ODAC rejects approval of dutasteride for prostate cancer prevention

Unfortunately — but far from unexpectedly — the Oncology Drugs Advisory Committee (ODAC) to the US Food & Drug Administration today voted against the approval of durasteride for the prevention of prostate cancer in men known to be at elevated risk.

This decision is understandable. There was a strong lobby against this approval (even within the urology community), and there are data that were always going to make approval difficult for the FDA — even if ODAC had felt able to vote for approval. At the end of the day, ODAC voted 14 to 2 against approval (with two abstentions), which will make the decision easy for the FDA.

The larger problem is the message that has been send to the biopharmaceutical industry. It is now clear that for any new chemopreventive agent to get approved for the prevention of any form of cancer, the degree of preventive impact will need to massively outweigh any possible side effects. This will mean that the costs and the risks associated with the development of such chemopreventive agents may be too high to justify from a business point of view.

The “New” Prostate Cancer InfoLink is not encouraged by today’s decision (which also affected potential modifications to the labeling for finasteride too). We would be surprised to see another preventive agent for prostate cancer brought before the FDA in the next decade.

6 Responses

  1. “the degree of preventive impact will need to massively outweigh any possible side effects. ”

    What exactly did they cite as side effects? … a slight loss of libido and …


  2. Rick:

    You might want to read this comment by Jim Waldenfels, who actually watched the hearing.

    The big problem associated with the approval of dutasteride (and finasteride) was always going to be the fact that in the original PCPT trial and in the REDUCE trial there was a very small increase in the number of men on drug who got diagnosed with Gleason 8 to 10 cancers compared to those on placebo. The urology community has long been divided over whether that is an artefact of the effects of the drug on the size of the prostate (because dutasteride and finasteride both shrink the prostate, thereby increasing the likelihood of positive biopsies in a smaller prostate) or an actual clinical risk.


    I am working my way through the information presented at the hearing and the background information, trying to sort the valid from the invalid, and trying to figure out whether I still consider the 5-ARIs wise for prevention.

    In addition to the spokespersons for the companies (Merck — finasteride, and Glaxo Smith Kline — dutasteride/Avodart), the spokespersons for the PCPT and REDUCE trials, and for the FDA, Dr. Peter Scardino spoke in favor of approval and Dr. Patrick Walsh spoke against. I’m raising some thoughts about Dr. Walsh’s comments.

    First, he has a fundamentally different view of the significance of the two main androgens — testosterone and DHT — than the one I have understood to be correct. In short, Dr. Walsh believes that testosterone is the dominant androgen involved in prostate cancer with DHT playing a minor role. For those believing that, it would be logical to oppose 5-ARI drugs (finasteride and Avodart) because those drugs prevent most of the conversion of testosterone into DHT, which results in more testosterone if the drug is given alone (and not coupled with another testosterone reducing drug, as it usually is in hormonal blockade therapy).

    In very sharp contrast to Dr. Walsh’s view, the doctors who seem to be leading experts in hormonal therapy have long considered DHT to be much more potent and dangerous to prostate cancer patients than testosterone, though they also regard testosterone as quite important. I believe it is well established that DHT has a far stronger “affinity” for the androgen receptor, meaning that it docks with the androgen receptor much more firmly and reliably than does testosterone. My impression is there is a consensus among medical oncologists that DHT is the more important androgen regarding prostate cancer. At this point, I consider Dr. Walsh’s view as uninformed and wrong, and I’m wondering if I am somehow missing something here.

    Dr. Walsh also was emphatic that 5-ARIs are not useful for treating prostate cancer, quoting such a statement from one of the drug labels in support. As a patient on finasteride continuously for 10 years as part of intermittent triple androgen blockade with finasteride continued during the vacation period, with visibility into the apparent effectiveness of finasteride based on periodic testosterone and DHT tests, I believe his statement is overly broad. It does appear reasonable to assert that the partial effectiveness of finasteride as sole treatment has not been proven, which to me is what the statement in the label means, and it is quite clear that the 5-ARIs are insufficient on their own to adequately control prostate cancer for many of us.

    Here’s another thought. Dr. Walsh was passionate in his opposition (with matching opposing passion from Dr. Scardino, Dr. Logothetis, and others which prompted the chair to figuratively pull the combatants apart). We will have to wait a while for the official FDA transcripts, but my notes from his words around 1:50 PM Eastern time record that he asserted that treatment with a 5-ARI drug was the last thing we should do.

    Considering that emotion, I’m wondering if his career-long mission in treating mostly low-risk prostate cancer patients is subtly threatened by use of 5-ARI drugs in a preventive role, or in support of active surveillance patients. All at the hearing were in agreement that 5-ARIs were effective in countering low-grade prostate cancer, specifically cancer with Gleason scores of less than 7. Well, such patients (or healthy men trying to prevent the disease who might become patients), especially when presenting with fairly low PSAs and negative DREs (or up to stage T2a), are the men who constitute the vast majority of the men upon whom Dr. Walsh has operated and conducted much of his great research. If the 5-ARIs operated as the trial leaders and company representative think they do, there would be far fewer such low risk men going for radical treatment. I can’t help thinking that awareness of that potential could be influencing Dr. Walsh and biasing his views. While he is one of our heroes and worthy of great respect, he is still a human being.

    I try to stay away from ad hominem arguments, and I hope that this thought is legitimate reflection and not ad hominem. The FDA is rightly highly concerned about conflicts of interest and bias, and I’m thinking that the foregoing observation — if sound (comments?) — fits in that area. Am I missing anything here? Even if Dr. Walsh were so biased, that would not invalidate his views, but it would mean that those evaluating him as a witness would be wise to recognize such a bias and consider it in weighing the evidence.

    I have great respect for Dr. Walsh, and I’ll add this — which partly counters the thought about bias. Active surveillance also reduces the number of men available for help through surgery, so you could use the same line of thought that Dr. Walsh would oppose active surveillance. However, Johns Hopkins has one of the most prominent active surveillance programs under renowned surgeon H. Ballentine Carter, and Dr. Walsh, a colleague of Dr. Carter at Johns Hopkins, has been a co-author on some of Dr. Carter’s papers that record impressive success with active surveillance. My impression is that he does support active surveillance.

    Dr. Walsh had other views on 5-ARIs, particularly on the high grade debate, but I’ll leave those for another time.


    I’ve been thinking through the issues from the hearing but still haven’t concluded for myself that finasteride and Avodart do safely reduce diagnoses of prostate cancer, though I’m heading that way.

    However, as a number of panelists noted at the hearing, the emergence of active surveillance as a sound option over the past few years may have pre-empted the role that 5-ARI prevention could have played. It was clear at the hearing that the 5-ARI drugs work almost entirely against prostate cancer in the Gleason 6 and lower range and not against high grade cancer involving Gleason Grades 4 and 5. That kind of low Gleason score cancer is also the kind against which active surveillance is so successful.

    Therefore, for a man who understands and accepts the value of active surveillance should he ever be diagnosed with prostate cancer, what is the added benefit of taking finasteride or Avodart, perhaps for decades?

    One benefit from a 5-ARI drug for prevention would be greater clarity in interpretation of PSA scores and DRE exams. Both have better “signal to noise” ratios when BPH is eliminated or reduced by a 5-ARI drug. Active surveillance does not have that specific benefit, but it works to enhance the signal to noise ratio in other ways after diagnosis, such as through the synergistic value of two or more negative biopsies during surveillance, or the simple passage of years with no substantial increase in the cancer, or very clear PSA velocity information.

    Another benefit from a 5-ARI drug for prevention is a greater likelihood that any cancer that is diagnosed will be clinically significant — more bang for the buck from the biopsy and diagnosis, so to speak. Results from active surveillance also filter out clinically insignificant prostate cancer.

    A third benefit, kidding aside, is that some of us will grow more hair in the male pattern baldness areas, but I’m guessing that a lower dose of finasteride (1 mg Propecia), would do the same thing. Active surveillance won’t help with baldness.

    A fourth benefit is that many of us will enjoy a higher testosterone level as less testosterone is drained off by conversion to DHT. Active surveillance won’t help with that.

    A fifth benefit from taking a 5-ARI drug is a likely reduction in the number of biopsies during one’s lifetime.

    But, assuming that Dr. Walsh and other critics of 5-ARIs are wrong, are the benefits listed above substantial enough to justify taking a 5-ARI for years, perhaps for a lifetime, in view of the fact that active surveillance appears to be just as effective in dealing with prostate cancer with a Gleason score of 6 or lower?

  5. Thousands of men take Avodart or finasteride for BPH. Is there any evidence that these drugs promote, lead to, or just delay the eventual diagnosis of high grade cancer?

  6. Dear John:

    There is considerable evidence that these two drugs delay the diagnosis of prostate cancer of all grades (see, for example, the information about the Prostate Cancer Prevention Trial and the REDUCE trial elsewhere on this web site). However, there is also a suggestion (from the same two trials) that use of these two drugs may induce a slight increase in risk for higher grade prostate cancer in those men who are subsequently diagnosed with this form of cancer. The “New” Prostate Cancer InfoLink has never been convinced that this suggestion is accurate. We think that it is an artefact of the trials, because of the way these two drugs shrink the sizes of the prostates of trial participants.

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