The Finasteride PCa prevention trial [PCPT] - Last Word?

[pjoshea13]

The Prostate Cancer Prevention Trial [PCPT] was launched in 1993. Results were published in 2003 [1]:

"CONCLUSIONS

"Finasteride prevents or delays the appearance of prostate cancer, but this possible benefit and a reduced risk of urinary problems must be weighed against sexual side effects and the increased risk of high-grade prostate cancer."

The following is from the current NEJM [2]:

"TO THE EDITOR:

"One man in nine will receive a diagnosis of prostate cancer during his lifetime. We previously reported the results of the Prostate Cancer Prevention Trial, in which 18,882 men were randomly assigned to receive finasteride or placebo for 7 years. The study’s primary end point — the prevalence of prostate cancer during the 7 years of the trial — was met: the relative risk of prostate cancer with finasteride was 24.8% lower than the risk with placebo. Paradoxically, the risk of high-grade cancer (Gleason score of 7 to 10) was higher with finasteride, a finding that led to recommendations against the use of finasteride for the prevention of prostate cancer. Subsequent trials showed that finasteride improved detection of prostate cancer and high-grade prostate cancer by improving the performance characteristics of the prostate-specific antigen (PSA) test, digital rectal examination, and the prostate biopsy. These biases could explain the paradox, but the questions of whether the greater number of high-grade prostate cancers could have led to diminished survival or to an increase in prostate cancer mortality persisted. In 2013, we addressed the first of these questions, finding similar survival rates in the two treatment groups of the Prostate Cancer Prevention Trial.

"To address the second question, participants with a potentially valid Social Security number, whether last known to be alive or previously deceased, were submitted to the National Death Index in December 2014. Deaths from prostate cancer were reviewed by an end-point review committee. The cumulative incidence of death from prostate cancer was calculated, including all participants who underwent randomization, with deaths due to a cause other than prostate cancer classified as a competing risk. (For details, see the Supplementary Appendix, available with the full text of this letter at NEJM.org.)

"Figure 1." (not shown here)

"Cumulative Incidence of Prostate Cancer According to Treatment Group.

"Figure 1 shows the results. With 296,842 person-years of follow-up and a median follow-up of 18.4 years, of 9423 men randomized to finasteride, there were 3048 deaths of which 42 were due to prostate cancer; of 9457 randomized to placebo, there were 2979 deaths, 56 due to prostate cancer. With the small number of deaths due to prostate cancer, the 25% lower risk of death from prostate cancer with finasteride was not statistically significant.

"PSA-detected prostate cancer will likely increase with recommendations to offer screening to men 55 to 65 years of age. Screening may reduce the risk of death from prostate cancer but often leads to the detection of prostate cancer that will remain asymptomatic during a man’s life. If indolent cancers are treated with surgery or radiation, complications, including impotence and incontinence, are common. If managed with active surveillance, up to 45% of men will ultimately receive treatment; they will also face frequent examination, repeated invasive biopsies, and anxiety. Finasteride is a generic agent that is used to treat lower urinary tract symptoms, prevents complications from these symptoms, and prevents prostate cancer. The early concerns regarding an association between finasteride and an increased risk of high-grade prostate cancer have not been borne out."

Phyllis J. Goodman, M.S.

Catherine M. Tangen, Dr.P.H.

Fred Hutchinson Cancer Research Center, Seattle, WA

Amy K. Darke, M.S.

M. Scott Lucia, M.D.

Leslie G. Ford, M.D.

Lori M. Minasian, M.D.

Howard L. Parnes, M.D.

Michael L. LeBlanc, Ph.D.

Ian M. Thompson, Jr., M.D.

CHRISTUS Santa Rosa Hospital Medical Center, San Antonio, TX

[e-mail]"

-Patrick

[1] nejm.org/doi/10.1056/NEJMoa...

[2] nejm.org/doi/full/10.1056/N...

[cesanon]

Thanks. Nice article.

[Garp41]

selfhacked.com/blog/hidden-...

Why use a drug when there are so many natural alternatives?

[curious-mind1]

Thanks for the summary. So, is it accurate to conclude, that Finasteride use reduces the likelihood of PCa, and does not cause/contribute to aggressive PCa among its users? If this is true, who should start taking Finasteride: men who've been diagnosed with elevated PSA, but not PCa?

In other words, if my dad and grandfather both have/had PCa that is clinically significant, should I ask my doctor whether I should consider taking Finasteride preventatively in the future? My own PSA have so far averaged 0.7 (I'm in my early forties).

Thanks again,

Arthur

[snoraste in reply to curious-mind1]

My MO at MSK started me on Finasteride a few months ago after, following Patrick's suggestion, I brought up the idea of DHT bloc. He had no issues with that, and mentioned there's a clinical trial in DanaFarber investigating avodart/finasteride (i did not look it up).

[pjoshea13 in reply to snoraste]

This is from the study [1].

"Dutasteride is a type I and II 5-α reductase inhibitor which prevents the conversion of testosterone to DHT, a more potent androgen that has the highest binding affinity for the AR. Studies have demonstrated that type I 5-α reductase expression is increased in both primary prostate cancer (PCa) and CRPC (10). Though the role of 5-α reductase inhibition in the prevention and treatment of PCa has been controversial, combination CYP17A1 and 5-α reductase blockade is hypothesized to result in more complete blockade of androgen biosynthetic pathways (11,12). More complete androgen synthesis blockade through this multipronged approach could provide greater clinical benefit than solitary pathway inhibition. Preclinical studies have demonstrated that the combination of abiraterone and dutasteride decreased intratumoral testosterone and DHT (13). Additionally, we previously conducted a phase II trial of ketoconazole, a less potent CYP17A1 inhibitor, with dutasteride and hydrocortisone in patients with CRPC (14). We demonstrated that 56% of patients had a ≥50% decline in prostate specific antigen (PSA), which compared favorably to published response rates of ketoconazole alone. Additionally, the median duration of response was a favorable 20 months, supporting ongoing investigation of CYP17A1 and 5-α reductase combination therapy.

"Based on these observations, we evaluated the effect of more complete androgen synthesis blockade through potent CYP171A inhibition with abiraterone combined with inhibition of type I and II 5-α reductase with dutasteride in patients with metastatic CRPC. We chose to use high dose dutasteride (3.5 versus 0.5 mg) to further reduce tissue DHT levels."

-Patrick

[1] ncbi.nlm.nih.gov/pmc/articl...

[homer13 in reply to curious-mind1]

You might want to check why Snuffy Myers preferred Dutasteride over Finasteride

[pjoshea13 in reply to homer13]

"Finasteride (brand names Proscar, Propecia) inhibits the function of two of the isoenzymes (types 2 and 3) of 5α-reductase. It decreases circulating DHT levels by up to about 70%.

"Dutasteride (brand name Avodart) inhibits all three 5α-reductase isoenzymes and can decrease DHT levels by 95%. It can also reduce DHT levels in the prostate by 97 to 99% in men with prostate cancer"

en.wikipedia.org/wiki/5α-Re...

-Patrick

[curious-mind1 in reply to homer13]

Indeed, my dad was a patient of Myers' and he prescribed Avodart over Proscar.

[pjoshea13 in reply to curious-mind1]

In, both, the Finasteride PCa prevention trial [PCPT] & the Reduction by Dutasteride of Prostate Cancer Events clinical trial [REDUCE], the number of lesser grade cancers was greatly reduced, but the number of higher grade cancers was slightly increased. This turns out to have been due to detection bias. (Prostates were smaller at the time of the repeat biopsy.)

But the results killed the products in terms of PCa prevention. If there were really more high-grade cases, there would ultimately have been more deaths - & that hasn't happened during the long follow-ups. So most will agree that the products are safe & will reduce the risk of cancer.

Note that in the U.S., PCa has been over-detected (& over-treated). The products could greatly reduce the number of cases that don't need to be treated, IMO. It's not clear to me what the risk reductions are for each of the different Gleason scores that need to be treated. I haven't seen any estimates.

Who should used the products & when should they start?

Those deemed to be at increased risk for PCa should consider doing so & begin well before the age when screening would normally start. PSA itself doesn't come into that decision.

Who else? From my initial post, above:

"the relative risk of prostate cancer with finasteride was 24.8% lower than the risk with placebo"

If it wasn't for the appearance that the drugs seemed to promote high-grade cancer, 5ARIs might have become more popular than statins.

"1 in 9 American men will get prostate cancer in their lifetime." [1]

(with a quarter fewer cases, that becomes 1 in 12 men.)

I think that many men would consider 1 in 9 to be a very significant risk & would ask for a 5ARI.

You wrote:

"... if my dad and grandfather both have/had PCa that is clinically significant, should I ask my doctor whether I should consider taking Finasteride preventatively in the future? My own PSA have so far averaged 0.7 (I'm in my early forties)."

As I say, the PSA is irrelevant, IMO, when there is familial risk. & early forties is not too young to start, IMO.

However, the U.S. Preventive Services Task Force has created an anti-screening (anti-treatment) atmosphere & that might affect what your doctor says.

-Patrick

[1] prostateconditions.org/abou...

[curious-mind1 in reply to pjoshea13]

Thanks Patrick,

I'm gonna bring this up at my next physical exam meeting with the doc.

Arthur

[larry_dammit]

I took it for 5 years or so, it masked the cancer and dropped the PSA to a artificial low number. Hide my cancer until it was stage 4. 😡😡😡🙏

[pjoshea13 in reply to larry_dammit]

I wasn't using it before diagnosis since I had no BPH. My PSA was only 0.8. I would never have been diagnosed before it was too late. "Fortunately", I had a nodule, found by DRE.

I think there may be a significant number of men whose cancers produce low levels of PSA. If they don't have BPH, with its additional PSA, they may fall through the screening cracks.

-Patrick

[curious-mind1]

I wonder if it makes sense for men (like me) who have family history of significant PCa, to start taking these drugs preventatively, the way low-dose aspirin is used for people at risk for heart disease?

[larry_dammit]

Beware of the Avadart, the false low PSA will give your urologist a false since of security .

[Coastguy]

I am 76 years old and have been taking 1.25 mg of Finasteride daily for over 18 years as a replacement for Propecia ( to prevent hair loss) . In fall of 2007 PSA was 2.8 but DRE resulted in a biopsy -5 positive - all Gleason 6 but 2 upgraded to Gleason 7 with 2nd opinion at Mayo. Proton beam at Loma Linda early 2008. PSA fell to .01 until spring of 2014 when it began to rise. Was 2.7 in November 2016. Bone Scan and MRI of Prostate negative. Gallium PSA 68 Scan at UCSF in September 2016 - PSA 11.2 showed a hot spot in left seminal vesicle. 30 core biopsy in November was negative. PSA has continued to increase- currently 36.2. Two Axumin scans in 2018 were negative. Scheduled for 18F-DCFPYL PET/CT at NIH in March. My Overall health is excellent- walk an average of 45 miles a week and played 204 rounds of golf in 2018.

[ezhoe]

What about after the fact? I quit taking Finasteride when I got the 6 mo eligard shot 8/28/18. now after RT (done 12/27/18) I'm wondering if there would be any benefit (or harm) to resume the "F" ??

[pjoshea13 in reply to ezhoe]

Ed,

I covered this yesterday in my preamble to:

"Dutasteride [Avodart] & Abiraterone [Zytiga]?"

-Patrick

[curious-mind1 in reply to ezhoe]

It depends on what your oncologist believes. But, from my dad's experience, his doctors have recommended he take Avodart along with the rest of his drugs, precisely because of the reasons discussed in the trials above.

Arthur

[ezhoe in reply to curious-mind1]

Every text I can find always references "F" in a pre PC role.. or post surgery re-occurrence.. very little reference or studies concerning post RT.. I have the prescription sitting here (was given by URO) just wondering if resuming it could be harmful.. also I'm in the VA system so getting info is a slow process. Ed