Hormone-Sensitive Prostate Cancer: Nuances in Therapy

Panelists: Joe OSullivan, MD, FRCPI, FFRRCSI, FRCR, The Northern Ireland Cancer Centre, Belfast City Hospital; Johann de Bono, PhD, MB, ChB, Institute of Cancer Research, Royal Marsden Hospital; Chris Parker, MD, FRCR, MRCP, Institute of Cancer Research, Royal Marsden Hospital; Bertrand Tombal, MD, PhD, Cliniques Universitaires Saint-Luc


Joe O’Sullivan, MD, FRCPI, FFRRCSI, FRCR: I was also really thinking about the earlier discussion we had about biology and the implications for downstream treatments of giving upfront docetaxel or upfront abiraterone. You are potentially changing the biology of the cancer as well, and, potentially, the following treatments may be less successful, depending on what they patient has had upfront. I must say my preference, if I was a patient, would be docetaxel in that it’s neater, it’s done, and then you can potentially have several years of just being on ADT [androgen deprivation therapy].

Chris Parker, MD, FRCR, MRCP: I was influenced by the data that Matt Sydes presented yesterday, and he showed that although overall survival is the same whether you have abiraterone or docetaxel, the time to progression is very different: much longer on abiraterone, and shorter on docetaxel.

Joe O’Sullivan, MD, FRCPI, FFRRCSI, FRCR: It’s ongoing therapy though, isn’t it?

Chris Parker, MD, FRCR, MRCP: True, but I was thinking that would actually influence patients. I would think patients would prefer remaining free of progression longer.

Joe O’Sullivan, MD, FRCPI, FFRRCSI, FRCR: It goes back to your point. If you don’t start abiraterone at the time of progression, is that as good? We don’t know yet.

Johann de Bono, PhD, MB, ChB: What was interesting is, if you look at those forest plots—and I don’t want to overinterpret forest plots, it’s the wrong thing to do—the overall survival data trended more towards docetaxel and not abiraterone. So, I think you have to be quite careful because, actually, we’re trying to compare apples and oranges. We can’t, because it’s truly 18 weeks of docetaxel and years of abiraterone. I don’t think that comparison is a fair assessment. In fact, I would have presented that data quite differently, and I think the disease-free survival data, or all those progression data, are irrelevant in this comparison.

Bertrand Tombal, MD, PhD: And also, something very important from a methodological standpoint is that it’s a hitch of releasing trials early. The reading of all these trials is based on repeat analysis. Basically, you define the number of deaths, and when you reach that number of deaths, you look at what’s happening in the other arm. So, that means we have a tendency to generalize the results of the trial, where, actually, we are only looking at the benefit of these treatments in the worst of the worst. And that’s a problem, because many things can still happen with the best responding patients. My view is that overall, we read the trial too early. That may have an impact, and that’s a problem for the next generation. I had this discussion many times with Karim [Fizazi], PEACE1 was actually using docetaxel quite late. So, if you read the results of PEACE1 too early, that will be patients who have not received chemotherapy. That’s why you’ve got that Bayer trial, which is called ARASENS, which is ADT plus docetaxel, ODM-201 versus no ODM-201. That trial is important, because it’s going to be the only one where every patient, at the same time, will receive ADT plus docetaxel.

Johann de Bono, PhD, MB, ChB: Can I just make a point? Our colorectal cancer colleagues have told us, and the point is, that actually getting all the active drugs into the patient at some point before they die is really key. The patients who will live the longest are the patients who, before they die, will get all the good drugs. It worries me hugely that if you give abiraterone first, much fewer patients will get docetaxel before they die. Because, actually, what will happen is they will be on abiraterone for a long time, and it will come to a point where the patients will be unfit, or deemed unfit, to get docetaxel. And therefore, if you want to give all your drugs—let your patients get all the active drugs to maximize benefit—the likeliest way of doing that is to give docetaxel first, because it’s much, much easier to give abiraterone later.

Bertrand Tombal, MD, PhD: But that’s my worry with LATITUDE, for instance. If you look at the number of deaths and the number of patients who have received subsequent treatment, it’s far away from 100% of the patients. So, we have many patients in this trial where the only effective drug they received was in the active arm, the experimental drug. After that, they had no other treatment.

Chris Parker, MD, FRCR, MRCP: I agree. I think it’s a really important message, isn’t it, that our patients should get as many possible life-prolonging therapies. I just wanted to pick up a point that Johann made. You were talking about the STAMPEDE data that Matt Sydes presented yesterday, showing no difference in overall survival. And you pointed out that there was, if anything, a trend favoring docetaxel rather than abiraterone. I just want to make the point that when he looked at cause-specific survival, the hazard ratio was 1.02, essentially 1. So the difference, if there was a difference, was actually in nonprostate cancer deaths. It did make me actually concerned. Is there a worry of abiraterone leading to toxic deaths?

Johann de Bono, PhD, MB, ChB: Well, I was surprised from the STAMPEDE data that a lot more patients than I expected with hormone-sensitive disease discontinued abiraterone for toxicity. Actually, I should ask Bertrand to comment on this because, in our experience giving abiraterone to patients with late-stage disease, we had very few patients coming off for toxicity. Transaminitis is very rare with abiraterone. It’s 3% or less. And, in fact, we saw a very similar proportion of patients on prednisone alone getting transaminase elevation. So, I don’t think that this drug is particularly toxic, although there are cardiovascular events that are obviously of concern. I don’t know if you want to comment, Bertrand.

Bertrand Tombal, MD, PhD: If you look at the 2 published papers and you look at the grade 5 toxicity, the highest occurrence of grade 5 toxicity is in the STAMPEDE abiraterone arm. We don’t know yet. When you have such a small difference between nonprostate and prostate groups—we know that very well from ADT—there is an excess of death. Where does it come from? From ADT, we’ve been pointing out cardiovascular disease for decades. It’s very difficult, but your observation is exactly what struck me yesterday as well. You say, “Well, there’s no difference in prostate cancer, but there is a difference in overall survival.” And it reminds me of something. We, the urologist, know very well what the intermittent androgen deprivation trials are, where actually, if you look at overall survival, there’s no difference between intermittent and continuous groups. But, if you look at prostate cancer death, there are more in the intermittent, meaning that when you need hormones, you need hormones. But then, there are more patients who are dead from other causes in the continuous group, meaning if you don’t need hormones, you’re going to die from something else. So, my worry is that by giving this drug to everybody for a long period of time, we’re going to have a slight increase in deaths from other causes.

Transcript Edited for Clarity 
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