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Advanced Prostate Cancer
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Zytiga ca. Xtandi

I understand Xtandi is getting good results with hormone-sensitive metastatic men, delaying metastatic progression... and the direction seems to be to push the second generation drugs back upstream into earlier stage ADT situations.

Can anyone pls explain the key differences between Zytiga and Xtandi, since they both seem to be showing up in these earlier settings?

Stuart

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Sure. Zytiga (abiraterone) blocks enzymes necessary for both the intratumoral and adrenal production of androgens. Xtandi (enzalutamide) blocks the androgen receptor (which has to be activated for the cancer to divide and multiply) and prevents it from "translocating" into the nucleus of the cancer cell (where it no longer needs to be activated by external androgens).

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Been reading your biology textbook again TA:-) OK, I'll take a stab at adding to what you just stated. Abiraterone is a "partial androgen receptor antagonist and also adrenal inhibitor" hence the need for co-therapy with steroids and enzalutamide is an "androgen receptor antagonist" without need for steroid co-therapy? I am on week 42 of the Embark trial assigned to enzalutamide only trial arm and was given a treatment break at week 36 for nondetectable. Gadzooks that stuff is potent and turned a 51 year old man into a 60 year old in 9 month's time yet my testosterone tripled from 200 to 600 while on therapy as the endocrine system compensates for the no show T.

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“Gadzooks”?? Well, I don’t know about the impact on your biological age, but from an entomological perspective at least, I can certainly see there’s been an impact!!

Seriously though, thank you both for the information - I occasionally forget the prednisalone and would prefer not to have to take one apart from food and the other with, but these are minor issues.

What I really don’t get is why they, or indeed any ADT agent, can supposedly kill micrometstatic or radio-sensitised PCa In an eSRT setting but only hold it at bay otherwise... I gather the second generation agents are hoped to be better in the eSRT support role, but it all just seems to be assertion and guess work.

Anyway, again, thank you

Stuart

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It's about getting the metastases early enough before they have evolved to the point where there are hormone-resistant clones. There is also an "abscopal effect" - the dead cancer cells from the radiation and the hormone therapy prime T cells that are able to go out and find other cancer cells elsewhere to kill.

You are right that the use of second generation hormonals adjuvant to radiation (either primary RT or SRT) has not yet been established. There are clinical trials like this one that may someday eliminate the guesswork:

clinicaltrials.gov/ct2/show...

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That’ will certainly be an interesting study - but it seems odd that they are mandating PSA of at least 0.7 when there’ appears to be consensus that eSRT should commence at around 0.2, and lots of people are actually going even earlier. I guess the higher value significantly increases the relevant audience, but it must also reduce the cure rate - surprising they don’t have a low-PSA arm as well, given that’s the trend.

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It's because it's an RTOG study. RTOG (aka NRG Oncology/RTOG) is a wonderful organization funded by NCI that has overseen most of the important clinical trials in radiation oncology. It is a set of very reliable randomized clinical trials (RCTs) that contribute successively to our understanding. An earlier RCT (RTOG 9601) found that there was no extra benefit to adjuvant hormone therapy when SRT began before PSA reached 0.7. Note the quote from Howard Sandler (the head of RTOG) about halfway down the page:

pcnrv.blogspot.com/2016/08/...

Other ROs that I greatly respect use an earlier PSA threshold for adjuvant ADT. A patient of Michael Zelefsky's at MSK, for example, told me he adds ADT to SRT when PSA is over 0.1. He also uses a higher dose - 72 Gy vs 66.6 Gy for Sandler.

I don't think anyone in radiation oncology seriously disputes that earlier is better (3 RCTs have proved this), it's only controversial when to add ADT to the SRT and which ADT to add. Because that RCT is about using adjuvant super-hormonal therapies, and Edwin Posadas is one of the lead investigators and he is at Cedars-Sinai (where Howard Sandler is head of radiation oncology), it makes sense that he is using the proven RTOG protocols (minimum PSA of 0.7ng/ml and dose of 66.6 Gy) in that trial.

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Thant’s an interesting piece of analysis, and no doubt makes sense - but I have gone for the second gen ADT starting at PSA of .12 purely on the basis of SVI and short PSADT (3.6 - 4 months), and I see they are mandating high risk pathology. My point is that people with newly discovered BCR and high risk features are likely being advised not to wait around for their PSA to reach 0.7, so I wonder in what direction adopting that criterion will bias their accrual....

Anyway, returning to my original query, do you have any idea why they would have gone for Xtandi over Zytiga for this study? The MO’s I consulted both felt Zytiga was the logical choice, but I didn’t press them on the issue...

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I don't know for sure, but I know Dr Posadas and will ask the next time I see him. My guess is that they are trying to build on RTOG 9601, which used a weaker anti-androgen, bicalutamide.

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ENTOMOLOGICAL???

I guess that's what you get for typing on iPhones in the dark... sorry rust, my lame etymological humour certainly wasn't intended to suggest that ADT has driven you to be interetsed in insects... although I guess that with sex off the agenda, we all need a hobby....

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Hobbies? You can dissect that again..

Good Luck, Good Health and Good Humor.

j-o-h-n Thursday 02/14/2019 7:31 PM EST

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Abiraterone is not really an androgen receptor antagonist - it affects the androgen receptor, but not by blocking it. Enzalutamide is a powerful anti-androgen. Since you are getting enzalutamide monotherapy on the EMBARK trial, that means that your testes continue to manufacture testosterone. But the enzalutamide prevents all that testosterone from being used, which is why it accumulates in the blood uselessly. It's great that your PSA is undetectable.

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Allen,

Using myself as an example; when and which of the 2 drugs would be prescribed to me next.

I just started casodex and will get my first lupron shot next week followed 30 days by radiation to the pelvic nodes and another 24 months of Lupron. My MO will not give me Zytiga prior to or after the radiation as requested. I assume she wants to save it for later.

If in 24 months after stopping Lupron my PSA rises which of the 2 drugs would likely be prescribed and why?

Thank you,

Jim

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It's possible that your insurance may not be allowing Zytiga adjuvant to radiation because of the lack of data from clinical trials. They usually try Zytiga next - it's cheaper.

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I thought Xtandi needed to be administered with Lupron or something similar.

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Monotherapy. That is what EMBARK clinical trial is testing.

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Since they do very different things, can enzalutimide and Zytiga be taken together to double team the cancer?

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Maybe. We await the results of a randomized clinical trial to see if there is any benefit to the combination.

There was a phase 2 (non-randomized) trial in men with bone mets and castration resistance that suggested the combination was tolerable:

astellasclinicalstudyresult...

However in men with localized high risk PC pre-prostatectomy, the addition of Xtandi to Zytiga+Lupron seemed to encourage AR-V7 resistance more than Zytiga+Lupron alone:

meetinglibrary.asco.org/rec...

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