5 Alpha Reductase Inhibitors & Chemoprevention of Prostate Cancer with Dr. Marc Garnick

E. David Crawford invites Dr. Marc Garnick to review the major findings and supportive studies for the proposed use of the 5-alpha-reductase inhibitors (5-ARIs), finasteride and dutasteride, for prostate cancer chemoprevention that was rejected by the FDA in 2010.  The implications of the pivotall stuides for 5-ARI use as prostate cancer prevention are also discussed by Dr. Garnick.


Biography:

Dr. Garnick is Professor, Department of Medicine at Harvard Medical School, and Professor of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts.  Dr. Garnick's perspective includes his experience from  serving on the Oncologic Drugs Advisory Committee (ODAC) that reviewed the supporting data for the supplemental New Drug Applications to the FDA. 

The full interview transcript is below:


David:

Hi, this is E. David Crawford from the University of Colorado. When I think back several decades ago when five alpha reductase inhibitors were first introduced, there was a lot of promise that these were the male pill, sort of for a male pattern baldness or benign prostatic hyperplasia, and maybe to prevent and even treat low-grade prostate cancers. They've been successful, I think in all arenas. We have Propecia for baldness, from the M pops trial, we studied finasteride and then there were the prevention trials. Two of them, one with finasteride and one with dutasteride that went to the FDA for approval. Joining me today is an outstanding scientist, Dr. Mark Garnick. He's a medical oncologist at Beth Israel and in the Harvard health system. Mark was on the FDA committee that reviewed the chemo preventative strategies for prostate cancer with five alpha reductase inhibitors. Mark.

Comparable Studies in 5-Alpha Reductase & Prevention of Prostate Cancer

Mark Garnick:

David, thank you very much. It's an honor to be participating in this very exciting educational conference. May I have the next slide please. The differences between the prostate cancer prevention trial and the REDUCE trial is shown here. One study used finasteride, the other used dutasteride and there were close to 24,000 or 25,000 patients that were incorporated into both studies. Slightly different end points, slightly different biopsy procedures, but in essence comparable studies in terms of assessing whether or not the use of a five alpha reductase inhibitor was going to basically prevent the development of prostate cancer.

Mark Garnick:

Again, large numbers of patient information and I would say that perhaps the most important study that has evaluated the natural history of prostate cancer was the PCPT trial because it basically provided an overview of what happens to patients regardless of what their PSA values are and the scope of those with less than four nanograms per milliliter, in terms of what is the likelihood of individual patients having prostate cancer as a function of the design of the study.

Major Findings

Mark Garnick:

Next slide shows the major findings, that overall both in the PCPT using finasteride and the REDUCE using dutasteride, there was a risk reduction of approximately 24 to 25%, essentially limited to those patients that had a Gleason score of less than or equal to six. In contrast, patients with Gleason scores eight to 10, there actually seemed to be an increased incidence and the development of high grade Gleason's cancers in those patients exposed to either finasteride or dutasteride, and there was this increase in the eight to 10 patient population that basically led to the ODAC advisory committee recommending against the longterm use of five alpha reductase inhibitors for the chemo prevention of prostate cancer.

Mark Garnick:

The next slide shows that a combination study looking at the increased high-grade cancer rates of both studies combined. If you focus on the right hand portion of the slide, that regardless of whether one used finasteride or dutasteride, there was a significant and substantial increase in the incidence of Gleason eight to 10 cancers. And despite multiple publications trying to explain that as a function of prostate gland volume reduction, on those data, when critically analyzed, did not seem to be valid, but rather the use of these agents actually in some way, induce the development of high-grade cancers.

Death Rates of High Grade Cancers


5 alpha reductase survival rates graph

Mark Garnick:

Next slide shows a very interesting offshoot looking at the death rates of high grade cancers induced by finasteride in the PCPT trial. This was published as a letter to the editor of the New England Journal of Medicine in which if you take a look at the five year survival and 10 year survival of high-grade cancers that were on the Finasteride versus placebo, the five and 10 year survival data were actually greater in the placebo population compared to the finasteride population, with the inference being that these cancers that are induced by five alpha reductase inhibitors may actually be very, very biologically important and biologically aggressive.

Non Approval of 5 ARI's

Mark Garnick:

And my final slide shows a very important component that led to the non-approval of 5 ARIs as a prostate cancer risk reducer. To reduce a low risk cancer, the treatment to prevention ratio was 60 to one, the treatment to increased risk ratio of actually developing a Gleason eight to 10 cancer was 200 to one, and the discussion at the ODAC committee suggested that many of these low risk cancers would not necessarily have any biological activity and may not even needed to be diagnosed in the first place. So why would we potentially expose a patient to the risk of developing a higher grade cancer, when the lower grade cancer that was being prevented would not necessarily have to have been prevented at all? Thank you very much for your attention.

Low Grade Cancer Reduction

David:

Thanks, Mark. You know, that was certainly one of the final blows to prevention in prostate cancer. As you well know, there are a number of other trials with betacarotene and vitamin E and selenium and so forth, and also with some nonsteroidals were also questionable. A couple of questions. One is that low risk cancers are sort of toothless lions, and I would agree, but you know, the problem is it would be best if we didn't diagnose those. And one way to do that is maybe not to do needle biopsies obviously, but to reduce low-grade cancers. So if you reduce low-grade cancers, you're actually benefiting the patient in a way, because you're not finding them and you're not sort of overtreating them.

Mark Garnick:

Totally agree, and that was the main premise of both the PCPT trial and clearly the REDUCE trial, that the morbidity associated with prostate needle biopsies and the morbidity associated with the treatment of a diagnosed low-grade or even very low risk prostate cancer, could be avoided by reducing the incidence of those numbers by 25%. I mean this is an incredible study in the fact that there are very few chemo prevention studies that reduce the incidence of the index cancer by 25%. I mean, so that was a remarkable finding in this study. Those are totally valid and correct parameters that led to the hypothesis generation of doing this study. Unfortunately, this adverse event really numbed all of those potential benefits.

Side Effects

David:

So, there are some other things that they do, including BPH, which were the symptoms of BPH and progression where were significantly reduced, but we didn't talk about side effects. Was that also an issue when you talked about some of the sexual and other side effects that might occur with these drugs?

Mark Garnick:

There's no question that the side effect profile is underestimated both from data reporting and from personal experience. You've got to appreciate when a side effect such as loss of libido or sexual or erectile dysfunction or sexual dysfunction occurs. Unless the patient specifically states that that is a problem, it's unlikely to be recorded unless there is a specific case report form that prospectively asks that information. And my own impression is that based upon the reported incidence of sexual side effects, they are grossly underestimated by both PCPT and REDUCE studies.

David:

Yeah. I'm still not convinced one way or the other. I think the volume reduction thing is important. We've looked at the ... There also might be histologic changes that occur with the treatment that may look like a higher grade cancer when it's not. I know you showed a slide that that probably is not the case. We know that hormone therapy, and this is sort of a weak type of hormone therapy, can affect a histology. Although I have, in the past couple of years I've seen an inordinate number of men who had been on 5 ARIs whose PSAs go up and you biopsy them and you find Gleason eight, nine and 10 cancers, mostly eight and nines. You see enough of that and you begin to question whether in fact this really is true.

PSA Levels, 5 ARI, and BPH Symptons

Mark Garnick:

Yeah. If I can just add to that comment, David. If your PSA did not go down by 50%, you had a threefold likely increased incidence of having prostate cancer and a six fold increased incidence of having high-grade cancer. That was in a small subset of patients whose PSA either stayed the same or actually increased while receiving a five alpha reductase inhibitor. So that is a very, very important clinical pearl, that if you are treating patients with a 5 ARI for BPH symptoms, I think following PSA at baseline and at six months for a year is very important. If that patient's PSA does not go down by 50% by six months, have a very high suspicion of that patient may be harboring prostate cancer.

David:

Right. And also once they're on it and they have a baseline and it deviates from that, it's also reason to be suspicious. Mark, thanks a lot. That was an excellent presentation, a pivotal study. A lot of time, a lot of effort, and a lot of capital went into these studies that again, unfortunately did not turn out in a positive manner that we would like to see. So thanks a lot.

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