Finasteride lowers risk for diagnosis with prostate cancer WITHOUT increased risk for prostate cancer-specific mortality


Something that most of us seem to have managed to “miss” at the American Urological Association (AUA) annual meeting in San Francisco in May was an update from Dr. Ian Thompson on the 25-year outcomes of the Prostate Cancer Prevention Trial (PCPT). It has the potential to be rather important!

The goal of the PCPT, when it was initiated back in the early 1990s, was to see if regular use of finasteride (a 5α-reductase inhibitor or 5-ARI initially approved to treat benign prostatic hyperplasia and later to help re-grow hair in some balding men) could also be used to reduce risk of diagnosis with prostate cancer.

The primary goal of the original trial was quite certainly met when it was shown that there was a 25 percent reduction in risk for diagnosis with prostate cancer among the men treated with finasteride in this very large trial (which enrolled and randomize 18,882 US patients to treatment with finasteride or a placebo). However, …

When Merck sought to gain approval to market finasteride (under the brand name Proscar) as an agent that could lower risk for diagnosis with prostate cancer, some individuals expressed concern that trial data suggested that treatment with finasteride was only lowering risk for prostate cancer diagnosis among patients who were already at low risk and that it might actually be increasing the risk for diagnosis of patients with higher Gleason scores who would then go on to have metastatic disease and be at risk for prostate cancer-specific death.

It should be pointed out that this suggestion was seriously disputed by numerous experts in the field at the time. However, in the end, the US Food and Drug Administration never approved the use of finasteride as a drug for the prevention of risk for prostate cancer, and, to this day, the US prescribing information for this agent carried the following statement:

PROSCAR may increase the risk of high-grade prostate cancer.

In his presentation of the 25-year follow-up data from the PCPT at the AUA annual meeting, Thompson clearly reported the following:

  • By use of the National Death Index (a centralized database of death records at the Centers for Disease Control and Prevention) they were able to show that
    • Average (median) follow-up of PCPT participants in this database was 18.4 years
    • Total follow-up was almost 300,000 person-years
    • The number of prostate cancer-specific deaths  of enrollees in the PCPT was
      • 42 among men treated with finasteride arm
      • 56 among treated with the placebo

Previous analyses have already, also shown that

  • Treatment in the finasteride arm of the PCPT improved detection of clinically significant prostate cancer (including high-grade tumors).
  • Study participants enjoyed the same overall longevity whether they received finasteride or placebo.

A detailed report on Thompson’s presentation can be found on line in Renal & Urology News. In that report, Thompson is quoted as follows:

What we ultimately found were fewer prostate cancer deaths with finasteride, demonstrating with prolonged follow-up that there was no greater risk of prostate cancer death with the drug, just fewer cancers.

He went on to state that these data “could benefit thousands of men each year in the US” and more specifically that

Urologists and their patients can now rest easy that these initial concerns regarding high-grade tumors are unfounded. Additionally, for a man who asks his physician, ‘How can I prevent prostate cancer,’ the physician can now tell him with confidence that there is a proven method to reduce his risk of this common disease.

There are three critical questions that are consequently raised by these data:

  • Would finasteride’s original manufacturer be will to resubmit all the available data to the FDA to seek an approval for finasteride as an agent that can lower risk for diagnosis with prostate cancer? (It should be noted that finasteride is now available as a generic drug, so there is no commercial benefit to Merck in making such an application, but the company has long taken the position that it is in the business of helping society to have access to high-quality care; thsi would be a chance for them to put that policy ahead of any potential profits.)
  • Would the FDA now approve finasteride as an agent that can lower risk for diagnosis with prostate cancer if Merck made such an application? (If the drug was so approved it might still carry the warning about risk for diagnosis with higher Gleason scores but that could be addressed in context by the now-available long-term survival data.)
  • Are guideline-writing authorities such as the National Comprehensive Cancer Network (NCCN) and the AUA itself willing to go on record and state that available data clearly demonstrate that finasteride treatment reduces the risk of diagnosis with prostate cancer by 25 percent with no increase in risk of prostate cancer-specific mortality?

We would be remiss if we did not point out that finasteride does have well known side effects that are unacceptable to some men, most particularly (according to the product’s prescribing information):

  • Impotence (in 18.5 percent of men treated with finasteride as opposed to 12.2 percent treated with placebo)
  • Decreased volume of ejaculate — defined as “Abnormal ejaculation” (in 7.2 percent of men treated with finasteride as opposed to 2.3 percent of men treated with placebo)
  • Decreased libido — defined as “Abnormal sexual function” (in 2.5 percent of men treated with finasteride as opposed to 0.9 percent of men treated with placebo)
  • Breast enlargement and breast tenderness — defined as “Gynecomastia” (in 2.2 percent of men treated with finasteride as opposed to 0.7 percent of men treated with placebo)

Men who have such side effects and find them unacceptable may well decide that staying on finasteride to prevent their risk for prostate cancer is “not for them”.

14 Responses

  1. Since there is no impact on total prostate-specific mortality, the drug would need to be justified on other grounds — specifically, quality of life. Does finasteride improve quality of life? I could see this going in both directions. First, there is the issue of side effects, and costs, and nuisance value of having to take a medication. Second, is the implications for surveillance. Likely, use of the drug would be associated with increased surveillance because of concerns about high-risk cancer. Presumably, it would also result in a reduction in the discovery of low-risk cancer, in turn resulting in less active surveillance of those low-risk cancers (biopsies, anxiety, etc., etc).

    In real world use it might lead to later discovery of more aggressive cancer (i.e., subjects in trials get very close monitoring, something unlikely to be replicated in the real world) — which in turn may require more aggressive, extensive treatment.

    Given all the complexities, it seems that, short of another trial (unlikely to be done), the answers to these questions will not be available. The net benefits and harms are unlikely to be compelling.

  2. I took finasteride for 10 years for BPH. It worked pretty well but I didn’t know that it was known to reduce PSA readings by some 50%. I assume this meant that PSA emitted by the prostate was actually cut in half.

    I had annual readings of 0.4 until age 65 when my PSA was 1.2. Then it increased annually until age 69 when it was 5.4 and upon re-test was 6.6. Was I really 10.8 and 13.2?

    My PCP sent me for a biopsy when my PSA level was 6.6 (13.2?) and I was diagnosed with a Gleason 9 prostate cancer which, on post-RP pathology, was stage pT3b! So I was one of the few who had high-risk prostate cancer while on finasteride.

    My gripe was that I was diagnosed a few years after my PSA started to double because it hadn’t reached the magic 4.0! But should my readings have been doubled to get my “real” PSA level? And if so wouldn’t I have caught my prostate cancer before it left my capsule?

    Bob

  3. Dear Bob:

    The fact that drugs like finasteride lower the PSA levels of patients who take them by about half has been well known for years. It is my entirely personal opinion that your PCP should have sent you to a urologist for evaluation once your PSA level reached somewhere between 1.5 and 2.0 ng/ml while you were on the finasteride. By the time your PSA had reached 5.4 ng/ml on the finasteride, your “real” PSA level was > 10 ng/ml.

    Can I guarantee that such an earlier referral would have caught your prostate cancer earlier while it was still confined to your prostate? No. Obviously no one can make that guarantee … but an earlier referral would certainly have increased the possibility of that outcome.

  4. Dear Peter:

    The cost of the conduct of trials like this would make it impossible to do such trials.

    Clinical trials are designed to meet very specific goals. Regulatory agents make determinations about whether the benefits associated with use of specific drugs based on those trials outweigh the risks associated with the use of those drugs, and they make those decisions day in and day out all around the world. Individual doctors and their patients then make decisions on whether they want to use those drugs. And in countries like the UK, other regulatory agencies like NICE make decisions about whether their health services are willing to cover the costs of those drugs, based on the costs as well as the risks and the benefits.

    There is sufficient data available for the FDA to make a renewed determination about whether using finasteride to lower the risk for a diagnosis of prostate cancer is approvable, and for others to assess the cost-benefit risk ratio as well. Whether an individual patient is willing to take the risks to get the available benefits can only be determined on a patient by patient basis. Some would probably say yes, and others might well decide that no it wasn’t. At present, however, the patients don’t even have the right to make that choice most of the time.

    There is sufficient data available for

  5. Dear Sitemaster:

    I agree with you. In fact I wrote to a lawyer specializing in medical malpractice. His response was that the case was too hard to prove particularly since even then (4 years ago) I was still alive. Maybe I should appeal after I’m dead.

    Bob

  6. Dear Bob:

    Sometimes things happen in life that one has to get beyond. I would agree with the lawyer that a case like this would be almost impossible to prove beyond a shadow of a doubt.

    Your anger is entirely understandable, but maybe it is time to just “let it go” and enjoy the fact that you are still alive.

  7. Dear Sitemaster

    In fact I got over it years ago. I’m grateful for the years I’ve had and hopeful about those ahead!🤗

    Bob

  8. Dear Sitemaster:

    I just remembered something. You said it was common knowledge that finasteride reduced PSA in half? Well only 6 months before my diagnosis, I applied for term life insurance. The insurance company sent out their “expert” to my home to do blood tests. My PSA was 2.7 (5.4?). I was approved for a $500,000 10-year policy.

    Bob

  9. Finasteride DID Lower Prostate Cancer Specific Mortality! (By a Lot!)

    Peter, responding to your post of June 13, 11:31 am, your statement that “there is no impact on total prostate-specific mortality” associated with finasteride in this study does not match what was reported! Data on this study, which has been heavily reflected in published papers, is available in, for instance, this paper.

    It shows there were 7,966 men in the finasteride arm; with the 42 prostate cancer-specific deaths here reported, the rate for prostate cancer specific mortality is 42/7966 = 0.53%. There were
    8,024 men in the placebo arm; with the 56 prostate cancer specific deaths, the rate is 56/8024 = 0.70% for the placebo arm.

    Just doing a rough cut at the risk ratio for the mortality percentages in the placebo and finasteride arms, 0.70% – 0.53% = 0.17, and (0.17/0.70) x 100 = 24%, virtually the percentage benefit estimated in earlier studies.

    There were 15,990 evaluable patients in this particular paper. I suspect statistical significance would be strong based on the large difference in these numbers and in the very large study population.

    As always, it is not surprising at all that no impact is seen on overall survival (“overall longevity”) because prostate cancer deaths are such a small proportion of deaths from all causes that very real effects are washed out statistically.

    I got 45 hits when I searched http://www.pubmed.gov for -finasteride AND prostate cancer AND thompson i [au], with filters for clinical trial and abstracts. A remarkable number of these papers are available for free online; I got 24 hits for this string when using the filter for free full text. Dr. Ian Thompson has been prominent in researching finasteride for many years. At least one quality of life study was published (in 2012), which was favorable to use of finasteride.

    (Since September 2000 I have been on either finasteride [for many years] or dutasteride [currently] continuously in support of therapy and now as a safety net, following what appears to have been a successful attempt at a cure [with TomoTherapy IMRT in 2013 supported by 18 months of ADT3 — my fourth round of ADT3] for my once life-threatening case. Finasteride or dutasteride were the third element in my ADT3 treatment.)

  10. The December 1, 2010 FDA Advisory Committee Hearing on the 5-ARI drugs Finasteride (Proscar®) and Dutasteride (Avodart®) for Prevention/Risk Reduction of Prostate Cancer
    — A Missed Opportunity that We Are Now Ready to Capture

    Sitemaster, thanks so much for publishing this important update to the finasteride saga! What happened eight and a half years ago is relevant to understanding this most welcome paper.

    As an enthusiastic patient advocate and consumer of the 5-ARI drugs for over 10 years at the time to counter prostate cancer (as part of my intermittent triple androgen deprivation therapy), I watched intently the FDA advisory committee hearing on December 1, 2010 on finasteride and dutasteride for prevention via simulcast from the Los Angeles area where my wife and I were taking a Thanksgiving vacation to see our son and his family. It was an awful time to schedule such an important hearing; I and I’m sure other advocates would have been there and spoken out if the hearing had been held on a decent date. The meeting materials, roster, transcript and minutes of the meeting as well as other pertinent documents are available online if you click here (scroll down to December 1).

    Despite that lousy date during the Thanksgiving holiday period, a number of doctors who understood the data on finasteride and its importance made the effort to show up. Unfortunately, they were effectively countered by less informed and more biased doctors. One of the latter was the great pioneering surgeon Dr. Patrick Walsh, as a witness (non-voting), and his Johns Hopkins colleague from the medical oncology community, Dr. Mario Eisenberger, MD (who had advised me to throw away my remaining pills from my first bottle of Proscar, which I fortunately did not do), was a voting member of the panel. However, being a superstar surgeon does not confer expertise in use of drugs against prostate cancer, and Dr. Walsh was, again unfortunately, given too much credibility in his long-standing opposition to finasteride or any hormonal therapy until patients show symptoms, a view I was then and am still convinced, as a now savvy survivor, is benighted. It was most unfortunate that Dr. Walsh was invited to testify. As he had been such a long-term opponent, advising his patients against use of finasteride (and likely dutasteride when it was approved later), he had strong motivation to denigrate the benefits of finasteride so that his prior well-publicized advice would not be exposed as dangerously misleading to his patients and followers.

    Several of the other noted participants whom I specifically remember were: Dr. Ian Thompson, MD, a prominent urologist and prostate cancer trialist, who was the speaker about the Prostate Cancer Prevention Trial; Dr. Christopher Logothetis, MD, a prominent medical oncologist and researcher, who spoke on the high-grade cancer aspect and for dutasteride; Dr. Peter Scardino, MD, a prominent urologist who spoke on chemoprevention of prostate cancer (see page 218 of the transcript for his summary that favored the 5-alpha-reductase inhibitor (5-ARI) drugs (i.e., finasteride and dutasteride); and Dr. Gerald Andriole, MD, who spoke on efficacy and safety.

    In the end, those who understood the benefits of finasteride were unable to convince the FDA that it (and dutasteride) should be approved for prevention/risk lowering, which would have also meant that no caution label was necessary; rather, finasteride simply improves detection of high-grade disease rather than causing it. (Essentially, by shrinking the prostate, finasteride makes a smaller target for the same number of biopsy probes that would be used in an unreduced prostate, which makes each probe more efficient in finding cancer, including high-grade cancer; hence, more high-grade cancer is detected. Also, by eliminating some lower-risk Gleason 6 and below cancer, finasteride causes a greater proportion of the total cancer that is detected to be high-grade.) The vote was 0 in favor and 17 against, with 1 abstention, for use of finasteride basically in a prevention/risk-lowering mode, with voting panelists expressing concern that there needed to be longer follow-up (check off that square favorably to the 5-ARI drugs now!) and that they had some concern about risk of high-grade disease, as well as concern that some men would use finasteride outside the proposed indication. The vote regarding dutasteride went down almost the same way. (See details in the Minutes.)

    The hearing was “spirited”, to put it mildly (e.g., p. 353 of the transcript, though that doesn’t completely capture the tone and volume of the exchanges). In fact, at one point the advisory committee chairman had to step in to calm down some of the opposing advocates, who were slinging sharp verbal barbs at each other and appeared to be not that far from throwing punches. The 396 page transcript captures some of that, but “seeing” via simulcast added to the overall impression. My recollection is that Dr. Thompson was a powerful and animated advocate, as were some of the others, even though he was on the losing side based on votes (as contrasted with true merit, IMHO). One way to core sample the transcript is to search for Thompson and follow his remarks. That can also be done for the other participants, of course, and the slides used are all available.

    I was greatly disappointed in the result of the hearing as well as what appeared to me to be bias against the 5-ARI drugs and ignorance coupled with difficulty some of the voting panelists had in connecting key dots to draw inferences. Admittedly, these hearings are a tough process, deluging the panel members with a ton of highly complex information, often outside their key areas of expertise, over the course of a single day, with voting taking place in the late afternoon. It’s a wearing endurance process.

    Again, this current paper reviewed by Sitemaster effectively favorably disposes a major concern of the voting panel members: follow-up that they considered too short. Also, to me and many others -– including prominent doctors and researchers, research on the 5-ARIs has effectively demonstrated that they make detection of high-grade disease more effective but do not cause it, which checks off the other major concern of the voting panel members.

    I would dearly like to see the FDA hold a new hearing on use of the 5-ARIs for prevention!

  11. Dear Bob:

    And exactly how many years ago was that? You still seem to be alive!

  12. Dear Sitemaster:

    I got the insurance coverage December 2012 and was diagnosed with prostate cancer in June 2013 and with stage pT3b in September 2013 after RP. So the term insurance ends December 2022. I had hormone therapy and salvage radiation therapy in 2014, hormone therapy and IMRT to all pelvic nodes in 2015 and hormone therapy and SBRT to a single femur met in 2017. So it’s a race to the finish line but I’m grateful for the relatively slow advance of my prostate cancer so far. I’m now waiting to see what happens with my PSA (which went from 0.16 to 0.32 in 2 months, meaning I’m probably castrate resistant, and am contemplating a PSMA PET scan vs an Axumin scan.

    Bob

  13. As a continuing prostate cancer patient ever since my initial diagnosis in November 1992, my journey into androgen deprivation therapy with recurrence in November 1996, and my recognition of the benefit of, in my case, dutasteride/Avodart somewhere around 2000, I have, like Jim Waldenfels, been a staunch supporter and user of this 5-AR inhibitor ever since. I have researched deeply the advantage of dutasteride over finasteride in ADT and this 5-AR inhibitor has served me well. I was extremely pleased, and honestly hoping, that Jim would provide his comments on this subject as he has. Jim and I have traveled this journey for many (thankful) years and have found we think much alike in what is appropriate in the prescribing of androgen deprivation medications that has proven to provide us our current longevity despite living with prostate cancer. My grateful thanks to Jim for his remarks/explanation here regarding 5-AR inhibitors.

  14. Is Hair Regrowth After Finasteride or Dutasteride An Indicator of Elevated DHT Presence Despite ADT?

    Chuck:

    As always it is good to see your posts, and thanks for your kind words! Of course you have been a great mentor to so many of us.

    I have been curious about the subject question for some time, and I’m wondering if you can shed some light on it. I’ll give a little background first.

    Apparently some of us on ADT will achieve excellent suppression of dihydrotestosterone (DHT), which is mainly made from testosterone. Of course this is important as DHT is a far more potent fuel for prostate cancer than testosterone, so its suppression is important, and DHT suppression is the main effect we get from the 5-ARI drugs as they prevent conversion of testosterone to DHT.

    However, it is known that some of us will still have excessive levels of DHT despite effectively suppressing testosterone with an LHRH agonist, like Lupron, Zoladex, etc., or surgical castration, and excessive DHT, of course, can wreck an ADT program. I’m wondering if hair regrowth after starting a 5-ARI drug while having been on ADT1 or ADT2 for some time is a sign that DHT has not been adequately suppressed. Do you have any thoughts on that?

    Here is my story about Proscar (finasteride), hair regrowth, and prostate cancer. I had been on ADT1 or ADT2 for a little over 9 months by the time I took my first Proscar tablet on 9/17/2000. (I started Lupron on 12/20/1999 and added Casodex on 3/3/2000.) My first testosterone (result, 22.1 ng/dl on 6/10/2000) and DHT (result, 3.6 ng/dl on 6/24/2000) results showed that I was getting good androgen suppression around the 6-month point on combined blockade with Lupron and Casodex, and my PSA had fallen from 113.6 ng/ml on 12/4/1999 to 1.9 ng/ml on 6/24/2000. It would continue to fall to 0.7, just before starting Proscar, but by a lower percentage than previously, and then to 0.6 on 10/19/2000, falling by an even lower, discouraging percentage and appearing to be leveling off despite being on Proscar for a month as well as the other drugs.

    I was initially disappointed in Proscar, but my hopes were soon rewarded as my next PSA on 11/25/2000 showed a 50% drop to 0.3, and that decline continued, with me now on ADT3, all the way down to < 0.01 (though it took a while, hitting that level for the first time by 5/3/2002, down from my previous PSA of 0.02 on 1/9/2002).

    Here’s the thing. I had been almost completely bald in my mid to front scalp area for years. Looking back at the log I kept related to prostate cancer, I’m reading that on 10/8/2000, 3 weeks after starting Proscar, I began to regrow hair in that bald area. It was funny how I noticed it, which I remember well. I was shaving in the morning after getting up from bed, and I noticed that the light on my head from the light fixture seemed different somehow. It’s not something we think about, of course, but it just struck me as odd, and I paused to check what was causing it. At that point I noticed a crop of very short new hairs growing all over. Then I remembered that Proscar was prescribed at a much lower dose (under the brand name Propecia) for hair regrowth (by suppressing DHT), and I was getting a side-benefit of Proscar. Since then I have had a somewhat thin but decent amount of hair in that formerly bald area.

    What I’m thinking is that the regrowth was a sign that I could still benefit cancer-wise from further suppression of DHT; it’s clear that the decline in DHT due to Lupron® and Casodex® — by reducing the supply of testosterone, had been insufficient to trigger hair regrowth. Restoration of the steady decline in my apparently leveling-off PSA values leads me to think that that was the case for me. I’m thinking that those of us who need just one or two drugs (or castration) to achieve the appropriate DHT suppression would not experience such hair regrowth. They might also tend to be less bald in the first place. I’m also wondering if anything is known about the percentage of men who need a 5-ARI drug versus those who will not get a benefit against prostate cancer. I don’t recall any good data on that. To me, it makes sense to err on the safe side by adding a 5-ARI drug to combined blockade.

    Your thoughts?

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