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Advanced Prostate Cancer
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Stop Casodex if on Lupron and Zytiga?

See my profile for more details. I've been on Casodex + Lupron + Zytiga for about 3 months. PSA is decreasing fast. During recent appointment, my oncologist said I can stop taking Casodex. I was a bit surprised because I've read that simultaneous Casodex (50mg tablet 1/d) and Lupron (injection 1/3 mo) is common. My oncologist said that, except to deal with flare, Casodex provides no benefit if you are also taking Zytiga. He mentioned that he was familiar with Zytiga trials, which demonstrated that. But he also implied that there was no particular harm in continuing Casodex for awhile.

Does anyone have any knowledge, experience, or opinions about this? I'm not sure what to do. Thanks in advance.

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Your oncologist is right. Casodex is a drop in the bucket compared to Zytiga. Eventually, the cancer learns how to feed on Casodex.

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The 2 drugs work differently. I have no recommendation, but do not believe the cancer learns how to feed on the Casodex. My reference point here is that the cancer does a work around, when a signal sent by messenger RNA, puts up a road block, not allowing the Casodex to continue to put its key into the lock of the Androgen Receptor--thus nullifying, its ability to perform, a blocking mechanism.

Nalakrats

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It seems that there are mutations in the AR making casodex to be an agonist instead of antagonist.

erc.bioscientifica.com/view...

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The Mutations that affect Xtandi and Zytiga are in the AR-V7 splice variant, and a couple of its subsets. What is not talked about, or properly considered are the Gene Mutations, and Pathologies of the beginning Stem Cells, and Initiating Tumor Cells. are these factors related to Casodex?

Casodex has worked for me for years, along with the Vantas Implant---and I do Alternating Vacations. Hitting into year 4--each to their own. But I understand, that my Alt. medical program, plays a big part of interfering with the signaling to the AR's.

Nalakrats

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You two crack me up! TA and NAL are the reason I'm donating to this blog tomorrow! (and all the other great brothers on this site)

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Good to donate... THIS IS A GREAT CAUSE!!! Thank you...

Good Luck, Good Health and Good Humor.

j-o-h-n Saturday 04/27/2019 8:52 PM DST

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From what I've read, Bicalutamide acts as an agonist with certain AR mutations as do other androgen blockers. This is from an article about Darolutamide which is showing promise in this area:

Bicalutamide was generally a weaker antagonist than the newer compounds. For AR modified at positions W742 or M896, agonistic activities of 90–100% or 50–60%, respectively, were observed upon treatment with 1 μM bicalutamide

onlinelibrary.wiley.com/doi...

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Bicalutamide belongs to the same family of drugs (the lutamide family) as its big brothers Enza, Daro, and Apa. Same mechanism of action except that Enza, Daro and Apa are 5 to 10 times stronger.

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If your Pca has not done the work-around to casodex you can always fall back on it at a later date.

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Good simple point that hadn't thought of. Thanks

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Zytiga (Abiraterone, Abi) is a CYP17A1 inhibitor, whereas Casodex (Bicalutamide) is an antiandrogen. Intuitively, one would expect synergy, or at least additive benefit with slower progression to resistance.

Note that CYP17A1 is the enzyme that converts pregnenolone & progesterone to DHEA & androstenedione, respectively.

I was reading a new paper yesterday [1] on "A bypass mechanism of abiraterone-resistant prostate cancer: Accumulating CYP17A1 substrates activate androgen receptor signaling", which concludes with:

"Activation of the AR by clinically relevant levels of Preg {pregnenolone} and Prog {progesterone} accumulating in abiraterone-treated patients may act as a driver for CRPC. These data provide a scientific rationale for combining CYP17A1 inhibitors with antiandrogens, particularly in patients with overexpressed or mutated-AR."

From a 2015 paper [2]:

"The CYP17A1 inhibitor abiraterone markedly reduces androgen precursors and is thereby effective in castration-resistant prostate cancer (CRPC). However, abiraterone increases progesterone, which can activate certain mutant androgen receptors (AR) ..." "Therefore, we sought to determine if CYP17A1 inhibitor treatment selects for progesterone-activated mutant ARs."

...

"These findings indicate that selection for tumor cells expressing progesterone-activated mutant ARs is a mechanism of resistance to CYP17A1 inhibition."

It's true that Casodex has the downside that with resistance, it can change from an AR antagonist to an AR agonist. Zytiga (Enzalutamide, Enz) is a newer antiandrogen that does not have that disadvantage. It is well-known that sequential use of Abi+Enz or Enz+Abi can be disappointing, due to shared resistance, but how about Abi & Enz together? Good luck with insurance. & combined side effects might be harsh, however:

From a recent paper [3]:

"In this phase II trial, we evaluate neoadjuvant enzalutamide and leuprolide (EL) with or without abiraterone and prednisone (ELAP) before radical prostatectomy (RP) in men with locally advanced prostate cancer."

"Seventy-five patients were enrolled at four centers. ... The pathologic complete response or minimal residual disease rate was 30% (n = 15 of 50) in ELAP-treated patients and 16% (n = four of 25) in EL-treated patients"

You asked: "Does anyone have any knowledge, experience, or opinions about this?" My opinions are such that I would resist efforts to halt the Casodex. But that's not advice, of course.

-Patrick

[1] ncbi.nlm.nih.gov/pubmed/310...

[2] ncbi.nlm.nih.gov/pubmed/253...

[3] ncbi.nlm.nih.gov/pubmed/308...

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pjoshea13: Thank you very much for your comprehensive reply. You should send me a consulting invoice for that. As a newbie, I understand most but not all of the terms and study summary explanations. But be assured that I'm motivated to look things up and learn more.

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My MO switched me Zytiga + Pred after nine months on Casodex. No particular reason... I was responding well to the Casodex, but the presumption was/is that the Z + P was a more aggressive treatment - even though there are not much data for those meds with hormone sensitive and a few mets (the studies were primarily multiple mets). My MO stopped the Casodex because he said doing all the meds was too much toxicity and unecessary.

Using both Zytiga nad Casodex may be better. I don't know. My MO is at Dana Farber and pretty much by the book. I also got an opinion form an MO at Johns Hopkins and he said no reason to continue Casodex when on Z + P.

Edited to add, doing Lupron all along with these.

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jdm3: Your scenario is somewhat similar to mine, so your reply is helpful. Thanks

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Just some antidotal evidence on the effectiveness of Casodex and Zytiga.... started C first, after 3 weeks, PSA dropped from 33 to 21, almost no SE’s at all. Added Z, after two weeks, PSA dropped dramatically from 21 to 4.5. T < 10, ALT/AST elevated moderately, and RBC/WBC counts down slightly, feeling full effects of AD. Adding Lupron next week.

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