Bipolar androgen therapy [BAT] sensitizes CRPC to subsequent ADT

[pjoshea13]

Sam Denmeade (Johns Hopkins) again [1] (12/28/20). Seems familiar, though.

BAT: "29 patients with CRPC received first-line hormonal therapy with 400 mg of testosterone cypionate intramuscularly every 28 days concurrent with a luteinising hormone-releasing hormone agonist/antagonist."

"After treatment with BAT, four of 29 patients (14% ...) experienced a PSA50 response.

"The median radiographic progression-free survival to BAT was 8.5 months ... for patients with metastatic CRPC.

"After progression on BAT, 17 of 18 patients ... achieved a PSA50 response and 15 of 18 patients ... achieved a PSA90 response on abiraterone or enzalutamide.

"Twelve of 15 patients ... with metastatic CRPC remain on abiraterone or enzalutamide with a median duration of follow-up of 11.2 months."

{I'm still waiting for the BAT study to prevent CRPC. BAT after CRPC is never going to work for everyone.}

-Patrick

[1] pubmed.ncbi.nlm.nih.gov/333...

Eur J Cancer

. 2020 Dec 28;144:302-309. doi: 10.1016/j.ejca.2020.11.043. Online ahead of print.

Bipolar androgen therapy sensitizes castration-resistant prostate cancer to subsequent androgen receptor ablative therapy

Laura A Sena 1 , Hao Wang 1 , Su J Lim ScM 1 , Irina Rifkind 1 , Nduku Ngomba 1 , John T Isaacs 1 , Jun Luo 1 , Caroline Pratz 1 , Victoria Sinibaldi 1 , Michael A Carducci 1 , Channing J Paller 1 , Mario A Eisenberger 1 , Mark C Markowski 1 , Emmanuel S Antonarakis 1 , Samuel R Denmeade 2

Affiliations collapse

Affiliations

1 The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.

2 The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address: [e-mail].

PMID: 33383350 DOI: 10.1016/j.ejca.2020.11.043

Abstract

Background: Cyclical, high-dose testosterone administration, termed bipolar androgen therapy (BAT), can induce clinical responses and restore sensitivity to androgen signalling inhibition in patients with previously treated castration-resistant prostate cancer (PCa) (CRPC). This trial evaluated whether BAT is a safe and effective first-line hormonal therapy for patients with CRPC.

Patients and methods: In cohort C of this single-centre, open-label, phase II, multi-cohort trial (RE-sensitizing with Supraphysiologic Testosterone to Overcome REsistance study), 29 patients with CRPC received first-line hormonal therapy with 400 mg of testosterone cypionate intramuscularly every 28 days concurrent with a luteinising hormone-releasing hormone agonist/antagonist. The primary end-point of the study was the PSA50 response rate to BAT treatment.

Results: After treatment with BAT, four of 29 patients (14%; 95% confidence interval [CI]: 4-32%) experienced a PSA50 response. The median radiographic progression-free survival to BAT was 8.5 months (95% CI: 6.9-15.1) for patients with metastatic CRPC. After progression on BAT, 17 of 18 patients (94%; 95% CI: 73-100%) achieved a PSA50 response and 15 of 18 patients (83%; 95% CI: 59-96) achieved a PSA90 response on abiraterone or enzalutamide. Twelve of 15 patients (80%; 95% CI: 52-96) with metastatic CRPC remain on abiraterone or enzalutamide with a median duration of follow-up of 11.2 months.

Conclusion: As first-line hormonal treatment for CRPC, BAT was well tolerated and resulted in prolonged disease stabilisation. After progression on BAT, patients had favourable responses to second-generation androgen receptor-targeted therapy.

Trial registration: ClinicalTrials.gov NCT02090114.

Keywords: Bipolar androgen therapy; Castration-resistant prostate cancer; RESTORE trial; Testosterone.

Copyright © 2020 Elsevier Ltd. All rights reserved.

Conflict of interest statement

Conflict of interest statement E.S.A. reports being a paid consultant/advisor to Janssen, Astellas, Sanofi, Dendreon, Pfizer, Amgen, Lilly, Bayer, AstraZeneca, Bristol-Myers Squibb, Clovis and Merck; reports receiving research funding to his institution from Janssen, Johnson & Johnson, Sanofi, Dendreon, Genentech, Novartis, Tokai, Bristol Myers-Squibb, AstraZeneca, Clovis, and Merck and he reports being the co-inventor of an AR-V7 biomarker technology that has been licenced to Qiagen.

[cesanon]

"I'm still waiting for the BAT study to prevent CRPC. BAT after CRPC is never going to work for everyone."

Does that mean there is such an ongoing trial. or that you are hoping someone will initiate such a trial?

Or that you think it is plausible that BAT can be used prior to the occurrence of castrate-resistant prostate cancer?

[pjoshea13 in reply to cesanon]

Denmeade no doubt has his own longterm agenda. It would be interesting to see it. So far he is progressing slowly (cautiously?)

pubmed.ncbi.nlm.nih.gov/?te...

-Patrick

[cesces]

What is "ADT1"?

[Schwah]

Nal, could you please restate what you said in “BAT FOR DUMMIES” language so the rest of can fully comprehend ? Greatly appreciated!

Schwah

[Bob10 in reply to Schwah]

Yes Nal

Please explain for us dummies .How long has that work for people with castrate resistant prostate cancer I spoke with Dr. Morgentaler. He’s Willing to do bat he does two months super high testosterone one month off .would love to hear any comments

[cesces in reply to Bob10]

Bob10

If the discussion hasn't helped sort things out for you. Let me know what you aren't getting and I will explain it.

[cesces]

So "BAT/w an ADT1" would mean alternating periods of(1) artificially high levels of testosterone, with

(2) artificially low levels of testosterone.

Correct?

If you do "BAT/w an ADT1" would there be any reason not to do BAT/w an ADT3?

[cesces]

"Waiting for its use with CRPC, is like an Oncologist suggesting Chemo, in late end stage Pca. And yet they do."

So what you are proposing is to start out alternating artificially high testosterone and androgen deprivation. Doing so prior to the onset of castration resistance?

Is that correct?

It seems sort of logical. Though complex biological systems often have their own logic.

Are you aware of any docs or clinical trials that are doing that? Or considering doing that?

[lewicki in reply to cesces]

Does doing BAT limited to those who are not CRPC ?Is the process no ADT one month when in that month high T is used then ADT no T one month continuous? If your ONCO refuses BAT find one that will if and when it is a good idea to do.

[pjoshea13 in reply to lewicki]

Denmeade uses continuous ADT. Not easy to stop non-oral ADT on a dime.

His protocol is to inject T cypionate every 28 days. I use a 2-month cycle to allow T to wash out & to get some benefit from the ADT.

-Patrick

[cesces in reply to pjoshea13]

Pjoshea,

What do think of the proposition of alternating high testosterone with ADT?

[pjoshea13 in reply to cesces]

I have done that for years. The best part of the last 16 years 10 months was when I was alternating 3 months of T > 1,000 ng/dL with 3 months DES. I felt really good for most of the time.

But now I am closer to the BAT schedule.

-Patrick

[middlejoel in reply to pjoshea13]

Patrick, If you were doing so great alternating high T with DES, why did you switch treatment?

[pjoshea13 in reply to middlejoel]

Well, my PSA after 3 months of T was inching up slowly. When it got to 37 I decided to try a more rapid cycle.

What I liked about my approach was 3 whole months of T. With BAT, the shot of T lasts at least a week but not much longer.

With a 2-month BAT cycle at 2mg DES, my PSA was last at 3.0. Nice to be back in single digits.

Best, -Patrick

[Hidden in reply to pjoshea13]

Wondering how you got a doctor to support your BAT regimen. Is he your MO, urologist, or general practitioner? Or integrated medicine type?

[pjoshea13 in reply to Hidden]

I think it might be 14 years ago that I asked my integrated medicine for Androderm, but my urologist has also offered to give me T. I get Diethylstilbestrol [DES] from the urologist, as well as Avodart, etc.

At this point, I have some credibility - the trick is getting started. Mostly that involved conversations & not making demands.

-Patrick

[Hidden in reply to pjoshea13]

Thanks. Could have an interesting conversation coming up.

[lewicki in reply to pjoshea13]

I think there is an ADT that leaves the body in one month starts with a V.

[cesanon in reply to lewicki]

lewicki

Because BAT is so non-intuitive to begin with... and the results to date have been somewhat erratic, patient to patient...

You are not going to find a lot of Docs willing to even consider using it. Any such Docs would almost certainly be ones associated with Denmeade.

Of those, perhaps the most aggressive leaning forward Doc would be Sartor at Tulane. If I were going to do BAT, he is the one that I would go to.

He might even be inclined to consider Nalakrats approach of mixing in some Avodart if it made sense to him.

[cigafred in reply to cesces]

There was one BAT clinical trial By Schweizer at U. of Washington for the castrate sensitive. It was sparse in its conclusions, mainly deciding that BAT was safe in that setting.

[cesces in reply to cigafred]

Thanks. Very very interesting.

[cesanon]

hmmm

You are saying use Avodart, DURING the High Testosterone Cycle?

That's interesting. That's very very interesting.

Have you seen or heard of anyone else suggesting or even toying with such an idea?

[noahware]

Regarding the questions and comments on whether BAT could or should be attempted before one becomes castrate resistant (CR): the prevailing standards of care virtually INSIST that you must first fail the mainstream meds (Lupron, etc.) before you pursue next steps. The "rules" may be unwritten, but those are the rules of the game.

If BAT appeals to an individual as worth the risk, it seems entirely logical and practical to try and pursue a BAT protocol PRIOR to reaching CR status. But good luck trying to find 1) a doc to work with you, and 2) an insurer to fund you.

For the foreseeable future, pre-CR modes of BAT will remain mostly in the realm of a DIY treatment or (eventually) clinical trials.

[pjoshea13 in reply to noahware]

Testosterone cypionate is easy to come by & not very expensive (insurance has stopped paying for mine this year - no big deal.)

I have been open with my docs. What I have seen is sympathy for a patient who has failed "curative" therapy & is otherwise going to be dead in a few years. I have a doctor who will now write me a script for anything that I ask for, within reason.

99.9% of his patients are content with the protocol" "First I give them ... & when that fails I give them ... " etc. Still a sequential approach for most.

-Patrick

[MateoBeach in reply to pjoshea13]

Can you message me with how to get the T cypionate please?

[Dmwalker in reply to pjoshea13]

How is it "easy to come by" if one can't find a doc who will prescribe it?

[pjoshea13 in reply to Dmwalker]

Try Googling <testosterone online prescription>. My understanding is that many in the U.S. are bypassing their doctors.

[Schwah]

I guess the part that confuses me is:

“The metabolism, starts by T going to DHT. DHT is not a friend to those with Pca. The AR will be very attracted to DHT.”.

I know what T is and “PCA. I am not clear on the DHT and AR are, and how they interact relate to your prostate cancer.

Schwah

[MateoBeach in reply to Schwah]

This explains why. You are cyclically disadvantaging CR cells from emerging and becoming predominant. nature.com/articles/s41467-...

[MateoBeach]

Agree with need for BAT trial in HS PC. When my PSA next progresses I am going to do a one month cycle of high T when ADT is restarted. Even if I have to use E2 topical without MO approval, then check PSA response. If favorable (small and not progressive increase in PSA) then I may consider repeating this every 3 to 6 months. Uncharted territory. There may be dragons.

[Bob10]

Yes

[cesces]

Does anyone know what Tall_Allen's views are on this topic?

He seems to be missing from the discussion.

[kaptank in reply to cesces]

TA in his other guise wrote some useful summaries in 2016 ( 2 parts) and kept up to date.

prostatecancer.news/search/...

[Hope59]

There’s a new trial at Hopkins that is not yet recruiting with BAT and Radium 223 that sounds interesting:

clinicaltrials.gov/ct2/show...