Even low dose finasteride may prevent PC

Some good news based on a nested case-control analysis within the Prostate Cancer Prevention Trial. Finasteride reduces the risk of prostate cancer by 25%, but it doesn't seem to matter how much one takes. This will come as good news to those concerned about possible sexual side effects, that affect about 20% of men taking it. Lower doses may avert those sexual side effects while still preventing the cancer. It may also be useful for men on active surveillance, although that is yet to be definitively determined.

The researchers also found some genes that affect serum levels of the drug.

Here's the study:
Finasteride Concentrations and Prostate Cancer Risk: Results from the Prostate Cancer Prevention Trial

-Allen

Allen, off line you had advised that neither Avodart nor Proscar have been proven effective for guys on ADT who in theory had been cured with radiation.

Does that opinion still hold given this finasteride finding?

prostatecancerinfolink.net/2015/02/17/iadt-dutasteride-and-the-avias-trial-not-the-result-some-would-want-to-hear/

Probably apples and oranges but thought I would check with you.

Post Edited (LupronJim) : 5/9/2015 7:43:55 PM (GMT-6)

I guess as a G9, I think I am not cured, just temporarily in remission, hopefully a long temporary but temporary nonetheless.

I have hit it hard giving the PCa a lot to deal with at once, and just want to keep pounding it into submission, but not with useless volleys.

Our posts crossed and I edited the prior one to add the link you had provided.

Post Edited (LupronJim) : 5/10/2015 1:25:15 PM (GMT-6)

Jerry L - Yup. LupronJim provided a link to an article about it.

It's a well-done randomized controlled trial, and the certainly the best info we have. What flaws do you see in the design? Klotz is no slouch when it comes to research. In fact, the study I posted in this thread may provide clues - serum levels of finasteride, and therefore DHT, are affected by genetic differences.

As in the BAT study, Klotz alerts us to a possible benefit to letting androgens recover during during the "off cycle."

- Allen

Re-read what I just wrote in my previous post. It addresses that. It turns out that inhibiting 5-alpha-reductase is more complex than first appears.

Allen,

Very good news from that trial about finasteride (assume 5mg) possibly preventing PCa. I took 0.5mg for 7 years to prevent hair loss but was diagnosed with PCa....very low dose, unhealthy diet, low D3, beer, and high DHT probably caused PCa....still have my hair.

MY MO believes I am in remission after IMRT - completed 8/8/13. This month PSA was 0.23 up from 0.20 in Feb. But, DHT was 363 up from 29 in Dec. 2014. "T" is also up to 561. I have asked about Avodart or Proscar to significantly reduce DHT. Isn't this one way to help maintain the remission, as Dr. Myers says? I have also been taking Metformin for a year now.

Robert

I continue to take Avodart for maintenance. My uro was a principal investigator in the three major trials that indicated that Avodart and Proscar could mitigate prostate cancer. Myers and others like to use the drugs as maintenance as the DHT is about 10 times the strength of serum testosterone as a PCa food.

Though DHT is derived from testosterone, just because testosterone reduces to castrate levels doesn't mean that DHT drops by the same amount. Studies from Japan indicate that a drop to castrate level testosterone may only drop DHT by one-half which leaves a significant amount of DHT as fuel. That is why many PCa medical oncologists include Avodart/Proscar in the CAB (Complete Androgen Blockade) regimen which we also refer to as ADT3.

JNF, I think that all changed when the results of the Phase 2 AVIAS trial were released in February. It provides the first randomized clinical trial evidence there is no benefit to taking dutasteride during intermittent ADT. I expect that many MOs are changing their protocols based on it - if they are going to stick with their old ways even in light of better data, why bother doing the studies?

In the AVIAS trial, the men were on CAB (a GnRH agonist and bicalutamide) and were hormone responsive, defined as PSA below 1 ng/ml. They randomly got dutasteride or placebo, and continued on it during the off-cycle. Both groups reached the same PSA nadir while on ADT, whether they took dutasteride or not. What happened then may surprise you: "Patients treated with dutasteride had a more rapid recovery of PSA and testosterone in the off-treatment interval compared to placebo (p < 0.0001)."

I think we have to take seriously Klotz's ending cautionary note:

Klotz said...
The PSA kinetics might be accelerated by the presence of 5ARI-resistant prostate cancer cells. It is also possible that 5ARIs exert a deleterious effect on prostate cancer in this situation, promoting more rapid recovery of PSA than expected.

5ARis may exert a selective pressure favoring DHT-independent cancer cells in the advanced/recurrent cancer setting. It is not the first time that a medicine that may be beneficial in one setting may be harmful in another. There is evidence, for example, that testosterone helps keep healthy prostate cells healthy in the pre-cancerous setting, while blocking testosterone kills prostate cancer cells in the advanced cancer setting. 5ARis are the best, indeed the only, prevention for PC. It may even shrink some low grade cancers that are already there - a potential benefit for those on active surveillance. But once the cancer has progressed to high grade, I think one should be cautious about taking it in light of AVIAS.

- Allen

I agree with him that Klotz's study was, by design, underpowered to detect a small advantage. It was a Phase 2 study, so they were only looking for a hint of efficacy. Had they found it, a much larger Phase 3 study was already planned. So if there is an advantage to taking Avodart, and a statistical fluke just happened to skew the results, it is not very likely to be a clinically significant advantage. And when you couple that with the inference that the 5ARi may be causing earlier DHT resistance, I can't see what benefit he sees that makes it worth the risk.

However, I know that Dr. Myers advocates "cocktails," and there may be some benefit if it were given as part of a cocktail with chemo, immunotherapy and growth factor inhibitors. The idea being to attack the cancer system on multiple fronts to prevent it from evolving into resistant strains.

The upside of "out-of-the-box" experimenting is that once in a while he'll find a great solution. The downside of it is that most of the time he won't. I admire his approach and I'm glad he's out there, but I hope he takes data like this study, not as criticism to which he only gets defensive, but as an opportunity to meet the challenge with a different approach.

- Allen

Too bad Tony isn't here to explain this, but I'll give it a try with a hypothetical.

Let's say Dr. J. Tull is a pulmonologist who specializes in severe lung cancer, and he thinks he has a cure - breathing in curcumin vapor. He's practiced for 20 years and the average survival of his patients was 9 months. They typically came to him after all other options were exhausted. After giving his curcumin vapor therapy for a while, he starts to notice that patients are living longer, say 12 months. Word gets out. He gets tons of new patients who want the Tull Therapy. He notices that life expectancy goes up to 20 months. Tull is enthusiastic, and he wants to get FDA approval. But they refuse. Why?

Here's why. His earlier patients had a higher proportion of smokers, and the air was more polluted, so lung cancer cases were more progressed back then. As his reputation got out, he attracted patients who just got their diagnosis, and so their disease was less progressed. Therefore, there was a longer lead time for them to survive under his care.

The FDA doesn't turn him down completely though. They tell him to randomly assign all his new patients to either curcumin vapor or water vapor. After 40 patients in each group are treated, he sees no statistical difference in survival - it was 21 months±10 months for curcumin and 20 months±11 months for water. Should he continue to collect more patients? Well, with 40 patients in each group of his study, he had a 80% chance (or power) of detecting a treatment effect if it were 33% or more. So if the survival was really increasing by 7 months or more, he he would have known it even with 40 in each group. Dr. Tull figures that he'd be happy to detect an effect size of even 3 extra months from the treatment. He calculates that this would mean over 200 patients randomized to each group.

I hope this explains why Dr. Myers can't know there is an effect without conducting a randomized clinical trial. In Dr. Klotz's trial, he was only looking for some extra time off cycle - not increased survival. He also found a possible safety concern, because PSA increased faster when they took dutasteride. That's why Dr. Klotz (unlike Dr. Tull) decided not to go forward with a Phase 3 study - the effect, if any, was too small, and there were safety concerns.

- Allen

Allen,

I like the hypothetical. I'm still thinking about it. I do hope in the study they dyed the water vapor yellow so it looked like curcumin.

Jerry

Allen,

I get it.  And thanks for the Tull Therapy write up. 

Let me just say that the way the AVIAS trial set up their IHT is not exactly how Myers does it.  With Myers, I believe you must have been on ADT3 longer than 9 months and PSA should be undetectable going into the "time off" period.  PSA, Testosterone, and DHT is checked monthly and DHT must be < 5 while on and off HT.

You said, "Patients treated with dutasteride had a more rapid recovery of PSA and testosterone in the off-treatment interval compared to placebo (p < 0.0001)."

What were the stats comparing rapid recovery of PSA?

JL