Lupron + Aberaterone or Aberaterone alone for mcrpc?

[dress2544]

After 28 months on lupron, when the pca turned to mcrpc my MO added Aberaterone to the treatment regime. But he says I have to continue lupron injections also along with Aberaterone. My urologist says that when I am taking Aberaterone,there is no need of lupron any more. Aberaterone itself is enough for disease control. I wish to get a wise opinion on this from my fellow members of this community.

[YostConner]

My MO at Hopkins intends to keep me on Lupron through all treatments. I used Abiraterone for 32 months and stayed on Lupron.

[dress2544 in reply to YostConner]

Thank you Yostconner for your reply. I am also of the same opinion of you

[pjoshea13]

There is a Sloan Kettering trial which has a Zytiga monotherapy arm:

"The purpose of this study is to evaluate abiraterone acetate and prednisone in combination with degarelix as a possible treatment for PSA recurrent prostate cancer as compared to abiraterone acetate alone and degarelix alone."

clinicaltrials.gov/ct2/show...

& a German trial:

"This is an exploratory Phase 2 multicenter, randomized, open-label study with a randomization allocation ratio of 1:1 [abiraterone acetate + prednisone + LHRH-therapy (Arm A) versus abiraterone acetate + prednisone (Arm B)]."

clinicaltrials.gov/ct2/show...

Zytiga was approved originally, based on trials where a LHRH agonist was also used, so that would explain some wanting to continue Lupron use.

And then there is the testosterone flare with Lupron withdrawal. That might be given as a reason for continuation.

Without test results, there might be reluctance to use Abiraterone as monotherapy.

-Patrick

[dress2544 in reply to pjoshea13]

Thanks for your very informative reply.

[Joes-dad in reply to pjoshea13]

Have you seen any results from the MSK trials you mentioned above? My current (and only) treatment has been the Firmagon + Zytiga + Prednisone. That's Group 2 in their trial (but I'm doing it elsewhere). It's only been a few months for me though but I'm happy with the initial results.

[pjoshea13 in reply to Joes-dad]

Nothing reprted in the past 12 months. -Patrick

[RyderLake2]

My oncologist told me that you have to think of Lupron as a train. When you become “castrate resistant” you add other therapies (e.g. immunotherapy, chemotherapy, hormone therapy, radiation therapy) to the train but you never take away the train. Hope that helps. Good luck!

[dress2544 in reply to RyderLake2]

Very good reply. Thanks a lot

[Dan59]

I read this wrong , I thought the Dr said to continue with Lupron with the zytiga. TA is right there is no need for a urologist after you are on hormone therapy.

[dress2544 in reply to Dan59]

Thanks

[Tall_Allen]

That is a perfect example of how ignorant urologists are about medical oncology, and why we should only be talking to MOs when we are managing the disease, rather than trying to cure it. Unless you have urological issues, there is no need to see a urologist anymore.

Lupron and Zytiga do two completely different things. Lupron cuts off the supply of testosterone coming from the testes. Zytiga cuts off the supply of androgens (like testosterone) generated by the adrenal glands, and also prevents the cancer from internally generating its own supply of androgens. It would be foolish to leave the main source of testosterone (from the testicles) while only turning off a minor source of androgens (from the adrenals and the cancer).

[dress2544 in reply to Tall_Allen]

Thank you Tall Allen for your detailed reply. I don't know why the urologist is so ignorant that he doesn't know that zytiga and lupron have different roles in the disease control. I really appreciate your reply explaining the rationale behind continuing lupron with whatever other treatments are added in future for mcrpc. Thank you Tall Allen once again.

[podsart in reply to Tall_Allen]

In terms of the Pca creating its own T, I thought that happens as a result of mutations that occur within the Pca . Are you saying that Zytiga can shut that down regardless of the form of the mutation?

Do you have references Re this phenomenon?

[Tall_Allen in reply to podsart]

Zytiga inhibits the enzymes that are needed to synthesize androgen both in the adrenals and intracellularly. Intracellularly, androgen synthesis is upregulated as the cancer cell mutates.

[podsart in reply to Tall_Allen]

Thanks

So the process that forms zytiga resistance , ARV7 or other splice variant ? , stops this ability or something else?

[Tall_Allen in reply to podsart]

No - that's different. There are about a half dozen different ways we know of that the androgen receptor (AR) mutates to get activated even without testosterone. One way is that it gets shortened so that it no longer needs androgen to get activated. AR-V7 is a shortened version that neither Zytiga nor Xtandi can deactivate.

[podsart in reply to Tall_Allen]

Thanks

[podsart in reply to podsart]

This abstract refers to splice isoform 2 -- so testing for ARV7 is not enough--

Castration-resistant prostate cancer (CRPC) requires tumors to engage metabolic mechanisms that allow sustained testosterone and/or dihydrotestosterone to stimulate progression. 17β-Hydroxyste-roid dehydrogenase type 4 (17βHSD4), encoded by HSD17B4, is thought to inactivate testosterone and dihydrotestosterone by converting them to their respective inert 17-keto steroids. Counterintuitively, HSD17B4 expression increases in CRPC and predicts poor prognosis. Here, we show that, of five alternative splice forms, only isoform 2 encodes an enzyme capable of testosterone and dihydrotestosterone inactivation. In contrast with other transcripts, functional expression of isoform 2 is specifically suppressed in development of CRPC in patients. Genetically silencing isoform 2 shifts the metabolic balance toward 17β-OH androgens (testosterone and dihydrotestosterone), stimulating androgen receptor (AR) and CRPC development. Our studies specifically implicate HSD17B4 isoform 2 loss in lethal prostate cancer.

[Tall_Allen in reply to podsart]

I should add that there is some controversy about this. In a poster presentation at the Hematology/Oncology Pharmacy Association conference some researchers from the University of Minnesota presented the results of a very small (n=57) retrospective study where mCRPC patients either got Zytiga alone (n=10), Zytiga+ADT (n=36), or Zytiga+ADT followed by Zytiga alone (n=11). They found serum testosterone levels were highest (1.9 ng/dL) for Zytiga alone and for Zytiga+ADT followed by Zytiga alone (4.8 ng/dL) and lowest (0.5 ng/dL) for Zytiga+ADT. All of them were very low. What remains unknown is whether that makes a difference in intratumoral testosterone, and whether it translates into a difference in overall survival.

practiceupdate.com/c/66281/...

It will have to wait until late this year or next year before we get the results of a small randomized clinical trial on this subject.

clinicaltrials.gov/ct2/show...

Meanwhile, Zytiga and ADT combined remains the standard of care for mCRPC.

[Raymonda100 in reply to Tall_Allen]

I don’t understand how Lupron continues working if the cancer is considered to be castration resistant.

[Tall_Allen in reply to Raymonda100]

"Castration resistant" only means that achieving castrate levels of testosterone (even below 20 ng/dl) is no longer good enough to prevent the androgen receptor from being activated. Even after it sets in, the cancer continues to be stimulated by testosterone. In fact, one of the ways the cancer uses to keep multiplying is to add a lot more androgen receptors on the cell surface. That means it becomes exquisitely sensitive to even the smallest amount of testosterone. Because of this, it is more important than ever to limit the testosterone available to it.

[leswell in reply to Tall_Allen]

As long as we have you specialists, i.e. you, Patrick, and Nalakrats for starters, we won’t make too many mistakes. It will be Vantas/Zytiga/Prednisone for now. BUT, please, what about the dutasteride and finasteride? To continue or discontinue?

[Tall_Allen in reply to leswell]

I doubt they add anything. With testosterone production so completely blocked by Vantas and Zytiga, there is little need for preventing its conversion into DHT using dutasteride or finasteride.

[leswell in reply to Tall_Allen]

We are still with an MO and urologist/surgeon/prostate cancer specialist. The former agrees to see us for PSA and CBC every three months. The latter has started Leswell on AA+Prednisone. (4 days and running). No side effects but reduced need for narco for bone pain. The Vantas implant is still working (T of 14 and many hot flashes) and will remain until the end of October after which, assuming survival, I think we will opt for 6 month leuprolide injections. Just adding one more case history to this site’s informal “trials”. Mrs. S

[Tall_Allen in reply to leswell]

You might consider orchiectomy rather than Vantas shots

[leswell in reply to Tall_Allen]

A convincing argument. Why fear conversion of T to DHT and E2 given a Vantas/Zytiga/ prednisone blockade. Our MO’s highest recommendation was for orchiectomy. Instead, we chose CAB-5 in the slight hope of a better PSA response and ultimate restoration of some testosterone.

Having arrived at dx with extensive bone metastases, a Nalakrats-like result wasn’t possible. Nor is another surgery since my husband is still recovering from inguinal hernia repair on May 3rd.

These days Les is walking as if he’s Prince Philip’s age instead of 79. (Actually, the grandfather of the groom is walking quite well following HIS surgery.) Les’s pain is from bone cancer, pain for which ibuprofen is insufficient. I wonder how much will be alleviated by Xgeva injections, the first of which will be on June 4th.

Always excellent, realistic suggestions from you—for others if not for us. I think we may try two shots of Lupron per year to avoid another surgical procedure. Our specialist mentioned it as a possibility. That selection would eliminate one of our three urologists, the one who expertly installed the Vantas in about five minutes. He asked first one and then the other of us to be quiet while he concentrated, an image which by now I’m sure many of you can vividly picture.

Our other problem these days is more colon related than urinary. We’re using JH’s recommendations for that “blockade” with a one day out of thirty success rate. My patient is, at present, replacing rusted, leaking plumbing in the basement concrete sinks. At least it’s not blocked. Sincere thanks. Mrs. S

[pjoshea13]

It is tempting to see Zytiga as an add-on, but while Lupron targets gonad production & not the adrenals, Zytiga targets steroidogenesis in general.

Zytiga inhibits CYP17A1. "It is ubiquitously expressed in many tissues and cell types, including the zona reticularis of the adrenal cortex and zona fasciculata as well as gonadal tissues." [1]

"Steroid 17-hydroxylase 17,20-lyase (cytochrome P450c17, CYP17A1) occupies a critical position in the pathways of human steroidogenesis, regulating the classes of steroid hormones produced by cells of the adrenal glands and gonads. CYP17A1 catalyzes two major reactions: the 17-hydroxylase and 17,20-lyase reactions." [2]

-Patrick

[1] en.wikipedia.org/wiki/CYP17A1

[2] sciencedirect.com/topics/me...

[dress2544 in reply to pjoshea13]

Thank you for the informative reply

[dress2544]

Thank you for for your reply.

[auroracham]

I am on Lupron, Zitiga, Prednisone since July 1 2017 diagnosis. Seems to be standard now. Three different opinions all agreed.

[G9doingfine in reply to auroracham]

Why has my MO not suggested anything other that Lupron after radiation ? Should I also request more drugs ?

[larry_dammit]

No disrespect but your urologist doesn’t know cancer as well as your cancer doctor. I liked my urologist but since starting treatment I have asked my cancer doctor several time if I should see him ,his reply is always the same no.