DR. KLEIN; Given the fact that the publication of the PCPT results was probably one of the most important events in urology in the last decade and the controversy surrounding the results I thought we would take a few minutes and hear from audience members and from Peter on the discussion on what we ought to be advising individuals.

Let me just ask for a show of hands. How many urologists in the audience are recommending finasteride to patients who ask how they can prevent prostate cancer?

(There was a show of hands.)

DR. KLEIN: A few, not many, okay. So, let us hear about what your reluctance is in this background and I throw this perspective which I think is an accurate one but which I throw out for discussion. Taking preventive agent is always about a risk/benefit analysis and so if for taking hormones in women postmenopause it seems like the risk of other kinds of cancers outweigh the benefits that you might get from osteoporosis, but I think the equation adds up differently for finasteride.

It is very clear. No one has challenged the primary finding that 25 percent fewer men got prostate cancer. The sexual side effects were known and really are pretty minor and if you look at what happened with sexual side effects in the placebo arm they are almost the same.

When you add up the fact that if you take finasteride you are 25 percent less likely to get cancer, you have a significant reduction on urinary symptoms that are associated with aging and a significant reduction in the risk of undergoing surgery for BPH and if you recognize based on the capsure database that 95 percent of men with newly diagnosed prostate cancer choose treatment, the other thing that finasteride prevents is treatment-related side effects and it seems to me when you add it up all that way and throw in the fact that perhaps at least some of the high-grade cancers might actually be histologic artifacts, it seems to me that this is on balance a very positive starting point.

We need to understand a little bit more about whether these high-grade cancers are real because there are some biologic hypotheses to suggest that they might be, but I am a little surprised that we are not stampeding and heralding to the world, "Hey, as urologists we did this great trial. We can prevent prostate cancer, and the benefits clearly outweigh the risks."

I would like to hear some discussion on that.

DR. GREENWALD: I agree with your assessment except for one thing. I would like the Food and Drug Administration to approve it for this purpose before we would recommend it.

DR. KLEIN: We are serving as advisers to FDA and as advisers to FDA that is what you would recommend?

DR. GREENWALD: It is up to the drug company to bring it forward, and I think taking a preventive drug is not an emergency. So, I think I would like to see the process play out, but I think the case they are making is sound.

Also, we will be getting more information with follow-up in men. So, those who are uncomfortable about that Gleason finding will have more information in the future as the studies go forward.

David?

PARTICIPANT: I am very concerned that finasteride masks PSA. The fact that doubling of PSA on finasteride is not an appropriate formula is evidenced by this study where at 3 years you had to readjust the PSA value, and I am concerned that the longer these patients are on finasteride this ratio may need to be readjusted even further, and that has not yet been worked out.

The studies of Jerry Andriol and really the leaders in this field who did develop the doubling formula did it on very short term basis and we are committing patients to take finasteride for a very long period of time.

DR. KLEIN: That is something that we learned about finasteride is the longer you stay on it, that double factor probably has to go higher, but, Ian correct me if I am wrong, didn't it plateau by the end of the study at 2.3 and what do you know about PSA kinetics during the course of the trial and does PSA velocity stay the same and would that still be a good surrogate for needing a biopsy?

DR. THOMPSON: I do not know about the kinetics over a longer period of time. Again, remember that they were being adjusted to have an equivalent number of biopsies in both arms. Unless you actually conduct the study again and go for 20 years you will not know the answer to that.

I think the principal issue with regard to Gabe's point is that 98 percent plus of the men were diagnosed, if you were following them and doing precisely what was recommended were diagnosed T1, T2 clinical.

DR. GREENWALD: I am not sure we would have a reason to recommend for more than 7 years based on the trial which was 7 years.

The other question I often get is what about petesha(?) does 1 milligram have almost the same effect on PSA as 5 milligrams and there are younger men taking it for a long time and we don't have a definitive trial of this sort. So, I would be interested in how you fellows are answering that question.

DR. KLEIN: It is more expensive.

PARTICIPANT: You know when you asked the question I raised my hand. I have no trouble recommending finasteride for some of my middle-aged men who already have BPH symptoms, high AUA scores but I really have problems. We have a lot of younger higher risk African-American men in the military and I really struggle with whether I should be recommending this for some of the patients who potentially may benefit the most whereas I have least trouble with some of the average risk white guys who probably might not need it anyway.

DR. KLEIN: The risk reduction in PCPT was the same for all risk groups. It was 25 percent and that was not statistically different amongst groups, and I think I have heard many people express that but I really wonder if that is correct. I mean it is our perception. The epidemiology is that black men are more likely to get prostate cancer, but really on a percentage basis, an epidemiologic basis no more likely to benefit.

DR. THOMPSON: Eric, may I introduce the next speaker, Dr. Walsh who if I can just say is going to be the Huggins Award winner after lunch but just to put things in perspective was one of the first describers of 5-alpha-reductase deficiency.

DR. WALSH: I don't think anyone knows the answer but let me just raise a few questions that I have in mind. First of all, I have always been a little annoyed about the rationale. First of all, as Ian said you know in the 5-alpha-reductase deficiency the patients don't develop prostate cancer but that is because they don't have a prostate.

Women don't develop prostate cancer either. So, I think that is sort of a straw man. Secondly, prostate cancers don't make much 5-alpha-reductase.

No. 3, when you treat people with advanced prostate cancer with Proscar you don't really get an effect and No. 4, there are animal models that show finasteride really doesn't, animal models of prostate cancer that finasteride doesn't do anything.

So, on the other side of the rationale there are a number of reasons to question whether finasteride actually has a therapeutic effect on cancer.

The next point that as I looked at the studies and I think many people may not understand is that there were, and I would like to focus on the for-cause biopsies because I think that is in the steady state as we would be using it clinically is where we are and in the for-cause biopsies there were fewer men on finasteride who agreed to undergo a biopsy because their PSA was elevated or they had a rectal exam and so the numbers that we see are exaggerated because if you look at the percent of people who underwent a biopsy it is actually a 10 percent reduction in cancer, the number of cancers in the for-cause biopsies in patients who were on placebo versus finasteride.

So, it is not a 25 percent reduction. It is really a 10 percent reduction if we were using it in practice. So, we are trying to reduce something by 10 percent with the question and I don't know the answer either to whether these tumors are more aggressive or not, long-term data on what radical prostatectomy showed in those patients, follow-up and things like that.

So, those are the questions that I have about the study. The final point I would like you to comment on is the shocking number of cancers that occur, you know, positive biopsy rates of 25 percent suggesting that many of these cancers may have been very insignificant cancers and that we really are not having an effect on the real significant ones.

So, that is really my question, but you can also throw darts at all my other comments.

DR. GREENWALD: On the first one you know when we start a clinical trial we almost always have to make a judgment of when do we have equipoise, that is when is there enough evidence that you with good judgment want to move ahead, but you don't really know the answer. I gather you wouldn't have started the trial from what you were saying. We did, and I take your point on the genetic condition, but we have a trial now with an exciting result that we would have started and you wouldn't have started as I understand it.

I am not quite sure about your second point. I have to think about the rate and the cancers that develop during the course of the trial. I agree that those are the ones that with our current knowledge would be extremely important to look at right now.

On the third point, is 25 percent high, well, it is not high compared to autopsy rates of occult cancer. So, I was not surprised at the high rate but we do have the dilemma of having to understand the significance of the cancers that were found and one thing unique about the study is we now have the biopsy material. There are some very exciting technologies that may give us a way of getting a handle on understanding that and one of the most important things we can do is try to figure out the meaning of that. I appreciate your comments.

DR. KLEIN: Mike, let me just make a comment? One way to look at this I think is that we have to refine what we mean by insignificant cancers because it is a little fuzzy, and I think we need to make a distinction between biologically significant cancers, ones that are destined to kill the host and clinically relevant cancers and we don't have good ways of knowing who has a biologically significant cancer. I agree with that comment completely.

On the other hand again the database shows that 95 percent of newly diagnosed men in the most recent period analyzed which was I think 1999 to 2001, who have a grade 6 cancer most of which probably aren't biologically significant choose therapy and so that is a clinically relevant cancer and one could make the argument that finasteride at whatever level whether it is 10 percent or 25 percent or maybe even higher since the finasteride glands were over sampled because they were smaller than the non-finasteride glands at some level we are not only preventing the cancers but we are preventing everything that goes on with treatment and all the potential treatment-related side effects and so again you could add that if you wanted to.

Take the case that this is a very positive trial, minimize the negatives and that would be a way to do it.

Howard?

PARTICIPANT: I yield the floor.

PARTICIPANT: If I may I want to point out Dr. Walsh is perfectly correct. The reduction in for-cause cases was 10 percent, but we should also recognize that was a statistically significant difference and that the rate of diagnosis in the for-cause group was 6 percent which is exactly what one would expect from the SEER data. So that group I think is really where to look for proof of principle that we are significantly decreasing the kinds of cancers that we are finding in practice.

DR. KLEIN: Okay, and we have to limit the comments to the remaining three individuals standing.

Mike?

PARTICIPANT: I was a little bit confused in trying to interpret the results of the study because at the very end when you started to biopsy people there was a sudden increase in the number of positives on those who had had finasteride and yet I don't think that that was really reviewed in the interpretation of the results.

The second aspect of it is if I don't understand the biology of the disease that we are treating here is the finasteride more effective in those cancers that are likely to be clinically insignificant, and I guess this was said in several ways by other commenters, and if we are trying to address the issue of prostate cancer, the genesis of that seems to be more of a molecular genetic genesis rather than an epigenetic type of thing. Should we then think if this is to be effective of earlier treatment to be more effective in ultimate expression of disease?

DR. THOMPSON: The reason for the change in the number of biopsies at the end was because these biopsies were for cause, an abnormal DRE or an abnormal PSA and because the men were reaching the end of the study and were going to go off the study at the 7-year mark there were more men who had been told previously that we recommend a biopsy who acceded to a prostate biopsy. I think your next question with regard to is it more effective or not and which tumors I don't think we know the answer to it. The final answer, if you don't mind, Peter there are molecular studies that are looking specifically at that.

DR. BRAWLEY: I would like to point out that in the for-cause biopsies those with the positive DRE or positive PSA over the 7 years it was more than 12 percent of men were diagnosed with prostate cancer. So, this is in keeping with your comment, Dr. Klein.

Biologically significant, clinically significant and detectable and screening are all three different things and we need to work hard to try to figure out what things truly are of risk to the individual's health, and my last point is again look at the placebo arm of this trial. Six percent of the men in the placebo arm had high-grade disease and the one thing that epidemiology can currently tell us is 3 to 4 percent of all men in the placebo arm are destined to die from prostate cancer.

So, this study actually questions even whether Gleason grade is predictive of the biologic behavior of the prostate cancer as it concerns the life of the individual.

DR. KLEIN: Dr. Schellhammer, as always the last word.

DR. SCHELLHAMMER: Not at all but just a brief comment with regard to visceral reaction. When you gave your discussion it was very convincing but I will say that what the public has heard I think overwhelmingly has been the reverse of that, namely, negative comments. So, the number of hands that go up may be reduced by the fact of that concern, but I would like to ask Dr. Greenwald, with getting off the PCPT trial vitamin E in the ADTC study was given in a 50 international unit dose and Select has 400. There are different isoforms. Selenium I understand now too little may be not good but too much may be equally inappropriate. So, how when the Select trial sorts out are these differentials going to be addressed because I can see the same discussion being brought up 3 years from now.

DR. GREENWALD: Right, there were workshops and committees debating and discussing that before we came up with a dose and the conclusion was the dose that biologically we would be sure would be effective and we would know exactly what was being given, but I mean in most of these studies you can only really do one dose unless you have a much larger study.

DR. KLEIN: Okay, thank you, Peter.

We are going to go to the poster session now for 30 minutes and we will begin the next session at eleven.

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