ECC 2015

ADT plus docetaxel or bisphosphonates in hormone sensitive prostate cancer: Systemic review

Dr Claire Vale - MRC Clinical Trials Unit at UCL, London, UK

I work in the Medical Research Council Clinical Trials Unit, based at UCL. I’ve been working in the Trials Unit for about twenty years, coming up to. I’m doing systematic reviews.

Particularly you’re looking at prostate cancer, a disease that’s got a whole range of treatments, hormone sensitive prostate cancer. What issue were you looking at this time?

I suppose that we were starting to become aware that trials were beginning to report that had looked at a number of different systemic treatments in addition to the standard hormone treatment for men with hormone sensitive prostate cancer. The systematic review is we wanted to try and pull that evidence together to get a clear picture.

And you can, of course, add chemotherapy, results have been good in certain stages of the disease with docetaxel. You can also add bisphosphonates which have anti-cancer results as well as bone affecting results. What did you look at?

We looked for all randomised trials that had added either docetaxel or bisphosphonates, as you say, over and above androgen deprivation therapy or that sort of basis of therapy in men with hormone sensitive disease. We looked for trials that had included men with both metastatic and non-metastatic disease and I would say that the strongest results we’ve got are with docetaxel, that’s where we can draw the most conclusions at the moment.

And what conclusions did you draw?

Slightly differing conclusions for the metastatic and non-metastatic setting but, based on the trials that we were able to include results for in the meta-analysis at the moment, for men with metastatic disease the addition of docetaxel improves overall survival but also reduces the failure rate in these men. So it improves overall survival, our current estimate is around 10% at four years improved survival. For treatment failures we see a reduction of around 15% in terms of the failure rate at four years in these men.

What about bisphosphonates? That has looked promising a little bit, hasn’t it?

When we put the studies together for bisphosphonates we had a mixture of studies in the meta-analysis which the majority had used zoledronic acid, which is one type of bisphosphonate, and one study had used sodium clodronate, which is an older bisphosphonate. When we put them all together, which is what we planned to do in the meta-analysis, we saw a moderate treatment benefit in men with metastatic disease. However, when we looked just at the studies that have zoledronic acid as the additional treatment we don’t really see any strong evidence of treatment effect.

So the only signal was with clodronate?

There’s only one study of sodium clodronate and it had a significant result on its own.

What about non-metastatic disease then?

So going back to docetaxel, first of all, for men with non-metastatic disease we see quite a strong signal of improvement in failure free survival, so a reduction in the treatment failure rate. I think that was around 7-8% at four years, so 7-8% fewer men failing treatment after four years. But for overall survival, although there’s a suggestion that docetaxel improves survival at four years, that’s not statistically significant at the moment. So our conclusion from that is that we need more evidence and that evidence will come out of some of the trials that we identified that haven’t yet reported their results but also from following up the other studies that we have included for longer to get more mature survival data.

What about bisphosphonates in non-metastatic disease?

The bottom line is that we don’t really see any evidence of a treatment effect with bisphosphonates in men with non-metastatic hormone sensitive prostate cancer.

Well you’ve done a meta-analysis, you’ve got clear results, what recommendations would come out of this naturally?

I think that the results that we’ve got for metastatic men mean that we’ve got really reliable evidence to say that the new standard of care for men who are fit enough to take chemotherapy should have a backbone of androgen deprivation therapy coupled with docetaxel. For men with non-metastatic disease we need to keep looking at the studies until we can properly evaluate whether there’s an effect of docetaxel on overall survival.

And the decision about whether or not to use clodronate or a bisphosphonate?

I’m not a clinician so I’m not sure what conversations the doctors will have with their patients. We don’t really see any benefit, so in terms of giving bisphosphonates as something which may improve survival we don’t really see a lot of evidence to support that, particularly for zoledronic acid, in men with either metastatic or non-metastatic disease.

What’s the bottom line message, then, coming out of this for doctors in how to interpret the data coming out of studies? You’ve done the meta-analysis, that’s it, they can really be guided by this can they?

Yes, I think so in terms of metastatic men with docetaxel, there’s a really clear picture. I guess for bisphosphonates in non-metastatic men we see a really clear picture the other way, that we’re not seeing any evidence of a treatment effect. What we couldn’t look at with bisphosphonates were other outcomes. So we know that bisphosphonates are active at the bone level so it may be that bisphosphonates have an important role to play on other outcomes but they’re just not having any effect on overall survival.