Abiraterone acetate with/out LHRH therapy.

[pjoshea13]

New German paper below [1], announcing a clinical trial.

"The trial will assess radiographic progression-free survival after 12 months of treatment with abiraterone/prednisone in patients who will be randomized to receive continuing LHRH therapy versus LHRH withdrawal at the time of starting abiraterone therapy."

CRPC is not a failure of the ADT drug, if testosterone continues to be castrate.

If the cancer continues to be dependent on androgen (usual case), CRPC is due to other sources having become available. Zytiga (Abiraterone acetate) inhibits one such source. It is an ADT extension - not an alternative therapy.

"The value of continuation of luteinizing hormone-releasing hormone (LHRH) therapy in castration-resistant prostate cancer (CRPC) remains controversial and clear evidence is lacking." ???

"... the proven increase of luteinizing hormone levels after LHRH withdrawal, which is even further increased by abiraterone, may counteract the effects of abiraterone by the induction of enzymes of steroidogenesis."

"Therefore, cessation of LHRH therapy when starting treatment with abiraterone in CRPC may display an unpredictable hazard to the patients."

You never know until there has been a clinical trial, but I wouldn't sign up.

It's a new paper but the trial was registered a few years ago [2]. It is still recruiting.

-Patrick

[1] ncbi.nlm.nih.gov/pubmed/289...

Trials. 2017 Oct 4;18(1):457. doi: 10.1186/s13063-017-2195-x.

Abiraterone acetate plus LHRH therapy versus abiraterone acetate while sparing LHRH therapy in patients with progressive, metastatic and chemotherapy-naïve, castration-resistant prostate cancer (SPARE): study protocol for a randomized controlled trial.

Ohlmann CH1,2, Jäschke M3, Jaehnig P4, Krege S5,6, Gschwend J7,6, Rexer H6, Stöckle M3.

Author information

1

Department of Urology, Saarland University, Kirrbergerstrasse, 66421, Homburg/Saar, Germany. [e-mail].

2

Working Group on Urological Oncology (AUO), Germany Cancer Society, Berlin, Germany. [e-mail].

3

Department of Urology, Saarland University, Kirrbergerstrasse, 66421, Homburg/Saar, Germany.

4

PJ statistics, Berlin, Germany.

5

Department of Urology, Klinikum Essen Mitte, Essen, Germany.

6

Working Group on Urological Oncology (AUO), Germany Cancer Society, Berlin, Germany.

7

Department of Urology, Klinikum Rechts der Isar, Technical University Munich, Munich, Germany.

Abstract

BACKGROUND:

The value of continuation of luteinizing hormone-releasing hormone (LHRH) therapy in castration-resistant prostate cancer (CRPC) remains controversial and clear evidence is lacking. Argumentation for cessation of LHRH therapy is the prolonged suppression of testosterone levels after the withdrawal of LHRH analogues and the fact that disease progression occurs despite castration levels of testosterone. Especially upon treatment with the life-prolonging cytochrome P450 17-alpha-hydroxylase (Cyp17)-inhibitor, abiraterone, which has the ability to further suppress testosterone serum levels over LHRH therapy alone, continuation of LHRH therapy seems to be negligible. However, the proven increase of luteinizing hormone levels after LHRH withdrawal, which is even further increased by abiraterone, may counteract the effects of abiraterone by the induction of enzymes of steroidogenesis. Therefore, cessation of LHRH therapy when starting treatment with abiraterone in CRPC may display an unpredictable hazard to the patients. This study will explore the role of continuation of LHRH therapy when starting treatment with abiraterone in patients with asymptomatic or mildly symptomatic, chemotherapy-naïve CPRC.

METHODS/DESIGN:

The trial will assess radiographic progression-free survival after 12 months of treatment with abiraterone/prednisone in patients who will be randomized to receive continuing LHRH therapy versus LHRH withdrawal at the time of starting abiraterone therapy.

DISCUSSION:

This multicenter, prospective, randomized, exploratory phase-II trial will bring about new data regarding the efficacy and safety of abiraterone/prednisone treatment with or without continuation of LHRH therapy. In addition, further insight into the complex hormonal changes under treatment will be gained and the results of this trial may give rise to a larger phase-III trial to examine the possibility of withdrawing LHRH therapy in patients with CRPC.

TRIAL REGISTRATION:

ClinicalTrials.gov, ID: NCT02077634 . Registered on 9 December 2013.

KEYWORDS:

Abiraterone; Castration-resistant prostate cancer; LHRH therapy; Luteinizing hormone; Testosterone

PMID: 28978327 DOI: 10.1186/s13063-017-2195-x

[2] clinicaltrials.gov/ct2/show...

[AlanMeyer]

I'll be curious to see the results of that trial. I assume that PSA results should be available within a few months of the start of treatment. Long term disease progression, naturally, will take longer.

When I first read about abiraterone I was under the impression that it interrupts the pathway that ALL sources of testosterone utilize. So I thought that it would also block production of T in the testicles. But it looks, from this trial idea, that the experts may not think that's 100% true and may also think that other effects of the drugs may interfere with or reinforce each other.

Alan

[pjoshea13 in reply to AlanMeyer]

Alan,

In theory, if Zytiga were an efficient CYP17A1 inhibitor, we would have no steroid hormones below pregnenolone/progesterone in the steroidogenesis cascade. I suppose that it must be only partially effective at the maximum safe dose, since the ADT drug is always continued - thus far.

The following statement seems strange to me:

"Argumentation for cessation of LHRH therapy is the prolonged suppression of testosterone levels after the withdrawal of LHRH analogues and the fact that disease progression occurs despite castration levels of testosterone."

The first part is OK. Dr Freedland has pointed out that the IADT off period is largely a continuation of castration for quite a while in most men. It takes many months for T to recover, & usually not to the previous high.

But the second part seems to miss the point of Zytiga, which is to further deprive the cancer of androgen. Why then permit any T recovery at all?

-Patrick

[BigRich]

From your comment. I am led to believe that you are not taking Zytiga.

Rich

[AlanMeyer]

Nal,

It looks like Zytiga is both an AR receptor blocker and CYP17A1 enzyme inhibitor, i.e., it inhibits an enzyme that is required for one of the steps in the conversion of steroidal precursors to testosterone to T itself. See: en.wikipedia.org/wiki/Abira... and related wiki pages for more. The wiki page includes the statement that: "Abiraterone acetate, via its metabolite abiraterone, has the capacity to lower circulating testosterone levels to less than 1 ng/dL (i.e., undetectable)." Looks like a pretty powerful inhibitor of T biogenesis.

[AlanMeyer]

I was once tempted to think that ADT has reached its limits and that further research should focus on other ways to stop the cancer, like immunotherapies and targeted therapies. But I think it's actually pretty clear that we haven't reached the limits of ADT research.

The fact that PCa usually continues to progress after some time on Zytiga and Xtandi begs the questions of how and why. Is Zytiga failing to cut off every molecule of testosterone biosynthesis - in which case there may be something we can do to enhance its effectiveness? Is Xtandi failing to block the import of every molecule of T into the nucleus - in which case there may be something we can do to enhance its effectiveness? Or are the tumors evolved to not require any T at all in order to continue replicating - in which case we want to know what mechanism they are using in the absence of T and how can we attack that mechanism?

I don't know nearly enough to make any recommendations for what the scientists should be researching, but I'm thinking that there is still critical basic research that needs to be done before we solve all the problems of hormone therapy. But in the meantime, lets keep up the research into immunotherapy and targeted therapy. Who knows, maybe right now someone is gazing into his microscope at an out and out cure for PCa.

Alan

[BigRich in reply to AlanMeyer]

Alan,

Google the drug Niclosamide, for off label use in inhibiting Xtandi resistant tumor growth.

Rich

[AlanMeyer in reply to BigRich]

Wow!

These researchers appear to have found at least one mechanism that PCa tumor cells can use to import testosterone in spite of Casodex or Xtandi blocking of regular androgen receptors AND they've got a way to fight it.

That looks like a real advance.

Alan

[BigRich in reply to AlanMeyer]

Alan,

I agree with you.

Rich

[BigRich]

I will be meeting with my two MOs on different days. Then, I will decide on going on Zytiga. I am leaning to go on this drug while staying on Lupron.

Rich

[BigRich]

Brother,

I have only asked for help in crucial times in my life. God in Heaven has always saved me.

Rich

[Dan59]

I believe answered prayers is the only reason, I am still alive, well said Nalakrats.