Bipolar Androgen Therapy [BAT] & CRPC - Sam Denmeade, Hopkins.

[pjoshea13]

Presentation at the 20th Annual Meeting of the Society of Urologic Oncology (SUO), Dec 04 - 06, 2019 in Washington DC.

Use the link to see the four slides. -Patrick

urotoday.com/conference-hig...

Note that tumors are in the castration state for a very short period & maybe a longer cycle would be better. Men are at supraphysiological T levels briefly, & growth-promoting T levels for much of the cycle. They barely reach castration before the next T shot.

"SUO 2019: Bipolar Androgen Therapy for Men with Castration Resistant Prostate Cancer

Washington, DC (UroToday.com) As part of the SUO 2019 advanced prostate cancer session, Dr. Samuel Denmeade discussed his work with bipolar androgen therapy (BAT) for men with castration resistant prostate cancer (CRPC). Dr. Denmeade reminds us that metastatic prostate cancer remains an incurable disease, with a median overall survival in the CRPC state of three years. The mainstay of treatment is androgen deprivation therapy (ADT), however it is associated with many side effects:

Depression

Decreased muscle mass

Breast enlargement

No libido/sexual impotence

Decreased bone mass

Abdominal fat

Fatigue

Lack of focus

One of the main challenges of treating advanced prostate cancer is the development of resistance with each subsequent line of therapy. For example, enzalutamide in PREVAIL had a PSA progression-free survival of only 11.2 months. According to Dr. Denmeade, there are three phases of androgen inhibition: shock, adaptation, and resistance. The shock phase is when there is androgen receptor activity inhibition, which is followed by adaptation, namely androgen receptor overexpression, gene amplification, and development of ligand-independent androgen receptor variants.

The hypothesis for BAT is that men with CRPC could respond to rapid cycling between polar extremes of supraphysiologic and castrate testosterone levels, whereby rapid cycling disrupts adaptive autoregulation of the androgen receptor. Adaptive downregulation of the androgen receptor expression may re-sensitize CRPC to androgen ablative therapies. Schematically, BAT is as follows:

SUO2019_Denmeade_1.png [see link]

Dr. Denmeade’s group conducted the RE-sensitizing with Supraphysiologic Testosterone to Overcome Resistance (The RESTORE Study), which the schema is as follows:

SUO2019_Denmeade_2.png [see link]

In the post-enzalutamide patients, the >50% PSA response was 30%, any PSA decline was 51%, the median progression free-survival was 8.6 months, and the objective response rate after 3 cycles of BAT was 43%.1 Additionally, 71% of patients with a >50% decrease in PSA had a median duration response of 4.8 months.

Dr. Denmeade’s group subsequently designed the TRANSFORMER phase II trial:

SUO2019_Denmeade_3.png [see link]

For the initial response results, progression free survival and objective response rate were comparable between the BAT and enzalutamide arms were comparable, however the time to PSA progression favored the enzalutamide arm (3.8 vs 2.8 months; p=0.012). For the crossover response results, objective response favored enzalutamide (28.6% vs 8.1%, p=0.045), as did time to PSA progression (10.9 vs 1.2 months, p=0.0005). Finally, BAT + enzalutamide sequencing increases overall progression free survival (PFS2):

SUO2019_Denmeade_4.png [see link]

Dr. Denmeade concluded with several take home points:

Pharmacologic testosterone (BAT) can be given safely to asymptomatic men with castration-resistant prostate cancer

Objective response and PSA response were observed in some men

BAT may re-sensitize CRPC to androgen ablative therapies

BAT improves quality of life in some men

Presented by: Samuel Denmeade, Co-Director Prostate Cancer Program, Professor of Oncology, Johns Hopkins Hospital, Baltimore, Maryland

Written by: Zachary Klaassen, MD, MSc – Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, Twitter: @zklaassen_md at the 20th Annual Meeting of the Society of Urologic Oncology (SUO), December 4 - 6, 2019, Washington, DC

References:

Teply BA, Wang H, Luber B, et al. Bipolar androgen therapy in men with metastatic castration-resistant prostate cancer after progression on enzalutamide: An open-label, phase 2, multicohort study. Lancet Oncol 2018;19:76-86.

TAGS: Bipolar Androgen Therapy (BAT)"

[dockam]

Thanks for this. About to start either Zytiga/prednisone or Xtandi and will have BAT as a follow up when it fails

Fight On Brothers

[cesces]

Sartor at Tulane believes it makes sense to just go straight to high doses of testosterone without flipping back and forth.

[pjoshea13 in reply to cesces]

Within 2 years after diagnosis, I raised my T above 1,000 ng/dL - full-time - for a few years. Finally switched to 3 months high T followed by 3 months castrate. Very high QoL with that. Switched to a version of BAT last year. Developed leg pain which increased over 5 cycles, but went away when I shifted to a 2-month BAT cycle. Full-time T is definitely not an option for me these days.

-Patrick

[cesces in reply to pjoshea13]

I assumed that he was still intending it to stop it at some point.

Once it has done its job.

[pjoshea13 in reply to cesces]

He has a 2017 paper:

Prostate-specific Antigen Response and Eradication of Androgen Receptor Amplification with High-dose Testosterone in Prostate Cancer. [1]

No Abstract. Using T to reverse AR amplification (which is a common response to very low T).

And this new study:

High-Dose Testosterone and Radium-223 Response in Metastatic Castration-Resistant Prostate Cancer. [2]

Also no Abstract.

-Patrick

[1] ncbi.nlm.nih.gov/pubmed/280...

[2] ncbi.nlm.nih.gov/pubmed/315...

[sammamish in reply to pjoshea13]

After 2 years of straight high T did you PSA start to rise?

Also why did you move away from 3 months on 3 months off?

[pjoshea13 in reply to sammamish]

My PSA was constant for 6 months while on T, but rose when I started to inject B12. I stopped the B12, but PSA continued to rise slowly. PSADT was ~24 months at that point. I switched to the 3 month cycle when the PSADT became <12 months.

On the 3 month cycle, my PSA rose to about 35 after 3 months of T. I would knock it down & it would bounce back to ~35.

Eventually, coming up to 15 years, I decided to become more aggressive & started BAT.

My version of BAT (which took me months to fine-tune) is to inject T on day 1 of month one & start 2mg DES on day 8 through the end of month 2.

-Patrick

[sammamish in reply to pjoshea13]

So the first 2 years was just High T injections every month with no

ADT, correct?

Then 3 months of T injections followed by about 3 months of no T and still no ADT?

Then later T injection followed by ADT(DES) then repeat after two months?

[pjoshea13 in reply to sammamish]

Actually, when I finally got up the nerve, I started out with continuous androstendione, a T precursor. I had almost a 2 year supply (it had been otc but was then banned when I started to use it.) When I was about to run out, my alt-doc prescribed 5mg Androderm patches (highest dose, which the company later reduced to 4mg.) I was on Androderm for more than a year before I felt the need to switch to 3 months on/off. During the off period, I used a product that used to be called Prostasol but had been renamed Quercetin Plus [Q+]. When I began using it, the creator, Dr. Dosbach, was in legal difficulties in CA & the product was no longer effective. But I had a supply of the last effective batch. It may have contained DES, but men had been using it for years without becoming resistant.

When I was about to run out, I obtained a prescription for DES & started using it earlier this year.

I switched to injections after many years when my insurance announced that they were going to make it more difficult to get the expensive patches. T Cypionate is cheap.

-Patrick

[vandy69 in reply to cesces]

Sartor did that to me with self applied AndroGel. T went up, but PSA more than doubled in 1 1/2 months. Two months later, I had 20+ lesions in liver. Coincidence?

Best Wishes. Never Give In.

Mark, Atlanta

[sammamish]

Patrick,

I wonder if there are any studies or clinical reports out there with folks in the Hormone sensitive phase of the disease?

[pjoshea13 in reply to sammamish]

As far as I know, the most important study, IMO, has yet to be done - starting BAT at the same time as ADT, so that the cancer never has a chance to adequately adapt to T deprivation.

There was a Denmeade study with BAT "following a 6-month ADT lead-in":

ncbi.nlm.nih.gov/pubmed/273...

-Patrick

Here are 6 papers by Denmeade:

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

[Rkoma]

Patrick,

according to different trials 200mg injection keeps testosterone in supraphysiological area for 1 week and the remaining 2-3 weeks in the normal area, what is not good.

Would starting topical application ( patch or gel) around day 5 and stopping around day 20 help to have steep high- low change of testo level. This should work because, 24h after stopping gel application, testo goes back to the baseline value.

The other question is: would waiting some time (2-3 weeks) until castration level has been reached be better than one injection every 4 weeks.

Regards

Rkoma

[pjoshea13 in reply to Rkoma]

I had leg pain for the first 6 months of last year. A bone scan showed nothing that might cause it. It was my regular doctor who eventually got approval for an MRI of the lumbar region, but it showed nothing that could cause the pain. My radio-oncologist sent me a top neuro-spine guy, who said that my spine looked really good for my age, & the pain must be due to cancer. He ordered an MRI of the sacrum, but it was denied. My radio-oncologist then ordered another bone scan, which I thought was a waste of time.

The 2nd scan showed the tiniest white spot at S1.

Meanwhile, I had decided to go to a 2 month cycle. On the 3rd day of the 2nd month, the pain was less & quickly went away, The radio-oncologist said that he could radiate S1, but I might want to keep that in reserve. He thought that I finally had the cancer under control.

I'm happy with 2 month cycles. It's important that the time being castrate balance the time of T restoration. I unwittingly used trial & error. I could have spent a small fortune testing T & PSA repeatedly, but I didn't. I assumed that I was castrate for a significant part of the month & I clearly wasn't.

Those interested in BAT should realize that the basic formula might need to be tweaked.

-Patrick