Preventing Drug Resistance - Thinking Outside The Box - PRINT Phase 2 Study

[jazj]

One of the biggest challenges of PCa treatment is eventual drug resistance. I've been thinking that maybe Oncologists may have their thinking locked in a box. This is understandable as most take a conservative approach probably, recommending what is "tried and true." So to speak. So I was thinking, what about a more novel approach that thinks outside of the historical clinicial results box intended to "keep the cancer guessing." Has anyone stepped outside the SOC and done things like rapid drug cycling and/or short duration intermittent ADT (<= 8 months on/off?)

This review out of Italy published March 2022 has some very interesting thinking described near the end. It is titled "Apalutamide, Darolutamide and Enzalutamide for Nonmetastatic Castration-Resistant Prostate Cancer (nmCRPC): A Critical Review"

ncbi.nlm.nih.gov/pmc/articl...

In section 2.7 titled "Not All That Glitters Is Gold" they state:

"Despite the exciting results of the SPARTAN, PROSPER and ARAMIS trials, the use of novel antiandrogens in nonmetastatic PCa might represent a double-edged sword.... However, several concerns arise due to the potential earlier occurrence of treatment resistance that can affect the availability of therapeutic options after progression to an AR-directed therapy in the metastatic CRPC scenario....

.... Histological dedifferentiation and lineage alterations, such as treatment-induced neuroendocrine prostate cancer (t-NEPC) and treatment-induced epithelial-to-mesenchymal transition (t-EMT), can result in rapid disease progression and resistance to both hormone agents and chemotherapy....

.... Strategies to prevent the treatment-induced lineage crisis might include rapid drug cycling with collateral sensitivity, innovative drug combinations, intermittent therapy and bipolar androgen therapy [57,77,78]. The phase 2 PRINT clinical trial is ongoing to assess the feasibility for cycling therapies to prevent resistance in patients with mCRPC [79,80]. This study might provide valuable data to test this approach also in the setting of nmCRPC."

So the PRINT trial could potentially represent a new paradigm in application of drug therapies. There's no official results but it says the study ended in Dec 2021 and here's the interview discussing the results. 20% doesn't seem like a very impressive number to me. Major breakthroughs are infrequent though. Baby steps are more common.

onclive.com/view/dr-oh-on-d...

[mrscruffy]

I am using an "out of the box" treatment that my Oncologist approves of, and of now it is working

[nyc_son in reply to mrscruffy]

What is the treatment?-

[mrscruffy in reply to nyc_son]

It's not so much of a treatment as taking a compound. It is called Ostarine, it suppresses Testosterone and helps build muscle. Been using for a few months. Stopped my PSA from rising, kind of a booster for my Zytiga that is beginning to fail.

[tango65 in reply to mrscruffy]

What is the dose you are taking?

[mrscruffy in reply to tango65]

I did 4 week cycle at 10mg, then 20mg for 6weeks. Began to feel fatigue so this time I am using 15mg at 6 week.

[tango65 in reply to mrscruffy]

Thanks. What brand do you use?

[mrscruffy in reply to tango65]

I have had great luck with SARMS Global

[tango65 in reply to mrscruffy]

Thanks.!!

[jazj in reply to mrscruffy]

Out of everything I've read about so far in this forum, Modified Citrus Pectin and Ostarine are the most intriguing. It appears that there is conflicting evidence on how it affects testosterone levels. This article says it increases it:

connect.aacp.org/blogs/step...

Yet this one says it decreases it at high doses over an extended period of time.

uspharmacist.com/article/re....

Have you been having your T checked while taking this?

I would be really interested to hear what pjoshea13 Patrick's take on this is.

[mrscruffy in reply to jazj]

Ostarine was designed to stop T and originally was designed as cancer drug. Stopped my PSA from rising

[jazj in reply to mrscruffy]

Not sure how much credence I'd give to this article but it seems overall the trend is that in decreases T as you say. The funny thing is of course this is viewed as a bad thing in most situations but not for PCa! Seems like this would be a no-brainer to take with ADT to preserve muscle! I'm surprised I never heard it mentioned anywhere in the context of PCa until now. So the question remains in my head, what's the potential downside other than fatigue at too high of a dose?

"Unlike many people's beliefs about Ostarine, it works as a natural testosterone suppressant… although not as effective as an anabolic steroid.

Nevertheless, it causes a noticeable drop in testosterone levels."

jpost.com/promocontent/osta....

[mrscruffy in reply to jazj]

It effects HDL, first cycle HDL went way up which is good, second cycle went down, will see after this cycle. I asked my oncologist why this wasn't being used and he said "people are stupid and wont follow directions when it come to cycling

[mrscruffy in reply to jazj]

huge gains

the other thin Ostarine does

[mrscruffy in reply to jazj]

It also gives cancer to rats in massive doses, massive like 6x's what I take

[Justfor_]

I am trying a proportional Bicalutamide mode for PSA stabilization. It seems to be working though is too early to tell. The principals behind it are two:

1) Proportional systems are better than switched which are in turn better than uncontrolled ones

2) Killing all hormone sensitive cells frees grounds to insensitive ones. Maintaining an equilibrium may prove a longer lasting tactic.

[jazj in reply to Justfor_]

I neglected to include in my original post that this thought came across my mind yesterday also. If once primary and salvage treatments have failed, knowing there is no curative treatment after that, would there be a significant difference in how long it took for the disease to become ADT resistant if you did "partial ADT" taking Testosterone down but not all the way down and thereby you end up at the same endpoint at about the same time but with much reduced side effects along the way?

It seems overall, looking at all these studies about treatments from a big picture perspective, the difference in time to an ultimate outcome is in general not that huge of a difference in the context of doing treatments over the course of 15+ years. Excluding doing nothing, is it generally the case that all roads take you to the same destination at about the roughly the same time? I acknowledge I am generalizing without specific data examples (I'm being lazy with study references tonight.) But do Advanced PCa patients risk getting too caught up in relatively short-term results at the expense of long-term quality of life with not a huge difference in ultimate outcomes? Sorry, I may be getting off on a tangent.

[Javelin18]

I had a question about switching on and off secondary ADT drugs. In the discussion, TallAllen provided a reference to how BAT therapy works. There appears to be signaling between resistant and non-resistant cells, which might also be at play here. You can find it referenced in this post:

healthunlocked.com/advanced...

[jazj]

It all seems like common logical thinking to me. Maybe the "in the box" thinking regarding SOC on systemic therapies is mainly constrained by the fact the Phase I & II studies for drugs that are going to make companies millions and billions of dollars are largely focused on maximum tolerable dose as part of the goals of the study. Then the thinking is, if you don't take the full dose, you won't have the full benefit. So pay us the "full money" and get the full dose. Yet PCa is tricky and says "go ahead and give me the full dose for a long period, that will just allow me to more quicky find a way to adapt to it."

[MateoBeach]

Like that you are thinking outside the box and asking these import questions, jazj. It is also called “Adaptive therapy” or using evolutionary Darwinian dynamics to stabilize competing sub populations. That is the basis of the modified BAT programs some here are using. Alternating treatment modalities, such as toxic chemotherapy following maximal T suppression is another. (Search extinction vortex.)However, the idea about using sub maximal androgen suppression (lowering T but not to castrate levels, appears to be a bad idea. Castrate, very low T levels, as well as very high levels (Supra physiologic or SPT) both suppress PCa growth. It is low but not castrate levels that appear to allow the most PCa progression.

Much has been written on this by myself and others here, but I don’t have access to my reference links at this time. See the prior posts of RSH1, Nal, pjoshea, myself and others. You are on a good track of inquiry. Paul