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Approval of dutasteride for reduction in risk for prostate cancer?

Posted Oct 25 2010 12:00am

On December 1 this year the US Food & Drug Administration’s Oncologic Drug Advisory Committee (ODAC) will meet to hear arguments in favor of and probably some against the approval of dutasteride (Avodart) for “the reduction in the risk of prostate cancer in men at increased risk of developing the disease.”

To date, the only agents approved in the USA for reduction in the risk of diagnosis of any form of cancer are tamoxifen and raloxifene , each of which has been approved for the reduction in risk of invasive forms of breast cancer in defined patient types. However, in each case the use of these drugs for reduction of risk has been significantly less than originally expected, and at least some in the medical community have suggested that other risks associated with long-term use of these agents to prevent risk of breast cancer do not justify the supposed benefits.

The results of the REDUCE trial, initially presented at an annual meeting of the American Urological Association in April 2009 and subsequently published in the New England Journal of Medicine , appear, at first sight, to be reasonably compelling. The absolute reduction in risk for a diagnosis of prostate cancer associated with dutasteride as compared to a placebo was 5.2 percent among a population of patients who met specific criteria for increased risk for a diagnosis of prostate cancer. This reduction is risk may seem small, but it was actually a 22.8 percent relative reduction in risk (from 25.1 percent in the patients who took a placebo to 19.9 percent in the men treated with dutasteride). There are certainly a group of men who would consider this to be a clinically significant and important reduction in their risk for prostate cancer.

However, there are three pieces of evidence that present reasons why approval of dutasteride might (or even should) not be approved:

  • The first came from the originally reported results of the Prostate Cancer Prevention Trial, in which it initially appeared that a small subset of men taking another 5α-reductase inhibitor (finasteride/Proscar) had an increased risk for a diagnosis of prostate cancer with high Gleason grade. The validity of these data have been much argued over the years, and the majority of researchers now seem to feel that this apparent result had more to do with the likelihood of a positive biopsy in men whose prostates had been shrunk by their treatment than it did with any real likelihood of finasteride increasing risk for Gleason 8-10 prostate cancer.
  • The second is that in the REDUCE trial, as similar finding occurred. Among men enrolled in the trial who underwent a biopsy in years 3 and 4 of the trial, a tumor with a Gleason score 0f 8-10 was identified in 12 patients treated with dutasteride but only in 1 patient treated with placebo. Is this also because the dutasteride shrank the prostates of the men who were treated with the active drug? It is certainly possible. Is it clearly provable? Probably not.
  • The third is that treatment with dutasteride was associated with a small but evident increase in the relative incidence of heart failure (30 events or 0.7 percent) compared to treatment with the placebo (16 events or 0.4 percent).

The “New” Prostate Cancer InfoLink is of the strong opinion that dutasteride should be approved for the reduction of risk for prostate cancer among men known to be at high risk. However, this does not mean that we think it will necessarily be widely used for this indication. The question that each doctor and his patients will need to address is whether the potential benefit from the reduction in risk and from the reduction in fear of that risk is substantially higher than the potential for adverse events. That may be a difficult equation to solve in individual cases.

The larger question that the FDA needs to face up to, however, is a public health question. How much benefit has to be demonstrated in trials of drugs to prevent risk for cancer as compared to how much risk for other problems? Failure to approve dutasteride for the reduction of risk of prostate cancer may mean that we never see another attempt to get any drug approved for the reduction of risk of cancer because the barrier to drug approval may appear to be set too high. The cost of conducting clinical trials involving 8,000 to 10,000 patients over several years is enormous. No drug company is going to invest in such trials if drug approval for such an indication requires a complete absence of any risk. It is much too hard to prove such a negative.

We shall have to wait and see what “plays out” at the ODAC meeting in December. In the present political climate, it seems likely that the FDA will have touch questions about the risk-benefit equation for dutasteride … but having tough questions doesn’t mean that they will not approve the drug. We finally have strong leadership again at the FDA with a commitment to good decision-making in the interests of the public health. We expect the FDA to make sound decisions based on that commitment as opposed to decisions based on the political winds that whistle through Congress every other year.

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