Estradiol Clinical Trial in UK? - Advanced Prostate...

Advanced Prostate Cancer

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Estradiol Clinical Trial in UK?

CrocodileShoes profile image
53 Replies

Since my diagnosis of hormone-resistant and metastatic, I've been researching my options, beyond SOC (my onco wants me to start enzalutamide + Leuprorolin immediately) . Having seen ronronHU post on Estradiol, I saw that there is a clinical trial taking place in the UK, so I am interested in joining it. Viewing zoom calls of Dr Richard Wassersug, he seems to have had extraordinary success with transdermal gel. If anyone here has either used it as a monotherapy (or in combo) or if anyone has done research on it, I'd be grateful for any light you can shed on the following:

1. Does it follow the usual path of second-line treatments (i.e. resistance sets in after a couple of years?

2. Is it even suitable for me, since Bicalutamide has failed?

3. If I had another Prostap injection (due in August) would that disqualify me from a clinical trial?

4. Is there even such a thing as castrate resistance if - according to my onco - my psa will fall with enzalutamide + Prostap? Isn't it more accurate to say that you just need increasingly stronger dosage? And why do we continue with Leuprorolin when hormone resistance has kicked in?

I'd be especially interested in any personal testimonies with Transdermal get or indeed any other non-SOC routes that you have tried. I know that I'm not in any immediate danger of 'popping my clogs' (US warriors may need to Google that) But it still seems to be a one-way road to a cul-de-sac.....

53 Replies
Brysonal profile image
Brysonal

Sorry I can’t answer your questions but I am in the UK and interested in the estradol trial. Do you have a link and is it patches or gel. I currently have just had no 7 Degarelix injection and getting to end of my other treatments want to discuss all options with my MO.

A link would be appreciated. Following this for answers too! Interesting post, thanks

CrocodileShoes profile image
CrocodileShoes in reply to Brysonal

If you Google PATCH CLinical Trial , being hosted by UCL, you'll find it.

Tall_Allen profile image
Tall_Allen in reply to Brysonal

It's been combined with the STAMPEDE trial (arm L):

clinicaltrials.gov/ct2/show...

clinicaltrials.gov/ct2/show...

CountryJoe profile image
CountryJoe in reply to Tall_Allen

TA, I have been taking Zoladex for the past three and a half years while my PSA has steadily declined. At last reading it was 0.136. I see my oncologist here in El Salvador this week and want to ask him about a vacation. Encoraged by the good results that Ronron has had with estrogel, I also want to try that. I know there are risks. I know that some would recommend to stay the line with a med that is working. But I am suffering from mild depresión and want my muscle mass back. Can you (or anyone else) please give some words of advice?

Tall_Allen profile image
Tall_Allen in reply to CountryJoe

It isn't yet approved for that purpose, but I think it will be. Gynecomastia may be an issue.

CountryJoe profile image
CountryJoe in reply to Tall_Allen

Thank you for this, TA. What is your opinión about taking a vacatión? Will I get my muscle mass back and stabalize emotionally if I do do, at least for several months?

Tall_Allen profile image
Tall_Allen in reply to CountryJoe

No one can predict how soon your testosterone will recover.

CountryJoe profile image
CountryJoe in reply to Tall_Allen

Thanks again., TA. I know that I am being a bit bothersome and I respect your reluctance to make decisions for others, but I really need the support of knowledge at this moment. Given the data that I have given on my own case, if you were in my shows, would you yake a vacatión at this point?

Tall_Allen profile image
Tall_Allen in reply to CountryJoe

I am not in your shoes. No one can make that decision but you. Only you can know how much you are suffering.

CountryJoe profile image
CountryJoe in reply to Tall_Allen

Thanks TA. Your a tough nut to crack, but I understand (and respect) where you're coming from. Have a great day. 😊

CAMPSOUPS profile image
CAMPSOUPS in reply to CountryJoe

I installed a printing press in San Salvador in the early 2000's.Extremely hot lol.

CountryJoe profile image
CountryJoe in reply to CAMPSOUPS

Did you get to see the country? Its quite beautiful.

CAMPSOUPS profile image
CAMPSOUPS in reply to CountryJoe

Well. Work as usual. I saw from the airport to the customer factory to the hotel and it was all nice.The company owner told me he had a cottage on the coast and someday I could return and include a vacation but darn it never happened. Oh well.

CountryJoe profile image
CountryJoe in reply to CAMPSOUPS

That's too bad. The coast of El Salvador is really quite beautiful. Be well and remember, "la vida es lucha". 😊

CAMPSOUPS profile image
CAMPSOUPS in reply to CountryJoe

Always able to savor the local customers culture, vibe on my work trips around the world in the evenings after work. San Salvador included.

I am doing good/well and I hope the same for you.

Many trips to Mexico and to Ecuador, Spain too but I'm not ready for the level 3 Spanish you threw at me there lol.

My friend/customer in Mexico City told me one time I sound like a Mexican Cowboy lol.

CountryJoe profile image
CountryJoe in reply to CAMPSOUPS

😊😊😊

Spyder54 profile image
Spyder54 in reply to Tall_Allen

TA, your link to Arm L of Stampede says “Error Occured”. Would you hv another link? Thanks, Mike

Tall_Allen profile image
Tall_Allen in reply to Spyder54

My bad:

clinicaltrials.gov/ct2/show...

clinicaltrials.gov/ct2/show...

Spyder54 profile image
Spyder54 in reply to Tall_Allen

Thanks TA

smurtaw profile image
smurtaw

patch.mrcctu.ucl.ac.uk/

pubmed.ncbi.nlm.nih.gov/335...

Guber profile image
Guber

Patch is working for me. 1 1/2 years

CrocodileShoes profile image
CrocodileShoes in reply to Guber

Were you hormone sensitive at the time of starting it?

Tall_Allen profile image
Tall_Allen

1. Does it follow the usual path of second-line treatments (i.e. resistance sets in after a couple of years? Yes.

2. Is it even suitable for me, since Bicalutamide has failed? Yes -it prevents your testicles from manufacturing testosterone. Bicalutamide is a weak anti-androgen that blocks testosterone at the androgen receptor of the cancer cell.

3. If I had another Prostap injection (due in August) would that disqualify me from a clinical trial? Yes. It is only for newly diagnosed patients.

4. Is there even such a thing as castrate resistance if - according to my onco - my psa will fall with enzalutamide + Prostap?

Castration resistance means that the cancer progresses in spite of stopping your production of testosterone. Eventually, the cancer will become resistant to enzalutamide too. The androgen receptor will get internalized and inaccessible to external blockade.

Isn't it more accurate to say that you just need increasingly stronger dosage? And why do we continue with Leuprorolin when hormone resistance has kicked in?

No. One of the mechanisms of castration resistance is that your cancer produces more androgen receptors. That makes it super-sensitive to even the tiniest amount of testosterone. It becomes vitally important to prevent all testosterone.

Justfor_ profile image
Justfor_

Even before Brexit, only NHS patients were eligible to the PATCH trial. I know first hand.

CrocodileShoes profile image
CrocodileShoes

I heard from my onco today (kudos to him for replying on a Sunday. He said that I would not be eligible for the PATCH trial, since it was only for hormone-sensitive men. He has offered to investigate other clinical trials that I might qualify for.

So, that's a bit crap. The question remains: would the transdermal gel be a useful off-label addition to the Leuprorolin injections and the enzalutamide? And is 2 years of tumour supression about the best I can hope for with Enzalutamide? If so, what next? (Please don't say putting your affairs in order!)

noahware profile image
noahware in reply to CrocodileShoes

"would the transdermal gel be a useful off-label addition to the Leuprorolin injections and the enzalutamide?"

I can't see how, unless you wanted to try a LOW-dose regimen, as a means of offsetting symptoms (bone loss, hot flashes, etc.) associated with the low levels of E2 that come with the low-T of the Leuprorolin injections. That, however, is not a means of actually fighting the cancer. But it might be worth discussing with your doc, as it could be added to Leuprorolin + enzalutamide for bone health.

The HIGH-dose use of transdermal gel or patches, per the PATCH trial, is simply a means of achieving castrate levels of T that is an alternative the Leuprorolin injections. The former is basic ADT, and the latter is basic ADT. So there is no reason to add one to the other, but only to do one INSTEAD of the other.

Why would one do HIGH-dose E2 patches instead of Leuprorolin? To reduce the side effects, as mentioned above. So one could do that either by doing Leuprorolin + LOW-dose E2, or by just doing HIGH-dose E2 alone. The appeal of the latter is obvious: is it easier and cheaper. The PATCH trial is important, because it demonstrates a treatment that will cost the system less money AND make men healthier, both at once... but it is NOT a demonstration of a treatment that in any way has been shown superior to standard ADT so far as PC progression itself.

We might then ask, why would one do Leuprorolin instead of HIGH-dose E2 patches? Because the HIGH-dose E2 patches might fail to bring your T down to castrate levels, and you might be left with "low-but-not-castrate" levels of T along very elevated levels of E2, a potentially dangerous combo that could make a seemingly non-aggressive PC far more aggressive.

Anyway, that seems to be what happened to me, because in the few short months that I attempted ADT via the PATCH protocol and failed to become castrate, my PSA and ALP soared and the few mets that formerly appeared confined to my spine expanded such that many more bones were riddled with metastatic lesions.

A recent post (that was unfortunately deleted) linked a few articles about how estrogen receptor alpha and beta can be intimately involved with cancer progression. The short version is, whatever means you use to reach castrate levels of T make sure you are CASTRATE and not just "kind-of-low T."

Kind-of-low T combined with kind-of-high E2 can be a recipe for disaster.

KocoPr profile image
KocoPr in reply to noahware

Here are those links i posted earlier but got deleted. I don’t know why they were deleted because they were legit.nature.com/articles/s41598-...

jitc.bmj.com/content/10/4/e...

CrocodileShoes profile image
CrocodileShoes in reply to KocoPr

I've read it and wouldn't pretend to understand it. Could you give a plain language summary please? Many thanks.

KocoPr profile image
KocoPr in reply to CrocodileShoes

I readthese articles several times and am concerned that is is a very complex interaction between ERa, and ERb in the tumor micro environment and opposite in the tumor cytoplasm.Matebeach has a decent explanation below. If your going to do E2 low dose or high dose is to do it under the care of you MO, or at least let him know and ask for specific tests and maybe more frequently. You can also pay for your own male sensitive E2 test.

What I am getting out of this for me since i am hormone sensitive and just starting lupron and soon to add darolutamide is I really need to delve into this more. I am also thinking for now eat phyto-estrogenic foods like soy. Make sure soy is organic it is heavily sprayed and GMO’d

Another thing I am definitely going to do is SARM’s (synthetic testoerone) like rad140 or osterine to support my muscles and bones. They have no affinity to aromatase (cyp19a1,), 5alpha-reductase, and DHT. I will certainly do them intermittently when I feel like I need to regain muscle and bone.

Farmhand profile image
Farmhand in reply to noahware

That is exactly what happened to me! Used estradiol gel and first three weeks PSA dropped 100 points, next two weeks PSA rose 900 points in metastasized everywhere! ( I have BRCA2 mutation….Not sure if that contributed to the estradiol feeding the cancer?)…..I went from no bone mets to riddled with bone mets within two weeks.Chose estradiol gel instead of Lupron to reduce side effects😐.

Initial diagnosis was: PC3bLN1MX

Some of us need to beware of steroidal hormones

CrocodileShoes profile image
CrocodileShoes in reply to Farmhand

Wow, that's a pretty dramatic reversal. I'll ignore the estradiol. Can I ask if as you presumably went back to Lupron, whether the PSA dropped as rapidly as it rose?

MateoBeach profile image
MateoBeach in reply to CrocodileShoes

These posts show individual examples of high dose estradiol alone as ADT can work for some long term, as it does for ronronHU. And can be detrimental and feed the cancer in others. What I know from studying the known mechanisms and interactions between the various estrogen receptors and prostate cancer is that it is complex, meaning adaptable and intrinsically unpredictable, just as prostate cancer itself is.

Estrogen can provide substantial health benefits in various ways when testosterone is absent. So generally low dose topical estradiol is beneficial. But adaptations can eventually make it harmful in PC control. The key is to keep monitoring and be ready to drop it when progression is suggested by rise in PSA or on scans. Just my considered opinion.

In the following very long and comprehensive article reviewing the roles of testosterone, towards the middle there is a section on the role and benefits of estrogen when testosterone is absent.

ncbi.nlm.nih.gov/books/NBK2...

You can flip through to sections of interest. And the summaries following each section are easy to understand.

CrocodileShoes profile image
CrocodileShoes in reply to MateoBeach

Paul:I wrote to you on one of your Lu 177 posts, (and DM'd you) as that is the other non-SOC i've been considering. I will take enzalutamide as my onco recommended, but I wanted to ask about early(ish) use of Lu 177. I'm going to be in Melbourne next year and need to investigate if I'm a suitable candidate. (I've already had a PSMA scan at the Peter Mac centre). Hope you don't mind me contacting you.

noahware profile image
noahware in reply to CrocodileShoes

Just want to throw in the idea, if you do consider Lu177, to read up on the potential importance of doing an FDG scan along with required PSMA scan.

Tall Allen has written much about this:

"Now that we know that heterogeneity can impact Lu-177-PSMA effectiveness, it behooves us to find a way of determining the degree of heterogeneity. One way is to give each patient two PET scans, so they could see the sites that exhibited PSMA expression as well as the sites that exhibited high uptake on an FDG PET scan.

It is futile to offer PSMA-targeted therapy if there are many sites that show up only on an FDG PET scan but few sites that display uptake of PSMA. It also may be futile to treat patients that show some sites where PSMA and FDG sites do not overlap — discordant. On the other hand, where there is a high degree of overlap between FDG and PSMA — concordant – the PSMA radiotherapy will kill both cancers simultaneously. Of course, the ideal candidate would display only highly PSMA-avid sites."

prostatecancerinfolink.net/...

Farmhand profile image
Farmhand in reply to CrocodileShoes

Yes I had a dramatic response to standard hormone deprivation after using estradiol. The estradiol landed me in the hospital for an emergency bilateral nephrostomy tube placement as the tumor quickly shut down both ureters causing kidney failure. At that time I started on bicalutamide to reduce Lupron flare and then after one month on bicalutamide started with Lupron for next six months and then switched to Orgovyx.After 1.5 years on standard hormone therapy my PSA is currently 0.8

However, last PSA indicated slow rise and will most likely add Zytiga.

No bone Mets were detected before estradiol but after rapid PSA rise on estradiol bone Mets were too numerous to count. And of course although they are currently not active, they still remain on some level….

My BRCA2 Germline mutation may have had a lot to do with the cancers ability to switch to using estrogen?

CrocodileShoes profile image
CrocodileShoes in reply to Farmhand

OK, well that clinches it. My mother died of Breast Cancer, and I have no desire to make an already bad situation many times worse. So, no E2. Ironically Richard Wassersug's book has just arrived, but I'm sure it's got good general info on ADT.Thanks to everyone who has shone some light on this highly complex area. I still don't pretend to understand it all, but I'm learning! And fortunately I have an oncologist that supports me investigating non-SOC and off-label approaches.

Farmhand profile image
Farmhand in reply to CrocodileShoes

Have you done next generation genetic testing? Do you have BRCA2 mutation?If so, even though estradiol may not be a good plan, perhaps in the future BAT could be useful

KocoPr profile image
KocoPr in reply to Farmhand

Since you have BRAC2 you should be eligible for checkpoint inhibitors like ketruds or the recent big news dostarlimab? Also look into N-terminus Domain inhibitors which inhibits the DNA transcription in the cancer tumors. That to me is the big prize.

John

Farmhand profile image
Farmhand in reply to KocoPr

Thanks John…will do. What are some examples of N-terminus Domain inhibitors?

KocoPr profile image
KocoPr in reply to Farmhand

Here are some recent articles on N-Terminus Domain in prostate cancer

This is my favorite for understanding the Non Androgen Genomic Pathways to CRPC

ncbi.nlm.nih.gov/pmc/articl...

“EPI-7386 is a more potent and stable NTD inhibitor (Anitens) that is advancing to clinical trials. “

mdpi.com/2072-6694/13/14/34... of an Androgen Receptor Inhibitor Targeting the N-Terminal Domain of Androgen Receptor for Treatment of Castration Resistant Prostate Cancer

pubmed.ncbi.nlm.nih.gov/303...

Combined N-terminal androgen receptor and autophagy inhibition increases the antitumor effect in enzalutamide sensitive and enzalutamide resistant prostate cancer cells

pubmed.ncbi.nlm.nih.gov/306...

Role of androgen receptor splice variants, their clinical relevance and treatment options

annalsofoncology.org/articl...

EPI-7386 is a novel N-terminal domain androgen receptor inhibitor for the treatment of prostate cancer

clinicaltrials.gov/ct2/show...

EPI-7386 phase 1 clinical trial

noahware profile image
noahware in reply to Farmhand

Yes, I was excited that I had discovered the "better" treatment in E2. Not to be.

I do believe that mutations probably play a role in the response, but can I ask: was your T being measured during this period of gel use, and how low did it get?

I used massive amounts of patches and even though my E2 measured high, my T would not drop to the expected castrate levels.

Farmhand profile image
Farmhand in reply to noahware

I used the gel/packets. And while testosterone dropped to low levels it did not reach castrate levels.… I will check my old records and see what exactly T dropped to during that time.

I only used it for less than two months. I used it before switching to Lupron and it was the only treatment I was on at the time, hoping to avoid Lupron. The first month PSA dropped from 200 to 100. Then within the Following two weeks it rose up to 900 and extensive metastases everywhere!

I have mentioned this before on this forum to warn people that sometimes this happens with Estradiol, but so far I had not heard of anyone else having the same response that I did.

Somewhere I did read about those with family breast cancer mutations might be more at risk for this type of response

noahware profile image
noahware in reply to Farmhand

I think not reaching castrate levels of T is the key to bad results, with mutations making it worse. My T only got down to 150 after over a month, and only to 80 after tripling my E2 dose. Not low enough! (Firmagon + Abi got me to <4 in no time.)

I believe men with naturally low T and higher E2 (as happens when we get old and fat) are at much higher risk for aggressive PC. A failed attempt at ADT, where low T gets even lower (but NOT castrate) and E2 gets even higher, might surely accelerate progression of that PC.

I still need to get my genetic testing done, but my mother died of breast cancer at 66. To find I have breast cancer mutations will be no surprise.

Farmhand profile image
Farmhand in reply to noahware

Thanks so much for all of your valuable information… It finally helps me to understand what happened….

MateoBeach profile image
MateoBeach in reply to noahware

That really is terribly unfortunate, noahware. So sorry that you had such a response, and so quickly.I too tried E2 patches per PATCH protocol (4 X 0.10 patches changed twice weekly in rotation) for ADT during short term adjuvant ADT to RT. After a month I was not castrate, >50, so I fell back on degarelix and continued E2 at low dose. I was fortunate not to have progression from that.

You are in my thoughts. Sending support and caring. Paul

GeorgeGlass profile image
GeorgeGlass in reply to noahware

Excellent info. Well written.

Bluebird11 profile image
Bluebird11

I haven’t read through the responses. My husband was diagnosed in 2007 with metastatic PCa. He lived 14 years

He did start with Casodex snd Lupron. The casodex for 8 months. The Lupron for a year. We took a year off completely. Then back to Lupron for months. Tried casodex again. Disliked the side effects and then went to estrodiol for maybe 4 years. We then decided to switch to Honvan. We used one pull a month in a two ounce homeopathic solution snd took 20 drops twice a day. That may have lasted another 3 years. It’s midnight here and I haven’t added up the correct years though we had a great run on estrogenic treatment where my husband stayed slim around the middle. He did grow breasts. We used vests. He might had tried the radiation prior to stop the breast growth though I have no recollection of the research I did at the time. We always used supplements we felt helped.

My husband remained active, lived fully with no regrets about our choices. I hope this helps. You can contact me privately if you want to talk about our situation. Good luck.

Surla profile image
Surla

Hi, I am using Estradiol gel since January 11, 2022, and my PSA fell from 0,4 to 0.01 after application for 3 months. I had prostate removed in November 2020, completed 35x radiation in June 2021, PSA 0.24 went to 0.4 in December 2021. No other treatment so far.

KocoPr profile image
KocoPr in reply to Surla

Hi Surla, thats great news. Can you update your bio with the E2 patch and results.What dosage and drug name are you using?

Im thinking of doing the same thing with .5mg patch twice/week as i am hormone sensitive and just started lupron and will be starting darolutamide soon I hope.

Surla profile image
Surla in reply to KocoPr

I have no further update except that so far I didn't have any noticeable met. I am not using patches but gel. Pictures of the gel are attached.

Oestrogel from Besons Belgium
Proflac profile image
Proflac

Hi God post to raised some useful questions and responses. In particular the fact that for some men Patch protocol definitely didn't work well- wouldn't it be great if we knew up front who is likely to benefit? I don't think you would get anyone in UK to give you mono tx estradiol outside of a trial and you're not eligible for the current one. I can't even get our onco to prescribe low dose add back! At my request, He got opinion on low dose from Prof Langley who led the Patch trial but she wouldn't commit to saying go for it, due to lack of trial evidence. Though she did say there is some evidence that it can help with SE from ADT. Neither wants to commit to a non SOC use. My onco is worried about blood clots but Patch showed no issue even at the high dose level. Bit frustrating for us as my guy is massively fatigued and I thought it might be worth a try. On another matter my guy tried enza and was completely floored and some major cognitive issues. Was switched to Zytiga (abiraterone) plus pred.and this was better tolerated and still effective at holding PSA around. 5 to.7 (no idea why it bounces around). Let me know if you get an add back dose from your consultant. Best wishes.

Break60 profile image
Break60

I’ve been using estradiol since 2015 for hot flashes. Just one .1mg patch weekly stopped Hot flashes. . I was using Lupron along with the patch on an intermittent basis. In 2019 Feb I stopped Lupron and switched to four then three estradiol patches after reading about the PATCH trial in UK and getting my urologist to write me a script. I switched due to Lupron side effects. From what I understand the trial is only open to UK residents. But other trials of the patches have been done as well. This April my oncologist added Xtandi to my patches. My psa is now undetectable. See my profile for details.

Spyder54 profile image
Spyder54

Read Break60 profile. He has had success for 8+ years. Most recently on E2 patches. One thought I have is this should extend Castrate Sensitivity. You could always restart ADT3. Also, as Nalakrats says….keep the PCa confused. Dont let it figure a workaround. Mike

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