Dutasteride as a single agent for low-risk prostate cancer

According to data just reported in The Lancet, some men with low-volume, low-risk prostate cancer may be able to delay progression of their disease if treated only with the 5α-reductase inhibitor dutasteride (Avodart®).

Fleshner et al. conducted a multi-center, randomized, double-blind, placebo-controlled trial (the REDEEM trial) in men aged between 48 and 82 years who had low-volume prostate cancer (Gleason score 5 or 6) and who had elected to follow an active surveillance protocol as opposed to any form of immediate treatment. All patients in this trial were recruited and treated at academic medical centers in North America. The participants were randomly assigned to be treated with 0.5 mg of dutasteride once a day or to a matching placebo; they were followed for  3 years (which is obviously a limited follow-up period), with 12-core biopsies at 18 months and 3 years of follow-up.

The primary endpoint for this study was time to prostate cancer progression, defined as the number of days between the start of study treatment and the earlier of either pathological progression (in patients with one or more biopsy assessment after baseline) or therapeutic progression (start of medical therapy).

Here are the results reported by Fleshner et al.:

  • The study enrolled 302 participants between August 2006, and March 2007.
  • 289/302 participants (96%) had at least one biopsy procedure after baseline and were eligible for inclusion in the current analysis.
  • At 3 years of follow-up
    • 54/144 men (38 percent) in the dutasteride arm had prostate cancer progression.
    • 70/145 men (48 percent) in the placebo arm had prostate cancer progression
    • This difference was statistically significant (hazard ratio [HR] =0.62;  p=0.009).
  • Adverse events occurred with similar frequency in each of the two treatment arms.
    • 35/144 men (24 percent) in the dutateride arm had sexual adverse events or breast enlargement or tenderness.
    • 23/145 men  (15 percent) in the placebo arm had sexual adverse events or breast enlargement or tenderness.
    • 8/144 men  (5 percent) in the dutasteride arm had cardiovascular adverse events.
    • 7/145 men (5 percent) in the placebo arm had cardiovascular adverse events.
    • There were no cases of prostate cancer-related death or of progression to metastatic disease.

The authors conclude that, “Dutasteride could provide a beneficial adjunct to active surveillance for men with low-risk prostate cancer.”

A different way to look at these data is to say that there is an absolute increase of 10 percent in probability of non-progression of low-risk prostate cancer at 3 years if you take dutasteride alone (which translates into a relative increase in probability of 38 percent).

According to a report on this study on the MedPage Today web site, these results did not impress the editorialist in The Lancet (supposedly because there was no impact on prostate cancer-specific or overall survival, although surely no one could have been expecting such an impact within 3 years).

The bottom line would appear to be this: taking dutasteride if you are on active surveillance for low-risk disease may well increase your probability of deferring disease progression (at least over a 3-year period). However, this trial was always going to be too small and carried out for too short a period to provide truly compelling data regarding the value of dutasteride alone as a means to treat low-risk prostate cancer. There is also the the very small, and much argued risk, over whether dutasteride carries a risk for inducing more aggressive forms of prostate cancer in some patients.

5 Responses

  1. Another commentary on this article is now available on the Medscape web site.

  2. This study raises several questions. Although seemingly well designed, it might not be truly blinded because men on placebo would know this by the absence of a drop in their PSA compared to the dutasteride group. This certainly could have led many men to choose treatment rather than continue active surveillance even though they had no clear progression.

    More importantly, with 48% showing progression, one has to question whether we are using the wrong outcome to assess active surveillance, as clearly half the people can’t possibly be in danger in 3 years.

    Finally, why was this paper published now? Three years is too early to know meaningful results and with the study unblinded, further results will not be possible. Certainly, this study cannot really justify routine use of this drug in these men, and the FDA is highly unlikely to give an approval. The bottom line is that we really don’t know if dutasteride benefits men on active surveillance.

  3. I was in agreement with you until you chose to add the last sentence. In my opinion, there has been absolutely no solid evidence that either dutasteride/Avodart or finasteride/Proscar “cause” more aggressive or high grade prostate cancer, and until there is it irks me when there is any continued suggestion that this might even be a remote likelihood.

  4. Dear Chuck:

    I was very careful not to say whether 5-ARIs did or didn’t induce high-risk prostate cancer in a small number of men. I said there was an argument over it. You are very strongly on one side of that argument, but you can no more dismiss the views of those who disagree with you than they can dismiss yours.

  5. Chuck,

    The reason the FDA did not approve the drug as a preventive agent is partly because of the unexplained risk of more high-grade cancers so they thought it was enough of a concern to not approve it.

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