Long-term use of 5-ARIs in low-risk men on AS


Perhaps unsurprisingly, your sitemaster was a little distracted on March 9 this year (by both the start of the COVID-19 chaos and by his birthday) and so he utterly missed what appears to be a rather important paper on the use of 5α-reductase inhibitors (5-ARIs) in men on active surveillance (AS) for management of low-risk forms of prostate cancer.

The paper by Finelli et al., in Prostate Cancer and Prostatic Diseases, provides a retrospective analysis of data from 288 men on active surveillance being managed at the Princess Margaret Hospital in Toronto, Canada. Only the abstract is available on the journal’s own web site, But for those who are interested, the full text of this paper is available on the UroToday web site, as is an associated set of editorial comments by Parsons.

The basic facts are these:

  • Finelli et al. looked back at their data on 288 men on AS for low-risk forms of prostate cancer from 1995 to 2016.
    • 85/288 patients (29.5 percent) had been taking a 5-ARI.
    • 203/288 patients (70.5 percent) had not been taking a 5-ARI.
  • All patients met normal criteria for diagnosis with low- or very low-risk prostate cancer
    • PSA < 10 ng/ml
    • Clinical stage T1c–T2a
    • Grade Group 1 (i.e., Gleason score ≤ 3 + 3= 6)
    • Three or fewer positive cores, with no more than 50 percent of a core involved at initial diagnostic biopsy
  • The average (median) patient follow-up for all patients was 82 months (nearly 7 years), but …
  • The median follow-up times were much longer for the men who were taking a 5-ARI:
    • 114 months for the 5-ARI users
    • 61 months for the non-users
    • This difference was statistically significant (p < 0.001).
  • Among the men who were taking a 5-ARI
    • 24/85 (28.2 percent) showed clear signs of pathologic disease progression
    • 19/85 (22.4 percent) exhibited grade group progression
    • 15/85 (19.7 percent) exhibited disease volume progression
  • Among the men who were not taking a 5-ARI
    • 114/203 (56.2 percent) exhibited pathologic disease progression
    • 82/203 (40.3 percent exhibited grade group progression
    • 87/203 (43.1 percent) exhibited disease volume progression
  • Non-use of a 5-ARI was significantly associated with an increased likelihood of
    • Pathologic progression (hazard ratio [HR] = 2.65)
    • Grade group progression (HR = 2.75)
    • Disease volume progression (HR = 3.15)
  • But … frequency of progression to high-grade tumors was not significantly different between the groups:
    • 11 men progressed to high-grade disease (Grade Group 4–5/Gleason score ≥ 8) after a mean follow-up of 65 months
    • 2/19 (11 percent) were taking a 5-ARI
    • 9/82 (11 percent) were not taking a 5-ARI

There are a few other things of importance to note:

  • The study cohort was limited to patients who had all had at least one repeat biopsy after diagnosis.
  • Men were excluded if they were on a 5-ARI before being diagnosed with prostate cancer, or if they had received definitive treatment at another center.
  • Finelli et al. do not tell us which 5-ARIs were being used for which patients.
  • They therefore do not tell us whether there were any differences in results between men taking finasteride and men taking dutasteride.

Finelli et al. conclude that:

5-ARI use was associated with reduced risk of both grade and volume progression. Most importantly, 5-ARI use was not associated with the development of high-grade (GG 4–5; GS 8–10) disease. Thus, 5-ARIs should be considered for secondary prevention in men on AS for low-grade disease.

Parsons, in his editorial comments, comes to a very similar set of conclusions:

… these results validate a robust and expanding body of Level 1 and 2 data supporting the efficacy and safety of 5-ARIs to prevent grade progression in AS patients. Consideration may be given to 5-ARI therapy in this patient population to reduce the risks of prevention and treatment.

Now, just to be extremely clear, the chances on anyone doing a randomized, controlled, long-term Phase III clinical trial of any 5-ARI for the prevention of disease progression in men with low-risk forms of prostate cancer is pretty much near to zero. However, it may be that a meta-analysis could be carried out across a number of cohorts of AS patients to see if such a meta-analysis confirms these data from the Princess Margaret Hospital.

In the interim, it seems extremely clear to your sitemaster that, while treatment with a 5-ARI cannot guarantee that patients started on AS will necessarily not progress over time, such treatment appears to roughly double the chances of non-progression (so long as the patient has few or none of the side effects that can occur with the use of this type of drug therapy), with a median follow-up of nearly 10 years.

 

2 Responses

  1. First .. happy belated B-day, Sitemaster …. who knew??

    I have not read the full paper in any detail but do notice that 27% of men discontinued AS. Is this part of or in addition to the 28% who progressed. This may impact your conclusion that taking a 5-alpha-reductase inhibitor doubles your chance of non-progression.

    I also question whether a 5-ARI reduces risk of pathologic progression with a number of 28% experiencing disease progression.

    The old heuristic guidelines from the UCSF and Sunnybrook cohorts suggest around 30 to 33% of men progress, 30 to 33% opt out for treatment, and 30 to 33% successfully remain on AS.

    Are these numbers that different to warrant taking a 5-ARI?

  2. Dear Rick:

    I would respectfully suggest that you read the whole paper. These are not “my” conclusions. They are the conclusions of the authors (from a highly respected Canadian institution) and of an independent editorialist.

    My interpretation of the full paper is that the men who discontinued AS for any reason are all included in the data. The study would be meaningless if they weren’t. You need to look at the statement about mean time on AS for the two different groups of men. This statement rather obviously implies that a much lower percentage of men came off AS when they were on a 5-ARI.

    With regard to whether these these numbers are sufficiently different to warrant taking a 5-ARI, all that I can tell you is that if I was diagnosed with low-risk prostate cancer tomorrow and there was no reason why I couldn’t take a 5-ARI, I would find these data very convincing (but I would still discuss them with my doctor in the context of my individual situation, like any wise patient).

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