Estradiol Patches combined with ARPI agents

[janebob99]

The results comparing tE2 + ARPI agents to LHRHa + ARPI agents were presented at the ASCO meeting in February, 2025. The primary conclusion is that PSA responses were similar in patients treated with tE2+ARPI or LHRHa+ARPI, further supporting the use of tE2 patches for ADT in prostate cancer management.

meetings.asco.org/abstracts...

Background:

Recent phase III data (n=1360) has shown that starting ADT with tE2 patches is non-inferior in terms of metastasis-free survival (with similar overall survival) to luteinising hormone releasing hormone analogues (LHRHa) for locally advanced (M0) prostate cancer. For both M0 and M1 patients, tE2 has advantages in terms of reported quality of life, bone mineral density, hot flushes and metabolic outcomes compared to LHRHa, with no excess of thromboembolic events. However, there is currently no data on the use of androgen receptor pathway inhibitors (ARPIs) (abiraterone, enzalutamide or apalutamide) with tE2.

Methods:

STAMPEDE [NCT00268476] is a multi-arm, multi-stage platform trial. This embedded phase 2 randomised study assessed efficacy and toxicity in participants (pts) randomly allocated (1:1) to tE2 patches (releasing 100mcg/24hrs, 3 patches changed twice weekly once testosterone ≤1.7ng/ml) or LHRHa (standard doses) and scheduled to receive ARPIs. Primary outcome measure was the proportion of pts reaching a PSA nadir of ≤0.2ng/ml during the first 6 months. Other PSA parameters, testosterone ≤1.7ng/ml at 12 weeks with tE2, and adverse events within the first 12 months (including hypertension, hot flushes and gynaecomastia) were assessed.

Results:

Between Oct-2020 and Mar-2023, 79 pts with histologically confirmed M1 prostate cancer (median (IQR) age 69 (65-75), median (IQR) baseline PSA 43.3 (11.5-296.2)) received either LHRHa+ARPI (n=41) or tE2+ARPI (n=38). Baseline characteristics were similar between the 2 groups. The proportion of pts achieving PSA ≤0.2ng/ml was LHRHa+ARPI 25/41 (61%) and tE2+ARPI 23/38 (61%). LHRHa v tE2: PSA90 (93% v 95%) and PSA50 (100% v 100%). 31/34 (91%) men treated with tE2 had testosterone ≤1.7ng/ml at 12 weeks. Hot flushes: LHRHa (grade 1: 32%, grade 2: 20%) v tE2 (grade 1: 24%, grade 2: 5%). Gynaecomastia: LHRHa (grade 1: 10%, grade 2: 0%) v tE2 (grade 1: 35%, grade 2: 8%) and any grade hypertension LHRHa v tE2 17% versus 5%.

Conclusions:

PSA responses were similar in pts treated with tE2+ARPI or LHRHa+ARPI further supporting the use of tE2 patches for ADT in prostate cancer management. tE2 patches provide patients with ADT choices about expected toxicity profiles, including reduced hot flushes (and subsequent impact on quality of life), and mode of administration.

[Doctorsceptic]

yes results are now published and message on benefits of E2 v ADT need to get out. I have mentioned it in some posts but not much interest.

[Vangogh1961 in reply to Doctorsceptic]

I spoke with my oncologist two weeks ago about this, this report wasn't out. Three months we'll have a different dialogue.

[dhccpa in reply to Vangogh1961]

Be prepared for terrified skepticism.

[Doctorsceptic in reply to Vangogh1961]

Lancet vol 387, p581-581 2021 reports the cardiovascular data. AnotherPATCH paper due out 2nd quarter this year.

Also see “ J Endocrine Soc vol 8, issue 7 2024 Bennink, Prowse et al Loss of estradiol by androgen deprivation in prostate cancer patients ….

[Alicat1]

What is ARPI?

[janebob99 in reply to Alicat1]

Androgen Receptor Pathway Inhibitor, like darolutamide, enzalutamide, apalutamide. They block the reception of testosterone by cancer cells (or any cell that has receptors for attaching to testosterone).

[JohnInTheMiddle in reply to janebob99]

This whole business of classifying the new generation prostate cancer drugs is confusing. Because you can find references for all the "lutamides" categorizing them as ARPIs. I think it's worth clarifying though, because there's two different things going on here.

1. An ARPI or "androgen receptor pathway inhibitor" seems to originally have applied to disruption of testosterone manufacturer "in the middle", before it gets to the androgen receptor. The best (and maybe only?) example of this is Zytiga / Abiraterone, which interferes with the CYP17A enzyme, which is in the middle of the steroidal cascade from cholesterol to testosterone and other wonderful hormones. Thus, "the pathway". Oddly one can find quite a bit of literature that includes the "lutamides" under this general category.

2. An androgen receptor antagonist ("AR antagonist") on the other hand, is a drug that jams up the androgen receptor found on any cell, especially prostate cancer cells, wherever they are found. I think of this phenomena as "at the end" of the testosterone synthesis pathway. It's the destination of the testosterone, more than the pathway. This therapy is used in conjunction with ADT of course, but because there's still some testosterone produced even with ADT, it's a great thing to be able to make sure even that little bit of testosterone can't get inside any cells. This "androgen receptor antagonism mechanism" is what some literature, strictly speaking, describes as the category for enzalutamide and the other "lutamides".

(Interestingly, apparently there were a few studies that looked at using both an ARPI and an AR antagonist together, along with ADT, and Docetaxel chemo, making it "quad" therapy - but combining all four therapies together didn't provide any additional benefit over a triplet therapy.)

Classifying these two prostate cancer therapy categories of ARPI and AR antagonist as distinctive seems to me to be helpful in understanding what's going on. Because the categories have distinct side effects as a category, not only individually as separate drugs.

For example, an ARPI not only stops testosterone hormone production, but also mineralcorticoid hormone production, a family of hormones which are essential for our health, such as cortisol, and without which we will die. This is why prednisone is always prescribed along with Abiraterone, to restart the production of this blocked steroid production pathway.

--------------------------------

As a lay person it's interesting that the new Patch Trial-based transdermal estradiol hormone therapy includes the possibility that the estradiol will be used along with what was referred to above broadly as "an ARPI".

We can see now that whether this "ARPI" is ARPI-ARPI or "AR antagonist" will result in a very different synergistic mechanism.

Sometimes I wonder if it's worth knowing any of this stuff. I was recommended quite early for triplet therapy and this therapeutic recipe has been very good for me so far. But I didn't choose it and didn't know anything about it at the time. The only therapy choice I've made so far is to stay on Firmagon rather than switching to the recommended Lupron.

A lot of us have the hope in the back of our minds I think, that if we hang on long enough, that more effective therapies will be discovered and adopted into practice. The Patch trial is a good example. Bravo!

[janebob99 in reply to JohnInTheMiddle]

Excellent comments! It is important to understand the mechanics of how these drugs work, to make informed decisions.

[swwags in reply to JohnInTheMiddle]

Hey John. What you're describing as ARPI is different than JaneBob's reference from the study. I read the study a while ago. Are the terms now interchangeable or did the patch trial specify the difference between AR antagonist and androgen receptor pathway inhibitor? Seem to me an important distinction.

[Alicat1 in reply to janebob99]

Thanks

[VictoryPC]

Any of the "mides"

[tennis4life]

Good stuff! My MO just prescribed the E2 patches for me. He had to check with the Director of Oncology first though. But it seems that it is finally being somewhat SOC. But you still need to be informed and firm about your position when dealing with them. Thanks for the update!

[dhccpa in reply to tennis4life]

It's good news, but based upon the terror on the faces of my MO and urologist within the last month, I suspect I may have to resort to slow torture for acceptance. Still, something has to give sooner or later.

[janebob99 in reply to dhccpa]

Roger, that. The wheels turn slowly...

[Horse12888]

Very good news. This is definitely the route I'm taking if my PSA continues to rise.

[dhccpa]

Bob, thanks for posting. Is there a Denmeade of sorts for this treatment? A guru nationwide? Or known doctors who are trying it and who have some standing. I think my MO would go for it if he had a guru behind him. That seems to be the key.

Does anyone know anyone in Florida (preferably NE Florida) using this on patients?

[janebob99 in reply to dhccpa]

Dr. Michael Schweizer in Seattle at the Fred Hutchison Cancer Center is prescribing estradiol patches following the PATCH protocols. You may want to contact him.

[dhccpa in reply to janebob99]

Thanks

[Shorter]

Bob, thank you for posting this. I am now on Xtandi as my cancer has progressed and have been wondering if I should continue the use of estrogen.

[janebob99 in reply to Shorter]

Are you also on ADT now?

[Shorter in reply to janebob99]

The testosterone factories were surgically removed in April of 2021. I have what T my endocrine system produces (normally 10 -12) and I take Xtandi daily

[janebob99 in reply to Shorter]

I'm not a MD.

But, that said, anytime estradiol (E2) levels are low in a man, he is at a greater risk for having osteoporosis, hot flashes, higher blood glucose levels, and higher bad cholesterol levels. Supplementing E2 with estradiol patches or gels/creams is one way to reduce or eliminate these risks.

However, gynecomastia and mastalgia are common side effects of supplemental E2 therapy.

[Shorter in reply to janebob99]

My oncologist is well aware of what I am doing. I took him a graph of my estradiol injection levels and hormone levels for the last 3 years or so. And yes, I now have boobs.

[janebob99 in reply to Shorter]

Very good.

Is there anything else I can help you with?

[Shorter in reply to janebob99]

No, thank you.

[j-o-h-n]

In a nutshell,

Estradiol Patches combined with ARPI agents.

The results comparing tE2 + ARPI agents to LHRHa + ARPI agents were presented at the ASCO meeting in February, 2025. The primary conclusion is that PSA responses were similar in patients treated with tE2+ARPI or LHRHa+ARPI, further supporting the use of tE2 patches for ADT in prostate cancer management.

Good Luck, Good Health and Good Humor.

j-o-h-n

[janebob99 in reply to j-o-h-n]

Thanks, John.

[swwags in reply to janebob99]

I mean no disrespect when I ask this but you are very much a proponent of the E2 patches Bob. Do you sell them?

[j-o-h-n in reply to swwags]

Maybe the two of us can team up and get on Shark Tank and have them set us up..... We can shoot for Mr. Wonderful.

Good Luck, Good Health and Good Humor.

j-o-h-n

[swwags in reply to j-o-h-n]

I'm with you in spirit brother!

[j-o-h-n in reply to swwags]

Deal. You're the worker, you do all the work......I'm the Boss, I get all the money...

Good Luck, Good Health and Good Humor.

j-o-h-n

[janebob99]

Ha... I wish! Actually, I've thought about starting a company that sells high concentration E2 gel or cream. Possibly teaming with my partner. But, that's a big undertaking...

Clearly, there's a need for a male-specific E2 patch...a "ManPatch", so to speak.