Androgen Receptor [AR] Axis Therapies

[pjoshea13]

Some thoughts on AR-axis therapy (androgen deprivation & AR antagonists) after reading a new assessment of the benefit of second-line drugs [1].

In a sense, I view myself fortunate to have been diagnosed in 2004. When surgery [RP] was not successful (nor salvage radiation) it was suggested that I begin ADT, but there was nothing appealing about premature use of Lupron. Indeed, it seemed reckless to begin palliative treatment before palliation was required, given its miserable mean time to failure [CRPC].

So I used PubMed study papers to navigate my way through the years. (Yes, I took epidemiolgical studies seriously.)

Along the way. it was discovered that "androgen-independent" PCa was really "castrate-resistant", since the androgen receptor [AR] continued to be involved in progression. I knew what this meant - BigPharma was going to stick with Charles Huggins [2] & eliminate all cholesterol-based steroid hormones. Abiraterone targets all hormones south of progesterone & pregnenolone.

As Abi & Enzalutamide emerged, with others in the pipeline, Dr. Myers seemed visible excited at the prospect of having so many options after years of nothing new. There were sceptics who pointed out that the benefit seemed to be months rather than years.

And treatment-emergent resistance appeared to be more difficult to manage than classic CRPC, which is difficult enough. So Lupron, Abi & Enza remain in my future at this point.

The new paper is titled:

"Marginal improvement in survival among patients diagnosed with metastatic prostate cancer in the second-line antiandrogen therapy era"

"Collectively, our observation suggests that despite the new treatment agents such as second-line antiandrogen therapies introduced in the modern era, the improvement in survival of metastatic prostate cancer patients has been surprisingly small."

It's wonderul, of course, that this group includes a number of men who have survived years on Abi or Enza, but the Huggins era should have ended years ago.

-Patrick

[1] pubmed.ncbi.nlm.nih.gov/347...

pubmed.ncbi.nlm.nih.gov/347...

Cancer Med

. 2021 Oct 29. doi: 10.1002/cam4.4074. Online ahead of print.

Marginal improvement in survival among patients diagnosed with metastatic prostate cancer in the second-line antiandrogen therapy era

Isaac E Kim 1 , Thomas L Jang 2 , Sinae Kim 3 , David Y Lee 2 , Daniel D Kim 1 , Eric A Singer 2 , Saum Ghodoussipour 2 , Mark N Stein 4 , Monish Aron 5 , Marc A Dall'Era 6 , Isaac Yi Kim 2

Affiliations collapse

Affiliations

1 Warren Alpert Medical School, Brown University, Providence, RI, USA.

2 Section of Urologic Oncology, Rutgers Cancer Institute of New Jersey and Division of Urology, Rutgers Robert Wood Johnson Medical School, The State University of New Jersey, New Brunswick, NJ, USA.

3 Department of Biostatistics and Epidemiology, Rutgers School of Public Health, The State University of New Jersey, Piscataway, NJ, USA.

4 Department of Internal Medicine, Division of Medical Oncology, Columbia University, New York, NY, USA.

5 Department of Urology, University of Southern California, Los Angeles, CA, USA.

6 Department of Urologic Surgery, University of California Davis, Sacramento, CA, USA.

PMID: 34713977 DOI: 10.1002/cam4.4074

Abstract

Since 2004, multiple blockbuster drugs have been approved for men with metastatic prostate cancer. Nevertheless, it has been reported that no improvement in survival was observed between 2004 and 2009. Herein, we have analyzed the SEER database to assess the survival outcome of metastatic prostate cancer patients since 2000. The results demonstrated that there was an improvement in both overall and prostate cancer-specific survival for 4 months among men diagnosed with metastatic prostate cancer from 2010 to 2016 when compared to those in the pre-2010 period. Interestingly, this survival benefit was limited to patients with bone and visceral metastasis (M1b and M1c stages). Collectively, our observation suggests that despite the new treatment agents such as second-line antiandrogen therapies introduced in the modern era, the improvement in survival of metastatic prostate cancer patients has been surprisingly small.

Keywords: M1 prostate cancer; metastatic prostate cancer; second-line antiandrogens; survival.

© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

References

REFERENCES

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Virgo KS, Basch E, Loblaw DA, et al. Second-line hormonal therapy for men with chemotherapy-naive, castration-resistant prostate cancer: American Society of Clinical Oncology Provisional Clinical Opinion. J Clin Oncol. 2017;35:1952-1964.

Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004;351:1502-1512.

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de Bono JS, Oudard S, Ozguroglu M, et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet. 2010;376:1147-1154.

Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363:411-422.

de Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011;364:1995-2005.

Scher HI, Fizazi K, Saad F, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012;367:1187-1197.

Virgo KS, Rumble RB, Singer EA. Second-line hormonal therapy for men with chemotherapy-naive castration-resistant prostate cancer: american society of clinical oncology provisional clinical opinion summary. J Oncol Pract. 2017;13:459-461.

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Schweizer MT, Zhou XC, Wang H, et al. The influence of prior abiraterone treatment on the clinical activity of docetaxel in men with metastatic castration-resistant prostate cancer. Eur Urol. 2014;66:646-652.

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***

[2] en.wikipedia.org/wiki/Charl...

[davenj]

PJ, What treatments have you used since 2004? Thanks

[Schwah]

What you seem to be discounting pjoshea, is the early use of these drugs (like Zytega) along with ADT at the initial diagnosis of hormone sensitive metastatic PC. Multiple phase 3 trials have noe shown years of extended life as opposed to mere months that were being tallied on patients that were already Castrate resistant. Are you suggesting that holding off on all of these drugs for newly diagnosed metastatic men will extend their lives?

Schwah

[pjoshea13 in reply to Schwah]

My issue has been with the obsession with the AR-axis, starting with classic ADT.

The LATITUDE [2] study paper of 2019 reported that:

"Overall survival was significantly longer in the abiraterone acetate plus prednisone group (median 53·3 months ... than in the placebo group (36·5 months ...)" ... i.e. +16.8 months.

In other words, for a newly-diagnosed guy with high-risk mPCa, median survival is 3 years with Lupron & almost 4.5 years with Lupron+Abi. For someone in his 50's, say, both are scary numbers. The prospect of being gone within 5 years must be terrifying.

Following Huggins castration research to its logical scorched-earth conclusion, with all of its ensuing morbidity, has not resulted in the stunning benefits many had hoped for.

-Patrick

[dhccpa]

Good info. That's been my own reading of it in my layman's mind. You'll get some machine gun fire for that one.

[Spyder54]

PJ,Can you explain to the group what you have done for these 15 years (or is it 17 years) to avoid Castration Resistance? You are obviously very well read and above average intelligence.

How serious was your Dx, what surgery, what radiation?

We all hate the side effects of this chemical barrage of multi level ADT. But we are all trying to survive. I’m trying not to make mistakes, but it would be a huge quality of life improvement to find a solid alternative to Big Pharma’s castration answer to Charles Huggins.

Thanks,

Mike

[pjoshea13 in reply to Spyder54]

Hi Mike,

Well, it turns out that testoterone has been a constant thread - but for changing reasons,

The first thing I learned about the AR was that it is 'wild-type' in the untreated male, whereas the estrogen receptors ERalpha & ERbeta are much changed at an early date.

So, having failed primary treatments with nothing attractive remaining, I decided to try continuous high-normal T + low-normal E2 (estradiol). It worked for a number of years. The key here is "untreated" (no ADT)

But I was following other paths too. Inhinition of NF-kB which also inhibits inflammation. My advice is to take a lot of polyphenols (natural plant protectors) & monitor albumin & CRP. Inflammation is a killer.

I was late to the party regarding coagulation, but it plays an important role in metastasis. Even when mets are present, blood clots should be inhibited. Monitor D-dimer & use nattokinase.

etc.

I have reported on many potentially useful areas the past 6 years, but there are now a ton of posts. Google <PJOShea13> with a subject in the search for something specific.

-Patrick

[Spyder54 in reply to pjoshea13]

Thank you Patrick. I remember you posting a piece that basically agreed with Learn All below,That ADT2 takes care of the less difficult cells leaving the more difficult cells remaining to divide & multiply leaving a larger abundance of growing, and more difficult cells along with Castration Resistance.

Do you still believe this to be happening? If yes, then it would seem imperative we find alternative ways to extend castration sensitivity, maybe with BAT or mBat, or your combo of High -Normal T with a normal-low estradiol patch (E2).

Curios for someone similar to me having been on ADT for 10-14 mos, but not yet resistant. To stop and basically change directions, must be different than you running out of options and exploring less travelled waters?

Mike

[pjoshea13 in reply to Spyder54]

Mike,

With classic ADT, the old studies note an increase in androgen receptor [AR] protein. & there are phrases such as "AR gene amplification" to explain "hormone-refractory prostate cancer".

With the newer AR-axis treatments we see references to the ligand-independent splice variant AR-V7, and also cells morphing to become stem-cell-like (they don't need AR at all).

A small tumor consists of a tremendous number of cells dividing at a fast rate. It's easy to see how the cancer might adapt over a couple of years. Fast-track Darwinism.

Normal tissue has mechanisms for triggering cell death in defective cells, but also for protecting cells when the tissue comes under bacterial or viral assault. Common adaptations in cancer include the permanent turning off of tumor-suppressor genes (e.g. via hyper-methylation in PCa) and the permanent activation of nuclear factor kappaB [NF-kB]. At the very least, AR-axis therapy should come with drugs that block the escape paths. e.g. a demethylation drug & a NF-kB inhibitor.

-Patrick

[LearnAll]

I am convinced that Continuous, combined androgen suppression lead to treatment emergent Androgen Resistant cancer cells and worse..It leads to Neuro Endocrine Cancer cells. They..the masters of onco universe do not want to tell this...also do not want men to know that certain foods, herbs and daily intense exercise can delay castration resistance and keep simple treatments working longer. Just Bicalutamide 50 mg a day kept me fine for over a year with almost zero side effects except very mild Gynecomastia.(not noticeable)

[Hidden]

What would replace the Huggins era treatments? I'm all for new and better treatments. With the emergence of biotech firms over the last 20 years, one would have thought the Huggins Era replacement would have emerged. But it hasn't. I don't believe Big Pharma is in the way is an adequate explanation given the explosion of new treatments in all areas of disease by the biotech community.In the end, and this will sound obtuse, it's a numbers game. How much will anyone invest in a treatment for a relatively small population of men...particularly older men.

[pjoshea13 in reply to Hidden]

A tremendous amount of research time has gone into the development of Abi, Enz & newer AR-axis therapies. & the trials involving those drugs occupy the time of the best PCa talent. If it had turned out that ADT-refractory PCa was indeed androgen-independent, the money & time would have followed other leads.

I was born in 1948 & diagnosed early (2004) so witnessed the exponential publication of PCa papers on PubMed. PCa was evidently viewed as a big growth area. We are not a small population. Dr. Myers once complained of the ageism that American men face (I haven't seen that yet), but there is plenty of money to be made from old guys. Medicare will pay handsomely for most things.

There are over three million U.S. men living today who once has a PCa diagnosis. Not a small population.

True, the advanced PCa sector is relatively small, but BigPharma is now making a play for the big non-metastatic population. They will milk the AR-axis for years to come.

-Patrick

[pablojaes]

So if I undertand correctly, once your PSA starts going up on Lupron and you receive the glorious stamp of castrate resistant is not worth to add any of the “new” drugs as eventually they will only prolong survival for a few months? ( plus the additional side effects, as Lupron is to be continued). I was offered Darulotamide and I am hesitant. My PSA is slowly going up ( now at 0.03 after month to years of undetectable). Gleason 9, mets to lungs found 3 years ago. Intial dx 9 years. Treated with Rx and ADT from 2012. Took a “vacation” for 18 nice months from 2015 to 2017 but then mets appeared. And Lupron was resumed with resolution of lung mets. MSK. Opinions welcomed. Pablo

[pjoshea13 in reply to pablojaes]

The results of the first Phase 3 trial of Abiraterone were published 10 years ago [1]. The cohort consisted of men with CRPC who had received chemo (Docetaxel) but experienced progression. There were some health-related exclusions, so these were guys who were otherwise in good shape.

Note that both arms (Abi & placebo) also received prednisone.

"After a median follow-up of 12.8 months, overall survival was longer in the abiraterone acetate–prednisone group ... (14.8 months vs. 10.9 months ..)"

"... time to PSA progression (10.2 vs. 6.6 months ...)"

"... progression-free survival (5.6 months vs. 3.6 months ...)"

So yes, to answer your question, waiting until one has CRPC before adding Abi to Lupron, might not add many months to survival.

But starting Abi when diagnosed with high-risk metastatic PCa is a different matter.

In the LATITUDE [2] study:

"Overall survival was significantly longer in the abiraterone acetate plus prednisone group (median 53·3 months ... than in the placebo group (36·5 months ...)" ... i.e. +16.8 months

This was published in 2019, whereas the analysis I cited stopped with men diagnosed in 2016.

-Patrick

[1] ncbi.nlm.nih.gov/pmc/articl...

[2] pubmed.ncbi.nlm.nih.gov/309...

[pablojaes in reply to pjoshea13]

Thank you Patrick. I am aware that if diagnosed today it would be beneficial to use 2 drugs. Too late for that in my case. However, my survival has been better than expected given the aggresiveness .of my Gleason 9. Thanks to Lupron? Who knows…

[Break60]

Yes I never went for the second level drugs and instead had SBRT to bone mets and dropped Lupron in favor of estradiol. So 8 1/2 years after diagnosis with Gleason 9 stage t3b I’m still going strong . I chalk it up to low volume Pca and oligomets in a bone here and there. My last mets were in 2018. Lucky I guess.

[lcfcpolo]

Hi Patrick. You write really eloquently and are spot on about us guys in their 50s. I am one of these. Put on quarterly PROSTAP and Enzalutamide, am M1, have spread to 8 bone Mets and to lymph nodes. So no surgery or radiation offered. Basically no other options offered by Oncologist. Just waiting for Enzalutamide to fail!

I have a reply from you earlier in the year regarding BAT, which is difficult to get supported in the UK. Do you have a view on how to remain hormone sensitive for longer, is it BAT or any other options? Thank you for posting. Graham

[pjoshea13 in reply to lcfcpolo]

Hi Graham,

I just received my latest PSA result. I had to do 3 months of ADT in the last cycle, since PSA was 'high' a month ago (4.6), but as of yesterday was 3.1 (my target is 3.0-3.4). Just as well, since I injected testosterone after the blood draw - I refuse to do more than 3 months of ADT without T.

I do have mets, but it seems that I remain castrate-sensitive. While my n=1 study is anecdotal, it does offer proof of concept of the durability of a BAT-like approach, I believe.

My doctors know what I do, & certainly support me, but I decide when to inject. If I couldn't get a T script from one of my doctors, I would explore the TRT sites. I believe that T scripts are easy to get hold of.

Do I know of anything else for hormone sensitivity? No. With T deprivation, it is only the periodic restoration of T that will reverse adaptation. IMO

-Patrick

[lcfcpolo in reply to pjoshea13]

Thank you Patrick. I really appreciate you taking the time to reply. I will discuss with my Oncologist in December. I think that by holding your nerve with a PSA in the 3s is very interesting and could be why you have had so much success. Long may it continue Sir.

[GP24]

Dr. Mohler made an overview of the available drugs for CRPC and the extend they prolong OS: up.picr.de/42361752ms.png This slide is from this presentation:

youtube.com/watch?v=xY5cqLM...(Not working as expected?)

youtube.com/watch?v=xY5cqLMRA_g

His conclusion is that if you take all available drugs you extend your OS by 23.3 months. Nobody will be able to take these in sequence though. The slide is not up to date but I think there will be a cross-resistance between Abiraterone, Enzalutamide, Apalutamide and Darolutamide. So you cannot add up the OS extension these drugs have shown.

[Hidden]

I was a fool and drank the ADT Koolaid. Added Erleada after 4 months of Eligard and went to undetectable in several months. Held like that for a year and a half then "KABOOM" -- PSA went to 0.1 and three months later, 0.2. Doesn't sound like much but when I followed up with a CT scan, the stunning result was two lungs with "innumerable" cancer nodules. I got that present on Xmas eve day of 2021. Will I see Xmas of 2022? I'm guessing the low PSA with that much visceral cancer is a sign of the dreaded -- and fatal -- neuroendocrine prostate cancer courtesy of the 2nd generation ADT drug Erleada. The problem is that long term survivors on ADT are cherry-picked for patients to ogle at and imitate. You don't hear a peep about the boogie man of neuroendocrine disease that can go with ADT. I wonder why that is? (He says with tongue in cheek).