5-ARIs, active surveillance, and prostate cancer progression

We will presumably be at least a little wiser about this issue when data from the REDEEM trial are presented at the Genitourinary Cancers Symposium in Orlando on Thursday; however, data from Canada already suggest that 5α-reductase inhibitors (5-ARIs) affect progression of low-risk forms of prostate cancer.

Finelli et al. conducted a single-institution, retrospective analysis of data from patients with prostate cancer being managed on an active surveillance protocol who were or were not also being treated with a 5-ARI (either finasteride or dutasteride). They carefully assessed available data on pathologic progression  of disease (defined as a Gleason score > 6), maximum biopsy core involvement > 50%, or the presence of more than three positive cores at the time of follow-up prostate biopsies.

Here are the top-line results of their study:

  • 288 men on active surveillance met the inclusion criteria for the study.
  • Average (median) follow-up was 38.5 months.
  • 93/288 men (32 percent) showed evidence of pathologic progression.
  • 96/288 men (33 percent) abandoned active surveillance.
  • Men taking a 5-ARI had a lower rate of pathologic progression than men not taking a 5-ARI (18.6 vs 36.7 percent; p = 0.004).
  • Men taking a 5-ARIwere also less likely to abandon active surveillance (20.0 vs 37.6 percent; p = 0.006).
  • Lack of 5-ARI use was strongly associated with pathologic progression (hazard ratio = 2.91)

Obviously this type of single-institution, retrospective data analysis needs to be interpreted with caution, and follow-up in this study only averaged a little more than 3 years, but there is clearly an effect of 5-ARIs on prostate cancer that appears to delay the need for interventional therapy in men with low-risk disease. Understanding the clinical significance of this effect will need follow-up of more like 10 to 15 years.

5 Responses

  1. I would submit that a possible reason that men taking 5-ARI were less likely to abandon AS is that they were treated and therefore felt they are taking steps to fight cancer. I think it is a psychological effect. To verify this hypothesis, a test should be conducted with a control arm.

  2. Dear Reuven:

    That is exactly why the REDEEM study was initiated in 2006, and why the results of this study will help to clarify the situation. It is a randomized, double-blind, placebo-controlled trial.

  3. Well, I know that 5-ARIs have been slowing progression for at least 10 years. Medical Oncologist Stephen Strum, in his 2002 “A Primer on Prostate Cancer – The Empowered Patient’s Guide” pages 144-149, reported much longer off-time from ADT when the patient had finasteride/Proscar included in his ADT (ADT3), then maintaining that off-time (intermittent androgen deprivation/IAD) with continued finasteride/Proscar after stopping the LHRH agonist and antiandrogen, than those patients on ADT2 (LHRH agonist and antiandrogen) who, when going to IAD, did not “maintain” with finasteride/Proscar. I recognize that this report regards ADT and not a 5ARI while on active surveillance (AS), but substantiates the effect of a 5-ARI on slowing progression of prostate cancer.

  4. Dear Chuck:

    I have a lot of respect for your knowledge, but — as you well know — there is actually no well-documented evidence from any clinical trial (or even from a well-documented case series) in the published literature, that shows ADT3 to be associated with longer survival than ADT2 or even ADT (when used intermittently or in any other manner) in men with progressive disease.

    I understand that Dr. Strum and some others believe this to be the case based on their personal experiences. Sadly, however, they have neither collected nor published data that can be used as evidence to substantiate this belief. At present all we have is opinion, based on the personal histories of selected patients who appear to have done well on this type of therapy (including you and Jim Waldenfels), but we have no data at all from the patients who may have tried this approach without any apparent success, and there certainly have been such patients.

  5. Dear Sitemaster and Chuck,

    First, thanks very much for this interesting article; I’m really looking forward to those REDEEM results.

    I am curious why the Scholz, Strum, Lam and colleagues group has not yet published their IADT3 results. I believe they have these results and that they are well documented. They have edged close to it, publishing their IADT2 (without a 5-ARI) plus finasteride for maintenance results in the prestigious Journal of Urology (Scholz MC, Jennrich RI, Strum, et al. Intermittent use of testosterone inactivating pharmaceuticals using finasteride prolongs the time off period. J Urol. 2006;175:1673-8).

    Perhaps they are concerned that finasteride has not been approved for this purpose (use in ADT3). However, that seems unlikely to me as the Primer that Chuck mentioned and other informal papers and presentations highlight finasteride in the ADT3 combination.

    I know that Drs. Strum and Scholz did submit a trial proposal for ADT3 many years ago, but they could not get key sponsorship for a trial that would have been expensive. I’m hoping that Dr. Sartor’s trial will begin to formally document ADT3 success. The Sartor trial does pose an extra challenge, as finasteride is not used up front with the LHRH agonist and the antiandrogen; rather, it is used after that combo can no longer control PSA. That suggests that a higher risk group of patients is involved, and it means that the 5-ARI is coming in at a time when the cancer has already built up momentum. Still, I have high confidence that at least some clear benefit will be observed.

    As for patients who are unsuccessful with the approach, I suspect there will be some, as there are with almost any therapeutic approach. We already know that some men have a genetic problem with Avodart (though apparently not with finasteride); this was mentioned by Dr. Myers. (I’m trusting that the Sartor team is measuring DHT to ensure that the drug is effective at decreasing DHT.)

    On the other hand, I’ve been impressed with the very high response rates that have been informally reported. My own response adds personal credibility, as do the responses reported by fellow survivors, but obviously we need objective trials to nail down what is happening.

    I’m hoping we will see some poster presentations at the IMPaCT conference in early March that throw light on ADT3.

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