I was curious.
I read here some do enzalutamide alone without ADT or bicalutamide alone and have low psa numbers even with their testasterone being very high
Whereas for those on ADT and ARSi both they say the testosterone numbers should be low and lower the better.
Can someone throw some light on this 😊
With ARs blocked, there is no outlet for T, it accumulates uselessly in the blood. It eventually gets metabolized into DHT and estrogen.
Would the same thing not happen when one is on ADT plus ARSi ? Then why is the Lower the better considered better for T levels when one is on Doublet therapy
The anti-androgens aren't perfect, and the cancer reacts by increasing the number of androgen receptors. You get more complete non-activation using both.
Allen what I am trying to understand is when one is on doublet while is a very low T number preferred and stressed on whereas when one is just on ARSi even high T numbers are giving a low psa result.
I just explained that. I'm sorry if you don't understand.
My understanding is the newer gen ARSI’s (Darolutamide, Apalutamide) are supposedly more”selective” in affecting PCa cells, but perhaps not every other endocrine/hormonal function dependent on T. An improvement over enzalutamide. If that is true, you would have similar PCa suppression affect as with anti-androgens alone and/or ARSIs in combination, but fewer side affects and some benefit from normal or high T in other endocrine functions which are also T dependent (muscle mass and recovery, weight management, hot flashes, libido, etc). No trials for this I’m aware of and TA could be correct that PCa AR’s are increased in number over time (which I agree should still occur similarly with any anti-androgen that suppresses T) , but seems to be the case for some on this site at least anecdotally. Maybe placebo effect? Who knows, but this has been my experience with darolutamide monotherapy for the last 2+ years and PSA remaining undetectable . Anti- androgen therapy really affected my QOL; ARSI mono therapy not as much, especially in the weight gain, hot flashes and muscle management depts.
TJS, Excellent bio! Love the well written history.
Very glad to hear your chronic hip pain has completely resolved.
Are you still on a daro vacation?
Make sure you are taking K2 with that calcium. Not sure you need calcium as it is very abundant in food, but K2 alone is very good for moving the calcium out of blood into the bone which not only helps bones but also helps reduce plaque build up. Good book on that is “Vitamin K2 and the Calcium Paradox”
For me, i do daro/orgovyx and mix in BAT either with propianate or cypionate.
I also use Osterine and cardarine during ADT cycles and that helps with all the joint and muscle pain.
Your statement on daro being maybe more selective is difficult to find. I have been searching.
Here is the biophacutics of daro/Nubeqa/NDA212099
Hi. What I am trying to understand that when one is in monotherapy their T levels are very high and psa low and doctors are ok with that - so why is it then when one is on ADT plus ARSI the the doctors want it less than 20 ?
It is a great and logical question. It could be chalked up to doctor's lack of precise analytical thinking. That's my theory at the moment. Similar but different to why each doctor has his own routine, sequence, choice of treatments, etc. Inertia and habit and failure to think past yesteryear's guidelines.
I believe TA's answer, above, is what you're looking for.
Yes one can do just monotherapy and it can be OK to have high T numbers.
But the ARSIs are not perfect; monotherapy alone may not be right for all patients. They would want to add an ADT so it suppresses the T as well as blocking the pathway for T uptake, since the cancer cells adapt by growing new T receptors.
So if you're on mono, high T + low PSA is the goal. Probably periodic scans to confirm things.
But if mono doesn't keep PSA low, or scans show progression, then escalate to ARSI + ADT. In this protocol, you want low PSA + periodic scans - because the ADT's job is prevent the manufacture of T. This gives patients a more complete blockade.
Keeping in mind that a higher T number with mono doesn't mean you have more potential for muscle growth. The pathway is blocked (mostly, anyway) and cells can't uptake the T as they normally would.
The purpose and action of Lupron/Zoladex and others go straight to the production of Testosterone in the testes and block the creation of T. This lowers circulating T, one hopes, and this lower T reduces the fuel for the PCa cells wherever they are in the body. Low T is the measure of success of the drug. The lower T should lead to lower PSA and lower tumor burden as follow on effects.
Androgen receptor blockers such as enzalutamide, etc, have no effect on the production of T and block T access on surface of all cells, cancerous and other. A different action in a different part of the body with a similar result of lower PCA cell activity, lower psa and lower tumor activity.
Success of each drug and pathway is measured in a different way.
Both methods play with the metabolism of hormones in differing ways which creates other effects that a patient must accept for the benefit afforded.
I have been on Enza monotherapy for seven years with differing dose, and psa has fluctuated from 0.01-0.03. T fluctuates 300-600.
Previously I was on Zoladex and had success in reducing T to a very low level, ~5 ng/dl. Psa reduced to similar low level under treatment. Both ways can work and are a choice of clinician and patient based on prior response, side effects, cost, access to drug and treatment (Shots require clinic visit regularly), and other issues. Both can be a correct choice.
Thank you 😊. Why did you switch from ADT to monotherapy on Enza ?
My long time oncologist (9 years) suggested mono enza at reduced dose and then raise dose if necessary. He had years of my responses on which to base his suggestion. I agreed because it gave me control of the treatment, options for dosing and I hoped for a long period success which has occurred. I prefer to avoid a prolonged off period of all drugs because a resumption of either type will lead to increased breast growth, an effect I wish to avoid.
Justfor_ this is your domain. Where are you 😊
I am here assessing the posts of others:
Best response by dhccpa: "It could be chalked up to doctor's lack of precise analytical thinking."
People with limited intellect themselves, or judging that others are so, or just plainly lazy as the alternative entails way more effort, comunicate in a binary manner. Examples:
- I will ask you about this and you will have to answer me by a yes or no.
The silly radio/tv show presenter frequenly use this line to manipulate their guests:
"Don't get into more details on the subject as this will bore our audience". (Don't take frequent PSA tests as this will cause you unnecessary anxiety" - another version of the former)
Worst response by TA: "... it accumulates uselessly in the blood" (emphasis added)
Just ask those on low T about brain fog and all the rest that it brings to the functiioning of the body.
Still does not clarify my confusion why docs are ok with T levels in hundreds on mono therapy but want it below 20 on doublet. 😊.
Because in binary there are only two symbols "0" and "1". There is no "2." Two in binary is "10".
I'll give the "ARSI/ARPI only Testosterone question" a try. Helps me think through things myself.
1. ADT (agonist or antagonist) - such as Lupron or Firmagon - suppresses testosterone precursors. This is the foundation of therapy for half a century. I think of this as "at the top".
Some years ago ADT monotherapy by itself was the only therapy. And once in awhile it seems to show up on this forum and the situation of under treatment.
2. ARPI / ARSI - Stops testosterone synthesis from precursors - a revolution more recently - best example is Abiraterone - blocks the CYP17 enzyme in the amazing steroidal cascade. Direct testosterone hormone production is suppressed, however with the important downstream side effects: (a) adrenal hormones are also suppressed and one needs prednisone add-back and (b) estrogen hormone production is also suppressed, leading to all the side effects we hear so much about. No add-back yet. I think of this as "the middle".
With just number one above and number two above, we yave the recipe for one type of doublet therapy. This would be ADT plus Abiraterone, for example. The whole idea is to reduce the actual testosterone floating around that may hit the rogue prostate cancer cells. As TA points out, prostate cancer cells are constantly looking for permission to grow.
3. ARA or androgen receptor antagonists. This is the whole new category of drugs, the "lutamides" that we have heard so much about. These drugs such as darolutamide, jam up the androgen receptors on the surface of the prostate cancer cells.
Correctly speaking, it's not correct to say that testosterone feeds prostate cancer cells. Cancer cells feed on sugar or perhaps get their energy from fermentation, but the testosterone is not this energy source. Instead, testosterone is a "signaling molecule" that tells them "do your job".
I think of ARA as "the bottom" of the prostate cancer production process.
With number one and number three above, we have the second major doublet therapy. Stop most testosterone production at the top, and jam up the use of any testosterone that leaks through so that the cells are enable to make use of it. ADT plus one of the "lutamides" would be an example.
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So thinking through this, maybe we can now figure out monotherapy and PSA etc.
It's important to note that PSA is the byproduct of an active prostate cancer cell. It's very downstream. And after the fact. Maybe too late!
So with a ARA monotherapy (only number three above), that is to say jamming up the androgen receptors on the prostate cancer cells, you might not care about testosterone upstream. The only thing we want to stop is the work of the prostate cancer cell. And if we manage to block all the signaling, then the prostate cancer cell will die or go to sleep or something.
There have been some studies apparently where people have tried to block all three levels of the chain, ADT at the top, ARPI in the middle, and then AR antagonist at the bottom. Apparently 1-2-3 doesn't have any benefit in terms of survivability, but you're dealing with more side effects. (Don't confuse this three-way hormonal therapy strategy with triplet therapy where the third item is chemo.)
So now we can understand why sometimes doctors might not worry about testosterone with ARA therapy. Because the therapy is so so effective at preventing the signaling to the cell.
On the other hand the doublet therapy combining ADT + ARPI is entirely predicated on stopping testosterone hitting the prostate cancer cell wall and all those receptors looking to get triggered.
As TA also interestingly shared above, there is intense evolutionary pressure going on here and sometimes the prostate cancer cells, in the circumstances of the doublet therapy I am describing here, evolve to multiply enormously the number of androgen receptors on their cell.
So upstream doublet therapy is not perfect. First, some testosterone might leak through. And second, over time the new breed of prostate cancer cells might evolve to thrive on just a tiniest amounts of testosterone. (I'm on upstream doublet therapy and at two and a half years, so far so good. I also had chemo at the beginning which made it at that time triplet therapy.)
Does this answer the question?
Upstream doublet therapy is all about "no testosterone for you". On the other hand downstream monotherapy doesn't care. The entire focus is on preventing the correct functioning of androgen receptors. And that's the goal of starving cancer cells of permission to grow is denied.
Aside from the different recipes and strategies for defeating metastatic prostate cancer, the two different approaches outlined here have different impacts on the body in terms of side effects.
And this could be a huge advantage for ARA monotherapy. Because you don't lose both testosterone AND estrogen! And you have fewer side effects presumably.
That's how I understand it; I will certainly appreciate being corrected.
(Slightly updated and re-edited.)
Thanks so much John for trying to explain but I guess it’s too complex for me and I am still confused. 😃. I hope you are doing very well. Dad is doing ok so far but the xtandi sure makes him worn out and tired.
Maybe those are not the same docs (or patients). I think mono-therapy on an ARSI is a bit controversial. For the docs that prescribe mono they understand that T is not being controlled…thus unconcerned when it is high. The docs that prescribe arsi with ADT assume some additional value of the ADT so want T low.
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