Xtandi Superior to Zytiga? Maybe Yes? Xtandi prevents resistance to Testosterone because it upregulates the AR while inhibiting its activity

[cesanon]

"Xtandi (but not Zytiga or other advanced antiandrogens) prevents acquired resistance to T because it upregulates the AR while it inhibits its activity." Tall_Allen

healthunlocked.com/advanced...

Does this mean you should just automatically favor Xtandi over Zytiga? It would certainly seem so, wouldn't it?

It seems straightforward to me. Or is this more complicated and nuanced than that?

+++++++++++

Update #4

+++++++++++

My synthesis of the discussion so far:

1. There is no downside to choosing Xtandi instead of Zytiga. Each may have side effects that are unique to the individual patient, but you don't know until you try. There is some anecdotal evidence that Xtandi side effects may be more common than Zytiga.

2. If you foresee Bipolar Androgen Therapy (BAT) in your future, it appears there may be good reason to start with Xtandi and stay on it if you find that you tolerate it well.

If you do not see BAT in your future, maybe Zytiga makes more sense. Xtandi is doing some fancy stuff with the Androgen receptors. Simplicity is always good.

And there are always considerations of cost and idiosyncratic side effects.

3. If you are finding that Androgen Deprivation Therapy is no longer working for you, it is worthwhile to get a second opinion on trying BAT for a few months. That second opinion should be from a Medical Oncologist who uses BAT therapy regularly as part of their practice.

4. Nice Explanation of BAT Therapy by Smurtaw:

" o Initially, nearly all prostate tumors are gas guzzlers: very fuel-dependent and powered by the androgen receptor as the engine. When treated with hormonal treatments gas prices increase and most tumors remain fuel-dependent but become more fuel efficient, able to go farther with less gasoline. But then as we make gas plentiful and cheap (high androgens or testosterone) the tumors become less fuel efficient since gas is cheap.

o In each cycle of pBAT, we go from cheap gas to expensive gas. The prostate tumors never settle down into gas guzzlers or gas-efficient vehicles (hormone resistance).

o For this to work we need to be able to make gas very expensive. This is one of the advantages of pBAT. By using testosterone propionate, we can go to very low levels of testosterone during the ADT phase and this makes the gas prices very expensive.

o We can see that, while pBAT will work with men who are hormone resistant, the optimum time to do pBAT is while the cancer is still hormone sensitive. The goal is to prevent it from completing its adaption to a low testosterone environment and pBAT is a means to that end." Smurtaw

5. More from Smurtaw:

"Also, Xtandi is that only ARSI that has been proven to upregulate ARs while also inhibiting them. Upregulation should improve the high T phase of BAT and inhibition improves the low T phase.

Other ARSIs might do this to some degree but it hasn't been tested. Hopefully we will find out more in the next few years." Smurtaw

Smurtaw's Book: "Adaptive Bipolar Androgen Therapy (BAT) for Prostate Cancer: Prostate Cancer Hormonal Treatments" Available on Amazon:

amazon.com/dp/B0B1V15PJ1/

+++++++++++

Update #3

+++++++++++

In response to smurtaw's comments below, I was thinking about how you would investigate whether or not Xtandi's upregulation of the prostate cancer cell Androgen Receptor would inform future treatment decisions.

One way to research this would be a retrospective study of the two groups of patients (Xtandi & Zytiga) and subsequent course of treatment data, but filtering out all the confounding variables.

BUT statistically filtering out all the different prior and subsequent treatment decisions. Even though both groups appear to have similar survival rates, maybe Xtandi suffers from easier future treatment regimes.

Those Docs never ever it seems measure anything other than survival/death rates. That's how the insurance companies justified withholding PSA testing until way too late for many of us.

If you can continue to use Androgen Deprivation Therapy for a longer time. That's a big win. But it is something you have to do looking for. If you limit yourself to cheaper retrospective data, you have lots and lots of confounding variables you need to filter out.

See Also:

"If I was going into it fresh I'd probably pick Xtandi instead of Zytiga. The fact that pBAT has worked so well for me stops me from second-guessing anything." Smurtaw

+++++++++++

Update #2

+++++++++++

From my favorite peer-reviewed journal:

1. Conjecture: "a conjecture is a conclusion or a proposition that is proffered on a tentative basis without proof"

en.wikipedia.org/wiki/Conje...

2. Theory: "A theory is a rational type of abstract thinking about a phenomenon, or the results of such thinking. The process of contemplative and rational thinking..."

en.wikipedia.org/wiki/Theory

3. Theorem: "a statement that has been proved, or can be proved"

en.wikipedia.org/wiki/Theorem

For those who now remember the difference in the hierarchy of a conjecture, a theory, and a theorem. Please replace your non-responsive posts with ones that contain substantive content. At the time of this writing, I have not seen one such post. If anyone here can do that, it would be TA, and so far he has failed to do so. Presumably, because he can't? (note the "?" please)

To the extent that no one here can do that, it is a step towards upgrading my proposed Conjecture to a potential Theory. I welcome being proven in error. I really do. But the vacuous spam is not helpful to anyone.

Thank you in advance

+++++++++++

Update #1

+++++++++++

See generally:

Sequential Testosterone and Enzalutamide Prevents Unfavorable Progression

clinicaltrials.gov/ct2/show...

Prostate cancer androgen receptor activity dictates efficacy of bipolar androgen therapy through MYC

jci.org/articles/view/162396

[Tall_Allen]

You took it out of context. That was only about BAT. Why would you post a misleading thread like this?

[cesces in reply to Tall_Allen]

If it is misleading you should explain why.

Many here may post incorrect information. But I have never seen anyone do it intentionally.

Asking a question (the title and every sentence has a question mark).

I asked in a manner calculated to give you the least offense.

If it is out of context you should explain to readers why. If the proposition is wrong. You should explain why. And what "complications" and "nuance" I may not be seeing.

Otherwise it seems to me that the proposition is right. That all things equal, it makes sense to favor xtandi over Zytiga.

Correct me if I am wrong. It will be welcome. But flaming a goodfaith question doesn't help anyone much I think. LoL

[beckymb3]

The way I took it, there was no assertion. He was asking for conversation about a comment which he quoted. There is so much information on this site and so many layers to delve into, everything should be taken with a grain of salt. No one statement should be taken as misleading because the whole is so complex. He was looking for feedback and continued dialogue, as far as I could tell. No reason for this to be frowned upon. He framed it with questions marks. There is to much to be learned and shared for us to be sidetracked by a title or comment.

[cesces]

What's the answer

[Hidden in reply to cesces]

I was thrown into this world of cancer, only since January. I don’t know as much as you all, as I am just a former dental hygienist with a husband that was not given too much hope. Here is why I choose xtandi over Zytiga, three weeks ago 1/2 dose. Zytiga came with prednisone, one more drug that can lower the immune system, a small dose, yes, but still. not an easy one to stop right away. My thoughts were let’s start uncomplicated and move our way up. I will let you know how it goes. I am the spouse, I can’t let fear stop me from thinking out everything cautiously. My husband has the strength for this battle, it is up to me to keep calm and think and learn from all of you… never be afraid to talk, ask questions, have discussions please… it keeps me going!

[cesanon in reply to Hidden]

"Zytiga came with prednisone, one more drug that can lower the immune system, a small dose, yes, but still. not an easy one to stop right away. "

To my recollection TA has indicated that the prednisone is merely a replacement to something the Zytiga depletes. So it is not that type of issue, so long as you get the dose right.

[Hidden in reply to cesanon]

thank you!

[cesanon]

"Xtandi is superior or inferior to Zytiga"

There appears to currently be no current clinical trial evidence that Xtandi is superior or inferior to Zytiga.

So if a scintilla of logic points towards one, why not take it. You are risking a little (actually 0) for something.

That was the genius of Dr. Myer's practice of medicine. He was always working with imperfect information. When others were stuck behind in SOC, he would move ahead balancing risks.

The choice between Xtandi vs Zytiga involves no risk. That has been proven. If one might possibly have a yet-to-be-tested advantage over the other, why not start with it?

The only other reason to favor one is side effects.

[cesanon]

"This is why I am almost totally a lurker. Not worth sharing with so much spite flying around."

A bunch of cranky old men with too much toxic masculinity. LOL

[meowlicious99 in reply to cesanon]

> toxic masculinity.

PC is a disease of toxic masculinity. You know, testosterone gone wild.. literally.

[anonymoose2 in reply to cesanon]

We’ll I take offense to that statement.

NOW GET OFF MY LAWN!!!!

GET OFF MY LAWN.

[cesanon]

1. "Zytiga is an irreversible CYP17 inhibitor."

hmmm was unaware that it was irreversible. One more strike against Zytiga then.

Anything that is irreversible is potentially dangerous. Including orchiectomy. Every year Standard of Care and the science behind it is changing. Don't want to get stuck in a dead end. LOL

2. " I have been using Zytiga with pBAT and the results have been good."

What is pBAT?

2. May I ask what doc you are using for BAT

3. Thank you for the first substantive comment on this post. I am actually going to go back and read it a second time.

[cesanon]

"I'm also considering a rapid BAT scheme"

What is rapid BAT? Compared to normal BAT?

[cesanon]

In retrospect would you have preferred to have started with xtandi instead of zytiga?

[cesanon]

It's sort of hard to moderate a forum like this. Lots of cranky old men given the nature of the disease. I think they do the best they can. Not that I always agree with them. LOL

[cesanon]

I just updated my original post to include proposed research that would confirm or disprove my conjecture.

In the meantime, it seems there is no reason not to favor Xtandi over Zytiga. At least nothing that anyone has brought up so far.

[cesanon]

Rapid BAT chart: WOW!

[Darryl Partner]

@mtnwife nothing containing content was edited out of your replies

[cesanon in reply to Darryl]

I think you do very well at a very difficult job.

As evidenced by the success of these forums.

I used to be a moderator. And no one is ever happy with whatever you do or don't do. LOL

[Darryl Partner]

@smurtaw Apologies for introducing a grammatical error.

[cesanon]

Those 12 hour cycles on the Rapid BAT must really whipsaw those androgen receptors. LOL

I don't know that I could keep up with it. At least not for any extended period.

[London441]

I will comment only anecdotally on the side effect comparison. If I didn’t later hear of possible Zytiga side effects, I wouldn’t have known there were any. I was never told to expect any, other than a slight rise in BP. I had zero.

I have not taken Xtandi, but I have talked to many guys who report very tough side effects from it (especially fatigue), much more so than Zytiga.

Since QOL seems to be so much in the front of many men’s minds here I thought it worth a mention.

[cesces in reply to London441]

Thanks.

I have been assuming that the side effects of each are different for different people.

Are you sure thst Zytiga is always better than xtandi?

[London441 in reply to cesces]

I’m not sure of anything. Retrospective studies have shown Xtandi causes more fatigue and that’s consistent with what I’ve heard. As I said, Zytiga was easy on me.

Since both are so often paired with Lupron and other LHRH drugs men will often stop taking one or the other if sides become onerous. As with all of it, results vary and there plenty of placebo effect involved.

[cesanon in reply to London441]

"Retrospective studies have shown Xtandi causes more fatigue "

Well that is a factor to consider.

[rfgh20]

I am on Zytiga for 4 months. Considered switching to Xtandi but $2200 a month versus $30 . I would pay it if good evidence in greater efficacy.

[cesanon in reply to rfgh20]

Survival rates are the same.

Side effects seem to vary.

But Xtandi mechanism may open the way for different treatment protocols that could potentially affect survival rate and/or quality of life.

[Spyder54]

cesanon, Xtandi did NOT work for me. Zytiga-pred has worked for me. Please remember that every man presents differently, then responds differently. At Dx (2yrs ago), I was started on Firmagon, PSA 47 and had great PSA & T reduction. Xtandi was started 3rd month, T rose next month, and PSA flattened. The next month T rose again, and PSA reversed upward. At month 6 after Dx I was switched to Zytiga/pred, and T back to zero, and PSA continued back lower. I have been very slow to reach my low PSA nadir. last month (month 23 since Dx) I hit my low of .022. Perhaps I will go lower??

[cesanon in reply to Spyder54]

"Please remember that every man presents differently, then responds differently. "

agreed

[LowT]

Anecdote is not data.

But it is MY story and something to ponder while questioning and looking for new possibilities adding to overall level of knowledge.

Hanging my hat on an anecdote is not wise in most cases.

Everything is about context and no two PCs are the same.

[podsart]

can you explain more about: “tumor androgen synthesis and only want to hit membrane ARs”

What is NPP?

What is pBAT?

[Darryl Partner]

ok

[MateoBeach]

How often (2x/wk?) and what dose do use to maintain very high T on pBAT, Smurtaw? It makes sense to add an AAR blocker (Nubequa or Xtandi) to the ADT during the castrate cycles of BAT to further diminish AR signaling and clonal replication to castrate resistance. I plan to add one of those in my next BAT- cycle. (Based upon this theoretical model and favorable results seen in clinical trials of ADT plus any AART choice.)

However, it may also make sense to include a periodic cycle with Zytiga to selectively disadvantage sub-population developing autonomous intracelular testosterone synthesis? Perhaps alternating strategies for castrate level BAT cycles between the two?

[podsart]

thanks

I thought that ARs start on the membrane surface but as the Pca responds to treatment pressure, one of the mutation responses is to internalize AR to reduce the need for external T therapy pressure. Other responses include AR mutations, including spice mutations like ARV7

[john4803]

Should we be throwing Apalutamide (Erleada) into this discussion as a possible alternative? I am new to this site & Ap is a relatively new AR inhibitor drug, so don't hesitate to "splain" to me.

My MO calls it Cassodex 2.0 & has 20 patients on it with generally the only SE of fatigue. Being on Lupron at the same time, one can argue it may be that instead? We are all still castrate sensitive, so that may interfere with the discussion - don't know?

Excuse my ignorance, I am probably missing something here? Should I be starting a new thread of Erleada vs. Xtandi & Ztiga? Probably should add some kind of links, also?

Thanks!

[Boywonder56 in reply to john4803]

I was wondering the same as ive ben on it since dx..maybe its a cost thing...or is enz vs aplutimide diffrnt...iv had good results...sofar....

[john4803 in reply to Boywonder56]

Couldn't tell from your bio how long you have been on Erleada? I have only been on for it 6 mon. & my PSA 7.3 (mets. throughout skeleton too numerous to count) has reduced to 0.1.

I am on Lupron, Erleada & Xgeva. Some of my cohorts have been on it for years, I think, but I am trying to get more stats. from my MO.

[Spyder54 in reply to john4803]

john, all information and data is good. We all can make our decisions. If what I read makes me request a change, then that is my decision alone. Feel free to post your thoughts. As I said above, we all present, and respond differently. If someone is having good success (especially long term), I want to know about it. Many of of believe that extending life is the secret for the cure (or extended remission) that eventually comes along. There is a perfect combo out there (probably slightly) different for each of us. Mike

[cesanon]

"Some people theorize that it is preferable to activate mAR vs. iAR."

Could you expand on this. I thought the goal was to deactivate or block the receptors?

[cesanon]

"I use SARMs to activate the skeletal ARs. This provides bone and muscle hypertrophy."

This sounds interesting.

What are SARMS?

Is this something you can use to help with muscle maintenance and muscle building when undergoing Androgen Deprivation Therapy?

If so this deserves its own thread!!!!

[Spyder54]

hi Smurtaw, what is an NPP?

Re-read your post. Borderline Oncologist discussion.

Thanks, Mike

[Spyder54]

thanks Smurtaw. Look forward to your results. Mike

[podsart]

thanks

[cesces]

"Upregulation also occurs"

What exactly is Upregulation?

Do we know that it is, or is not, associated with increased sensitivity to or response to androgen deprivation therapy?

Or is there no evidence one way or the other? But perhaps logic supports a conjecture one way or the other?

[cesces]

So upregulation caused by Xtandi will improve results from subsequent ADT?

[cesces]

Smurtaw

"No. It possibly increases stress if you use high androgens. Opposite if you are using ADT."

I'm not certain I understand what you just said. Might I ask you to restate it using different words?

[cesanon]

Thanks. Now I get it.

[cesanon]

Hmmmm

So would you agree, that if you expect to see BAT therapy in your future, that is a good reason to use Xtandi instead of Zytiga.

Assuming all other things equal.

And generally, there is no reason not to choose Xtandi instead of Zytiga... except possibly for idiosyncratic potential side effects. Which if you run into such side effects, then you can switch to Zytiga,

[cesanon]

My synthesis of the discussion so far:

1. There is no downside to choosing Xtandi instead of Zytiga.

Each may have side effects that are unique to the individual patient, but you don't know until you try. There is some anecdotal evidence that Xtandi side effects may be more common than Zytiga side effects.

2. If you foresee Bipolar Androgen Therapy (BAT) in your future, there is good reason to start with Xtandi and keep on it if you find that you tolerate it well.

3. If you are finding that Androgen Deprivation Therapy is no longer working for you, it is worthwhile to get a second opinion on trying BAT for a few months.

That second opinion should be from a Medical Oncologist who uses BAT therapy regularly as part of their practice.

I would appreciate hearing some REASONED Ayes and Nays on this provisional assessment. All I am asking for guys is the reasoning behind your opinion... name calling, flaming, empty gainsaying isn't helpful to anyone. Is it? Well if you think it is, have at it. LOLOL

Thank you

[Spyder54 in reply to cesanon]

Aye !

[cesanon]

Book? What book?

No wonder you seemed so knowledgeable. LOLOL

How about putting an amazon link to it here please.

thank you

[Stevecavill]

"Xtandi (but not Zytiga or other advanced antiandrogens) prevents acquired resistance to T because it upregulates the AR while it inhibits its activity." Tall_Allen

Does this mean you should just automatically favor Xtandi over Zytiga? NO

It would certainly seem so, wouldn't it? No, why?

It seems straightforward to me. Or is this more complicated and nuanced than that? YES, much more complicated.

I really don't know where to begin. There's no science in your hypothesis at all. Why would enzalutamide be superior to abiraterone in all instances, just because it MIGHT be superior when used in BAT?

If you want to compare enzalutamide to abiraterone, then find a trial that does that, or at least build a hypothesis on the science of how the drugs work in the first place. Do I know how they work? No, that's why I leave the research to people with PhDs and 20 years of research.

[cesanon in reply to Stevecavill]

Steve

1. Nice Explanation of BAT Therapy by Smurtaw:

" o Initially, nearly all prostate tumors are gas guzzlers: very fuel-dependent and powered by the androgen receptor as the engine. When treated with hormonal treatments gas prices increase and most tumors remain fuel-dependent but become more fuel efficient, able to go farther with less gasoline. But then as we make gas plentiful and cheap (high androgens or testosterone) the tumors become less fuel efficient since gas is cheap.

o In each cycle of pBAT, we go from cheap gas to expensive gas. The prostate tumors never settle down into gas guzzlers or gas-efficient vehicles (hormone resistance).

o For this to work we need to be able to make gas very expensive. This is one of the advantages of pBAT. By using testosterone propionate, we can go to very low levels of testosterone during the ADT phase and this makes the gas prices very expensive.

o We can see that, while pBAT will work with men who are hormone resistant, the optimum time to do pBAT is while the cancer is still hormone sensitive. The goal is to prevent it from completing its adaption to a low testosterone environment and pBAT is a means to that end." Smurtaw

2. More from Smurtaw:

"Also, Xtandi is that only ARSI that has been proven to upregulate ARs while also inhibiting them. Upregulation should improve the high T phase of BAT and inhibition improves the low T phase.

Other ARSIs might do this to some degree but it hasn't been tested. Hopefully we will find out more in the next few years." Smurtaw

Smurtaw's Book: "Adaptive Bipolar Androgen Therapy (BAT) for Prostate Cancer: Prostate Cancer Hormonal Treatments" Available on Amazon:

amazon.com/dp/B0B1V15PJ1/

3. Apparently there is no research that helps you choose. What there is shows equal survival/death rates.

Up in my amended original post at the top, I propose some low cost retrospective research that might give some insight into whether Xtandi, with its AR upregulation may set you up better for BAT therapy. The current research is silent on that.

5. Other than that there is not any basis upon which to chose to start with Xtandi or Zytiga, unless you are aware of any such data.

6. If you are expecting to escalate to BAT therapy in the future, it is a low risk / high reward decision to choose to start with Xtandi first. Given the current data.

7. Do you have any better basis upon which to make such a decision, when the current data show it is a 50/50 decision?

[cesces]

What do you think about using BOTH Xtandi and Zytiga together concurrently?

[Teacherdude72]

Might Nubeqa be an alternative?

[cesanon]

"He did provide the link and phrased it in the form of a question. "

That's what I did. And it certainly was my intention.

As a result of all this discussion, I have revised my conjecture making it more favorable to Xtandi.

Please take a look at my revised original post and title. Please let me know what you think.

I did also include a link to your book if that is OK.

[Stevecavill]

I'm not too interested in BAT at the moment as the evidence is pretty thin, so I'm not taking that into account.

3. There is already quite a bit of retrospective data, which as you identified, is inconclusive.

6. agreed

7. I haven't had to choose yet. But I would base it on side effects.

[cesces in reply to Stevecavill]

"I'm not too interested in BAT at the moment as the evidence is pretty thin, so I'm not taking that into account."

yes. Bat has a low success rate.

But for those whom it works, maybe 25-50%, it works well.

It seems to me that it is a low risk high reward QOL quality of life decision to give it a try for a few months when the time comes.

Perhaps with the new fast BAT it's an even easier decision to just give it a try. They need more clinical experience with it, but maybe the testing could take only a few days.

The side effects are irrelevant to the decision of which of the two X or Z you try first, if you think about it.

[cesces]

Something More on the Subject

BAT question

Denmeade states that "BAT should not be combined with Zytiga, Xtandi, Erleada, or Nubeqa (or with taxane chemotherapy)."

Does anyone know why? I would have thought that Zytiga would be good to use during the low T phase of BAT.

healthunlocked.com/advanced...

[Seasid]

i am introducing lot of grammatical errors but usually I have some idea what I want to say.

My mother tongue is Hungarian and it is sometimes difficult for me to have in Indo-European languages a perfect grammar.

[Seasid]

Better to know one (English) well than 4 languages bad like me.

[cesces]

Very clear think

[Seasid]

i am jealous how well and grammatically correct you can express yourself.

If you want you can find out your Jung personality type at.:

humanmetrics.com



[cesces]

And you know none of those tests are verified with the equivalent of an rct.

They are all feel good ouija board science. Only the ouija board actually has some science behind it. LoL

[cesces]

They have been ruthlessly tested to make humans feel happy and content with the test results.

They just have no proven predictive ability for anything of utility or value. LoL

I would classify them as the equivalent of an entertaining optical illusion.

You look at it, nod your head approvingly, and then move on. And hopefully not make any important business decisions based upon it.

[Seasid]

i am a silly billy ENFP or maybe INFP.