Targeting the 5α-reductase enzyme in treatment of prostate cancer

A recent review article concludes with the statement, “5α-reductase inhibition does seem to have beneficial effects on prostate cancer incidence, and the role of [5α-reductase inhibitors (5-ARIs)] in combination with other agents should be further evaluated for the treatment of [castration-resistant prostate cancer (CRPC)].”

This review by Nacusi and Tindall, initially published in the May issue of Nature Reviews Urology and now also available in full text on the Medscape web site, provides a careful assessment of the continuing potential of the 5-ARIs (drugs like finasteride and dutasteride) in the overall management of prostate cancer, subsequent to the decisions of U.S. and European regulators not to approve the use of these products to prevent prostate cancer.

The authors make the fundamental argument that the combination of one or other of these agents with other agents that either suppress androgen levels or target the androgen receptor may still have significant potential benefit in the clinical management of progressive forms of prostate cancer. This is an argument that will find favor with the advocates for intermittent, three-drug androgen deprivation therapy (ADT3) — although interestingly the authors do not mention this particular use of 5-ARIs in the course of their review.

The authors focus their review on the mechanisms available to suppress androgen levels and target the androgen receptor, on two ongoing trials,and on data from two completed studies.

The ongoing trials are:

  • The ARTS Phase II clinical trial, in which dutasteride at a dose of 0.5 mg/day is being compared to a placebo in treatment of patients with localized tumors and increasing PSA levels after either radical prostatectomy or radiotherapy. The primary endpoint for this trial is the effect on time to PSA doubling after 2 years of treatment.
  • The TARP clinical trial, in which the combination of dutasteride + bicalutamide is being compared to placebo + bicalutamide in treatment of patients with CRPC. The primary endpoint for this trial is time to disease progression after up to 18 months of treatment.

The two completed trials are:

  • The REDEEM trial, in which dutasteride at a dose of 0.5 mg/day was compared to a placebo in men with  low-risk and low-grade localized prostate cancer. According to data filed with the US Food & Drug Administration, the REDEEM trial showed that, at 1.5 years of follow-up, the incidence of progression favored dutasteride (23 percent of the 142 men receiving dutasteride had progressed compared with 35 percent of the 144 men receiving the placebo); however, at 3 years of follow-up, patients in the dutasteride and the placebo groups had a similar incidence of progression (21 percent of the 106 remaining men receiving dutasteride had progressed compared with 24 percent of the 86 remaining men in the placebo group).
  • A much earlier Phase II study (see Taplin et al.), which suggested that ketoconazole + hydrocortisone + dutasteride was capable of increasing the median progression-free survival of men with CRPC (compared to historic responses to treatment with ketoconazole alone).

A detailed analysis of the results of the REDEEM trial (and the differing points of view about the results of the data from this trial) is also available on the Medscape web site.

The potential of 5-ARIs in the treatment (and the prevention) of prostate cancer remains a highly controversial issue even within the specialized world of urologic oncology. However, a key question that is raised in Nacusi and Tindall’s recent review is whether combination of 5-ARIs with the next generation of hormonal agents (abiraterone acetate, MDV3100, etc.) may provide greater benefits than those already evident for men with CRPC when treated with these products.

[Editorial comment: To access the full texts of the above-mentioned articles on the Medscape web site, you must register with Medscape, but there is no cost for this service and it is easy to limit unwanted e-mail offers from Medscape and its business partners.]

5 Responses

  1. I.e., “We know it effectively treats prostate cancer, but we don’t want to acknowledge its preventive value and shut down our market of being able to treat indolent and low-grade prostate cancers like their more serious cancers.” Despicable.

  2. Tracy:

    (1) We still don’t “know” that it effectively and safely treats any form of prostate cancer. What we “know” is that it appears to have a small, short-term impact on the occurrence and the progression of localized prostate cancer in some men.

    (2) I know of very few urologists (other than Dr. Walsh) who have categorically come out against the use of 5-ARIs in the prevention and early treatment of prostate cancer. I don’t think your conclusion is fair or accurate, and I would note that your personal experience is in complete contrast to this. A lot of patients, when given the various options in a neutral manner, still insist on surgery to “get it outta there.”

  3. Mike, You’re correct that our personal experience is in complete contrast to my (relatively embittered) statement. However, my husband has the great fortune to have access to one of the principal investigators of the research on the value of 5-ARIs. If he didn’t have access to this level of expertise, as many hundreds of thousands of men do not, he would be subject to the fiscal incentives and intellectual motivations (or lack there of) of Main Street docs with Da Vinci’s to pay off, malpractice premiums to keep low, and the hard work of learning new skills to avoid (including teaching patients when radical solutions are required or not) to improve the outcomes for their patients.

    My best shot at protecting my husband in the short and long term is to do whatever possible to bring along the culture of treating prostate cancer to reflect the actual science. The FDA advisory panel had to consciously “suspend disbelief,” purposely ignore the evidence, to make their ruling — subjecting thousands and thousands of men to unnecessary risks and side effects of radical treatments, when a far safer, less invasive alternative is both readily available and quite affordable. For heaven’s sake, the 5-ARIs can still be marketed as vanity drugs for baldness, but can’t be prescribed for chemoprevention? It makes me want to start a charity that hands out free tweezers to men when they get their PSA tested, so they can appear to be balding if their results comes back high.

    When I read this article this a.m., I’m sure I was not the only one who noted the irony that this study suggests that 5-ARIs are helpful in treating the type of prostate cancer they were accused of creating when considered for chemoprevention. I’m sure the science is a great deal more complex than that surface-level irony, but I look forward to the results when that seeming contradiction is addressed.

  4. Tracy:

    The irony of some of this apparently conflicting information may be only irony. When used to treat male pattern baldness, men take finasteride at a daily dose of 5 mg (as opposed to 20 mg for BPH). Also, I don’t think there are very many specialists who would consider treating a man with Gleason 8 to 10 prostate cancer with a 5-ARI alone.

    I have no problem with your observations about all of the conflicting evidence, but I don’t believe that the majority of urologists are not giving men 5-ARIs because it would impact their surgical revenue streams. The numbers of urologists who are now carrying out RPs on a regular basis has dropped significantly in recent years as a subset of real specialists in radical prostatectomy has come to the fore: surgeons who do well over 100 radical prostatectomies a year. There are probably less than 1,000 urologists in America who now do the vast majority of RPs that are carried out each year, and that’s out of about 7,500 practicing urologists. Your average Main Street urologist actually isn’t doing RPs very often at all (and may well be happy not to), and so he or she would have no problem treating appropriate men with a 5-ARI if he or she actually thought it was appropriate to do this.

    Finally, I don’t agree with you at all that the FDA’s advisory committee had to “purposely ignore the evidence” in making their recommendation to the FDA. I think they just saw the evidence in a different way to you (and to me). That doesn’t make them stupid and it doesn’t make them “bad” people. They simply were working from a different mindset: they see the benefit as marginal and the risk as very real. You see the benefit as huge and the risk as minimal.

  5. I, too, “see the benefit as huge, and the risk as minimal.” I’ve expounded favorably on the prescribing of 5-ARIs, and particularly dutasteride/Avodart, as a medication to be included in androgen deprivation therapy as well as during intermittent androgen deprivation (IAD) off-time from LHRH agonists and antiandrogens, in several posts to this website — often enough that I need not repeat myself.

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