The current study, really, is taking an old drug like docetaxel which ten years ago was the hit, it was the first drug that showed overall survival in prostate cancer for men with castration resistant disease. So shortly after there we started a study looking at how early in the disease could we add docetaxel in to common treatments such as hormonal therapy to see if we could advance survival. So this study started in 2006, completed in 2012, but while we were doing this study all these other agents came on board, many of them targeting the androgen receptor, other chemotherapy, immunotherapy, so a lot more advances have come into place and where Taxotere, or docetaxel, fitted in was really being relegated to more end stage disease. Then along comes this study; this study was looking at men who present with metastatic disease for hormone naïve, chemo naïve, and we looked at taking men and offering them hormones plus or minus the docetaxel and showed an overall survival advantage with adding the docetaxel.
What did you look at in the men you studied?
These 790 men were asked to, at the time they presented with metastatic disease and we were going to start hormonal therapy, we randomised half of the men to get six cycles of docetaxel which was a reduction from the ten cycles which was done in the TAX 327 study from 2004. So we were trying to shorten the amount of docetaxel but give it very early in the disease to see if we could advance survival.
What were the results in terms of survival?
This was a study that was heavily weighted in enrolling men with extensive disease which we define that as four or more bone metastases or visceral involvement and 70% of the patients had extensive disease. In the end the overall outcome, looking at interim analysis, we had a difference in survival of about 13 months for the entire study and yet if you really look and hone in on those 70% of the men who had extensive disease, the difference in median survival was 17 months. So that had a hazard ratio of almost 40% reduction in death with the docetaxel.
So you’re getting the best results in those with extensive disease?
That’s because they were the predominant men who were joining the study. We have that data now; the data for the folks with lower volume disease, which represented 30% of the population has not matured yet. You have a sense that the overall population has an advantage but it’s probably weighted by those men with extensive disease, saying the higher burden disease men probably derived the greatest benefit.
What about toxicity?
It was almost non-existent. We had one case of sudden death on the docetaxel arm; we had 1% of neutropenia but in reality we also didn’t use prednisone, these are early men, stronger marrow, not heavily pre-treated and we used six cycles of docetaxel rather than ten. So the toxicity profile was actually dramatically reduced although, again, real for these men who are participating.
What are the clinical implications?
When I see my patients in the clinic who present to me with metastatic disease and I look at them and get a sense of volume, with that if I think they have extensive disease this data tells me I now have to speak to them about the role of chemotherapy using docetaxel at this point. Again, going over the side effects as you’d already mentioned, the concern is do it now or do it later. But this really looks at doing it early and showing a survival advantage.
Should docetaxel be used as a last resort or sooner?
The whole progression of castrate resistant prostate cancer is you’re on the hormones, the cancer gets smarter than the hormones and then you add in the super hormone drugs and then you can add in Provenge or sipuleucel-T, you can add in radium. So chemotherapy kept getting pushed further to the folks as they approached the end of their life. Now here the question is well maybe we should use it up front, which doesn’t negate the other data because enzalutamide, abiraterone were all originally tested in men who have already had chemotherapy. So we really just have more options and timing it for the patients which is the key element.
What would your advice to doctors be?
Those with extensive disease, when you’re starting hormonal therapy, adding in chemotherapy really needs to be considered and probably from this data I would say I would recommend it. In the developing world and even the US we need to look at cost, if we’re able to do this now, extend survival by 17 months with a drug that’s off patent, cheaper, people are used to and comfortable using it, that’s the real advance. In places where there are more restrictions on finances this really makes a difference in men’s lives.
So it’s cheaper and also more effective?
Again, we haven’t done a lot of comparison studies yet but that is probably the next wave, do you have to have chemo or could you use one of these super-targeted androgen receptor drugs but that’s a big study as well and many years to come out. But with docetaxel now we really are making an impact on these men and I would start using the data at this point.
What is the take-home message for doctors?
If you see patients who present with metastatic prostate cancer, working with urologists, medical oncologists need to be a team to offer the best care and at this point I think really docetaxel would be a part of that regimen.