 2010 Annual Meeting, 4—8 June 2010, Chicago

Interview with Professor Robert Coleman (Weston Park Hospital, Sheffield, UK)

Factors influencing the choice of bone metastases treatment

What exactly do these three categories of agents do in the patient to achieve their benefits - the bisphosphonates, zoledronic acid, and denosumab?

Well, all of these drugs share one very important common mechanism, and that is that they inhibit osteoclast function, and we know that tumour cells just don’t have the machinery to break down bone themselves.  They have to use the normal post-osteoclast cells.  So, by inhibiting the osteoclast either directly – which is what a bisphosphonate does – or through the signalling mechanisms – the RANK ligand signalling that denosumab affects – then you basically switch off osteoclast function.  Denosumab is better because it’s just a little bit better at switching off osteoclast than zoledronic acid or other bisphosphonates.  But, they work in broadly the same way.

What about the downside of using an antibody which is very specific and very powerful in that way?

Well, there are a number of potential concerns, you know?  Signalling systems are not located to a single organ system, so the RANK ligand system is relevant in immune function as well.  So, there were concerns that there might be some tendency for patients treated with this agent to get more infections, and that’s not been seen.  And, there’s not only a cancer program but there’s an osteoporosis program, and that hasn’t appeared.  That’s a theoretical concern.  The other is, I suppose, that some of those effects against the cancer that we were talking about with the bisphosphonates might not occur with denosumab, because it’s so specific, whereas bisphosphonates, they affect bone but they also have effects on angiogenesis.  They have effects on tumour cell adhesion and invasion.  They’re what you might call a rather dirty drug, but in some cases that can be turned to an advantage.  So, we might not see the anti-cancer activity with the denosumab that we seem to be seeing with bisphosphonates.

What sort of cross-reaction does this monoclonal antibody have with other agents, which are used in the patient, and are there any synergies?

I’m not aware of any synergies, and there have been no drugs identified that one can’t combine this agent with, including being able to give it with other antibodies.  So, if a patient needs to have trastuzumab for their breast cancer, then that’s fine.  They can be given side-by-side.

Are there tests you can do for the patient to predict whether the agent will be useful, and perhaps think of using it in the adjuvant or neo-adjuvant setting?

Well, we have predictors of skeletal complications.  We do know who’s most likely to get a complication, and that is obviously, if you’ve already had one complication, you’re more likely to get another one.  But, more specifically, one can measure biochemical markers of bone metabolism, specifically the bone breakdown products, and the higher they are, the more likely a patient is to experience a skeletal complication, and actually, the more likely they are to die of their disease.  So, one could pick patients at higher risk of complications as if you were going to be selective in your use of these drugs.  I don’t know that that is going to translate into the adjuvant setting.  I think for choices in adjuvant therapy, we’re probably restricted to underlying risk. Is the cancer likely to come back or not based on the classic biological and pathological factors?  But in the future, maybe we’ll learn through gene profiling, which cancers really like to go to bone or go to bone first.  We don’t have that information yet.

So, do you have any idea of how many, what proportion of patients could benefit from the use of denosumab?

We do know that bone metastases are extremely common in breast and prostate cancer.  So, if the cancer comes back, you know, three-quarters or more of those patients will get bone involvement.  So, if you just take in the UK, you know, there are 10,000 to 12,000 women dying each year of breast cancer.  So, the vast majority of those women could benefit from a bone-targeted drug and the figures are not dissimilar for prostate cancer.  So, this is applicable to a very wide range of patients.

A wide range of patients, but doctors always have to choose and advise their patients who will gain the most benefit.  Can you give me some idea of how you would select a patient who is most likely to benefit?

At the moment, in advanced cancer of course, they would have bone metastases first of all, and then for prostate cancer they need to be escaping from their first-line hormone therapy.  So, normally hormone therapy would control disease for many years, but as that wears off and they’re entering their last year or two of life, then that’s probably the time to start.  You can be more specific and sophisticated by selecting on the basis of bone markers, but most people don’t do that at the moment.

The data that has emerged from the breast study and the prostate cancer study, does that need any further ratification, or is it ready for prime-time, ready for recommendations to be made?

I think there are some details that we still need to see from those studies, and there will be some further updates of those trials, but I think they’re pretty definitive.  It’s probably going to come down to health economics as to whether we change from bisphosphonate to denosumab in terms of what is the price of this new agent?  I mean, from a patient point of view, it works better, it’s less toxic, and it’s given by subcutaneous injection instead of intravenous infusion.  So, it’s very attractive to the patient, and I think, like a lot of developments, it’s a case of can we afford it with a limited budget?

Sparing a thought for the jobbing oncologist, how would you advise the doctor?

I think when denosumab becomes available, where it will probably be used is for patients who are on a bisphosphonate and not doing well.  They’re having complications, they’ve got pain.  People will try it as a sort of second-line therapy, but where I would want to use it is probably much earlier.  I think if we can avoid patients having to come to a hospital every month for intravenous infusions and give them a better-tolerated alternative, then, you know, that’s personally what I would want to do.

Now, denosumab has a specific target that’s doing what you want.  Do you see other agents coming along, perhaps even cleaner agents in the future?

I don’t know that there will be cleaner agents.  There are other therapeutic targets in development.  There’s a whole family of drugs that affect SAR kinases, which are relevant for cancer biology but are also very relevant in bone biology.  So, drugs like dasatinib have been shown to have quite powerful effects on bone metabolism as well as some direct anti-cancer activity.  So, that is one drug, but it has its own toxicities.  There are also some enzyme inhibitors.  Cathepsin K is a very important enzyme in bone physiology, and there are some drugs in development that inhibit that enzyme.  They’re largely being developed in osteoporosis at the moment, which is also a very large potential market, but we expect to see some further results in cancer in the coming years.

In your own work, I know you have quite an emphasis on translational research.  You like to get into the lab, you like even to look at animals and moving over to patients.  Is that sufficiently productive at the moment?  Have you got interesting things in the pipeline?

Well, I think it’s very important to have a lab program to underpin a clinical program, and try and work backwards and forwards between the two.  Over recent years, we’ve been very interested in the way that bisphosphonates and chemotherapy seem to synergise with each other.  We’ve shown that, first in-vitro and then in some animal models.  We’ve just finished a study in women with breast cancer, a neo-adjuvant study where we’ve basically taken exactly the therapy model that seemed to work in the mice and we’ve applied it in women with breast cancer.  I can’t tell you the results of that study yet because we’re going to be presenting those at San Antonio this year, but, you know, there are some interesting biological interactions between the two treatments.