CRPC & Avodart [Dutasteride].

[pjoshea13]

New study below.

Some may recall that I'm in favor of shutting off all escape paths while on ADT - e.g. via Zytiga, Casodex, Simvastatin & Avodart. If you are closing the door, close the windows too.

The conventional view is that since 5alpha-reductase converts testosterone [T] to dihtdrotestosterone [DHT], castrate T = castrate DHT.

I had read a paper on PCa cells finding an alternate DHT path that did not involve T. So I was very interested when Dr. Myers posted on the subject. But, as I recall, the focus of the post seitched to natural over-producers of DHT. Myers himself is one, and a small minority of his patients fail to achieve castrate DHT when placed on ADT.

Myers thought it irresponsible for doctors not to test DHT levels. He said that T was not the problem - DHT was the hormone we needed to control.

Myers' target for DHT was <=5 pg/mL. He prescribed Avodart, if necessary - quite often, only low doses (e.g. 1 cap/week) were needed.

IMO, the post didn't adequately address the issue of PCa cells escaping ADT by manufacturing DHT via an alternate path. Unless there was leakage from the cells, what value would a DHT blood test have? And such a test would have to be repeated periodically to detect ADT resistance involving DHT.

The new study is an eye-opener.

"Between 2010 and 2013, CRPC was diagnosed in 41 patients at the Tokyo Metropolitan Tama Medical Center. Following diagnosis, the patients received 0.5 mg dutasteride daily. The patients' median age was 77.3 years (range, 63-90). Bone metastases were recognized in 12 patients. All the patients received dexamethasone."

"Twenty-four (59%) patients had previously undergone chemotherapy, while 11 (27%) received docetaxel, and 24 (59%) estramustine."

"The prostatic-specific antigen (PSA) level declined in 17 (41%) patients from the baseline value, following dutasteride treatment. The median value for the PSA decrease was 23% (range, 4.3-89.8%), and the median duration of the response was 4 months (range, 1-10)."

"The PSA response rate (defined as >50% decline in PSA from the baseline value) was recognized in 7 (17%) patients. The median duration of the response was 3 months (range, 2-10)."

"Dutasteride was efficacious against CRPC in certain patients and may be a promising option in CRPC treatment."

The extent of the PSA declines (which the authors attribute to dutasteride), suggests that the DHT escape route is not uncommon.

The FDA has approved Dutasteride for BPH - not for PCa - so it is somewhat amusing to see it used for CRPC in this instance.

If Avodart were to be prescribed at an earlier stage, perhaps CRPC might be significantly delayed in those men who were destined for the DHT escape path?

So, what's next for these researchers? Perhaps Simvastatin for CRPC cases that have failed Avodart? Just kidding.

-Patrick

ncbi.nlm.nih.gov/pubmed/293...

Mol Clin Oncol. 2018 Jan;8(1):133-136. doi: 10.3892/mco.2017.1480. Epub 2017 Nov 2.

Effect of dutasteride on castration-resistant prostate cancer.

Azuma T1, Matayoshi Y1, Sato Y1, Nagase Y1.

Author information

1

Department of Urology, Tokyo Metropolitan Tama Medical Center, Fuchu, Tokyo 183-0042, Japan.

Abstract

It has previously been demonstrated that the intratumoral generation of the potent androgen dihydrotestosterone (DHT), contributes critically to the progression of prostate cancer and its castration-resistant form, castration-resistant prostate cancer (CRPC). Circulating testosterone is converted into DHT by 5α-reductase (SRD5A). Dutasteride is a dual inhibitor of type I and II SRD5A. The present study assessed the effectiveness of dutasteride in the treatment of CRPC. Between 2010 and 2013, CRPC was diagnosed in 41 patients at the Tokyo Metropolitan Tama Medical Center. Following diagnosis, the patients received 0.5 mg dutasteride daily. The patients' median age was 77.3 years (range, 63-90). Bone metastases were recognized in 12 patients. All the patients received dexamethasone. Twenty-four (59%) patients had previously undergone chemotherapy, while 11 (27%) received docetaxel, and 24 (59%) estramustine. The prostatic-specific antigen (PSA) level declined in 17 (41%) patients from the baseline value, following dutasteride treatment. The median value for the PSA decrease was 23% (range, 4.3-89.8%), and the median duration of the response was 4 months (range, 1-10). The PSA response rate (defined as >50% decline in PSA from the baseline value) was recognized in 7 (17%) patients. The median duration of the response was 3 months (range, 2-10). Dutasteride was efficacious against CRPC in certain patients and may be a promising option in CRPC treatment. A prospective randomized trial is necessary to verify the efficacy of dutasteride.

KEYWORDS:

castration-resistant prostate cancer; dutasteride; prostate cancer

PMID: 29387405 PMCID: PMC5769310 DOI: 10.3892/mco.2017.1480

[Hazard]

I asked my MO about avodart when I became castrate resistant (Zolodex and Casodex double blockade). His response was "So you are a fan of Snuffy Myers are you". He also stated that DHT is for BPH and declined to prescribe it for me. I am seeing him again in a few weeks, I need to show him this study.

My T level is 12 (low) and I had to ask my GP to get a DHT test - its around 6 - this is close to the recommended limit, but if PCa cells make their own DHT, does it show up in blood serum tests?

[pjoshea13 in reply to Hazard]

Hazard,

I just don't believe that a process that happens in the privacy of a PCa cell, leaks enough DHT to be meaningful.

The expert response might be: "What about PSA?" However, prostatic cells create an enzyme in response to DHT, & this enzyme metabolizes DHT. DHT gets a window in which to act, & then any excess DHT is changed to something else.

True, PCa cells produce less of the enzyme.

Anyway, I'm not taking a chance - I'll stay with Avodart.

In the STERPROSER trial [1]:

"evidence for higher DHT concentration {than plasma} in high volume prostates, that could reflect either higher 5-alpha reductase expression or lower expression of downstream metabolizing enzymes such as 3a-hydoxysteroid dehydrogenase."

Also from 2017 [2]:

"Benefits associated with lowered serum DHT levels after 5α-reductase inhibitor (5AR-I) therapy in men have contributed to a misconception that circulating DHT levels are an important stimulus for androgenic action in target tissues (e.g., prostate). Yet evidence from clinical studies indicates that intracellular concentrations of androgens (particularly in androgen-sensitive tissues) are essentially independent of circulating levels."

-Patrick

[1] ncbi.nlm.nih.gov/pubmed/289...

[2] ncbi.nlm.nih.gov/pubmed/284...

[Dan59]

Avodart is the one constant I have taken every since day 90 after dx, when I first got myers book. It may have something to do with my extended survival. There is a study out at New England Journal of Medicine with Avodart /dutaseride increasing time to progression with ketoconazole. Called KHAD. Taplin et.al it was significant. I wonder being they are similar drugs the same could be assumed combining it with Zytiga?

[BigRich]

Yet evidence from clinical studies indicates that intracellular concentrations of androgens (particularly in androgen-sensitive tissues) are essentially independent of circulating levels." Then what good is the DHT blood test?

Rich

[dave2]

Patrick,

Thanks for the new study and your comments about dutasteride/CRPC.

Note that Myers's serum DHT target for men on dutasteride was <5 ng/dl, not 5 pg/ml. [5 ng/dl = 50 pg/ml]

This can get confusing--a few years ago I discovered that different labs were using units to report my DHT results.

[pjoshea13 in reply to dave2]

Dave,

I couldn't immediately locate the Myers vlog post, so dug out a standard reference range for the units. Hoisted by my own petard. Some finesse the problem by just giving a number & no units. Evidently, that could be quite misleading - but at least not wrong.

Sample normal ranges:

Quest: 16-79 ng/dL

Mayo: 112-955 pg/mL

Thanks for pointing out the error.

-Patrick

[EdBar]

Like Dan59 I have taken Avodart daily around 90 days after reading Snuffys book and later after becoming a patient of his. I remain hormone sensitive as of this date, almost 4 years after DX, PSA remains undetectable, scans are clear (I had multiple mets throughout skeleton and several nodes at time of DX). I plan on continuing to take it and Dr. Sartor, Snuffy's replacement concurs. If it works don't fix it.

Ed

[jwick527 in reply to EdBar]

EdBar, is the Dr, Sartor in New Orleans?

[EdBar in reply to jwick527]

Yes but I don’t think he’s taking new patients but it doesn’t hurt to ask.

[Dan59]

Here is that study I spoke of which showed increased time to progression when keto was used with dutasteride from Harvard medical NEJM. Some pretty famous prostate cancer researchers authored this paper.

clincancerres.aacrjournals....

[pjoshea13 in reply to Dan59]

Dan,

Already over 10 years old ("From June 2005 to April 2007, 57 patients were consented

and started on therapy.") Today, the "inhibitor of CYP17A1 (ketoconazole)" would be Zytiga. Certainly established proof of concept.

-Patrick

[Dan59 in reply to pjoshea13]

Patrick, I agree proof of concept is in this study to use zytiga with Avodart as both are 3YP17A1 inhibitors. Except for the current study you posted it is the only other study I know of with avo/dutasteride and APC.

I have been on Avodart/Dutasteride since first months almost 12 years ago, I am currently approaching 5 times the survival data you gave earlier for my disease, and I believe avodart May very well be factor in that.Besides that I have had no urinary issues and my hair stayed nice and thick ,and zero side effects to avo/dut.

Thank You for all you do for us!

Dan

[homer13]

I am on AS since August 2016 and fortunate to have been at Snuffy's office twice during that time. Avodart (daily) and Metformin (2000mg twice a day )are both part of my protocol. I will go with the expert's expert until proven otherwise.

[jwick527]

I was a patient of Snuffy's and sad to see him retire. All the oncologists I have seen since are clueless. Can you tell me exactly what your protocol consists of?

Thanks

[homer13 in reply to jwick527]

Who did you end up with after Snuffy?