ASCO 2016

Adjuvant docetaxel fails after radical prostatectomy for high risk prostate cancer

Dr Goran Ahlgren - Lund University, Malmö, Sweden

Could you tell us about the trial that you’re presenting?

Yes, it goes back to 2004 when the new studies on docetaxel came out with a survival benefit in metastatic disease in prostate cancer. When we looked at breast cancer and colorectal cancer this also transferred to a benefit in the adjuvant setting after surgery. So our idea was to test docetaxel adjuvantly after surgery for high risk prostate cancer. That’s why we started a trial back then in 2005 and then we randomised the patients between six courses of docetaxel q 3 weeks and the control arm was surveillance only.

The endpoint of the study is a PSA rise to 0.5 or higher, above 0.5. We have followed patients for at least five years now. We recruited from 2005 to 2010 and then we have followed the patients until 2015 and then we have analysed our data. So that’s what the study is.

And what results are you finding?

The finding from the study was, surprisingly, that surveillance had a trend to be better than docetaxel treatment adjuvantly for prostate cancer patients. The p-value was 0.07 so it’s quite close to being an advantage for surveillance. This is the first time the study has been conducted with docetaxel only without hormonal treatment and also without continuous corticosteroids. So this study differs from any other study that has been published, you can say.

So these are new data and what we saw was that initially in the docetaxel arm the progression rate was lower so it was a better outcome at the beginning but when taxanes were stopped there was a quite dramatic drop in the experimental arm, the number of progressions were high from approximately six months to two years. Then after, beyond two years, the curves were parallel to that in surveillance but at a 10% lower level.

So how shall we interpret this very strange result because the curves are crossing obviously? Well, we have discussed that a lot and there are some theories, hypotheses, to explain this phenomenon. We believe now that what we see is a subgroup of patients where the cancer is stimulated by the taxane treatment in some way so we would see a higher progression subgroup of patients. How come? Well, if we look through the literature there are references describing how prostate cancer stem cells can do symmetric cell division and they divide themselves and become more stem cells. These stem cells then go through asymmetric cell division when taxane is removed and give rise to differentiated tumour cells that produce PSA. So this could explain why we suddenly after the taxane treatment observe a very rapid increase in PSA producing cells giving a PSA value above 0.5.

The second explanation that we can come up with is that the taxane treatment, the docetaxel treatment, gives rise to an elevated level of repair genes of the DNA. So the damage from the docetaxel treatment to the DNA is repaired by these enzymes and thereby there is a quick recovery of these tumour cells.

I suppose the question there is what does this do to docetaxel therapy?

Yes, I think it’s a kind of resistant mechanism that we observe and why hasn’t it been observed before, that’s the question. Well, I believe that, as I said, most studies have hormonal treatment parallel to the docetaxel treatment and then you mask the rising PSA. So that’s why it hasn’t been observed before. And how can we see survival benefits in metastatic disease because that’s well-known. Well, I think that in the metastatic setting you have a lot of tumour cells that are differentiated more or less and these cells are responsive to docetaxel treatment, most of them. It depends on the numbers of cells that are non-responsive to docetaxel treatment in the total tumour burden on what response you will get to docetaxel treatment. We know that the response rate is approximately 50%.

It sounds like it raises more questions than it answers.

I agree. As I said, we were surprised by the finding and sometimes that is research. Now we will have to further analysis of this subgroup, try to identify it and then do analysis of the characteristics of these cells. So this is the next step in what we plan. We also plan, of course, to see if this first endpoint, biochemical progression, transfers to a worse prognosis regarding metastatic free disease and also survival. So it’s important to follow this cohort ten years and maybe fifteen years as well. It raises a lot of hypotheses that have to be proven but, anyhow, it’s new data, it hasn’t been observed before.