ESMO 2024: Phase 3 evaluation of tran... - Advanced Prostate...

Advanced Prostate Cancer

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ESMO 2024: Phase 3 evaluation of transdermal estradiol vs LHRH agonists for androgen suppression

Maxone73 profile image
43 Replies

This is very interesting for us all, even if these results are for non metastatic patients!

Results demonstrated that transdermal estradiol was non-inferior to LHRH agonists, with metastasis-free survival rates of 86% and 87%, respectively. Overall survival slightly favored the estradiol group (hazard ratio 0.89), although this was not statistically significant. Both groups achieved similar rates of sustained castration, defined by low testosterone levels over one year.

In terms of side effects, patients using transdermal estradiol experienced less hot flushing (44% vs. 89%) but had a higher incidence of gynecomastia (85% vs. 42%) compared to those on LHRH agonists (note: gynecomastia can be solved with a few radiations before starting estradiol).

Importantly, transdermal estradiol improved bone mineral density and did not increase cardiovascular toxicity—a notable advantage over oral estrogen therapies. Quality of life assessments also favored the estradiol group, with significant improvements observed at six months.

urotoday.com/conference-hig...

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Maxone73
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PresidentOfBelgium profile image
PresidentOfBelgium

Thanks for sharing 👍👍👍

janebob99 profile image
janebob99

Exciting results (which were expected)!

Thanks for posting them.

Tinkudi profile image
Tinkudi in reply tojanebob99

You talk about this often I think

janebob99 profile image
janebob99 in reply toTinkudi

Yes. I'm a strong believer in it, and have done a lot of research on it. The implications for third world countries is huge, economically. Some forms of transdermal estradiol are 100 to 1000 times cheaper than Lupron and Orgovyx. Stay tuned!.

Justfor_ profile image
Justfor_ in reply tojanebob99

No margins for kickbacks. Great disadvantage.

KocoPr profile image
KocoPr

This proves a few of the warriors on this forum were right all along.

Maxone73 profile image
Maxone73

We still don't have results for metastatic patients I suppose it is because for metastatic patients the endpoint is OS. But I hope they will say something about castration resistance as well.

GP24 profile image
GP24

This is a link to additional information about the trial results: mrcctu.ucl.ac.uk/news/news-...

Dr. Mehra discusses three presentations, the second one is this trial: urotoday.com/conference-hig...

The advantages I see:

- low cost

- no bone loss - no denosumab needed

- hot flashes reduced in half

- improved overall quality of life scores

- disadvantage: breast enlargement frequent - radiation or tamoxifen needed.

janebob99 profile image
janebob99 in reply toGP24

Thanks for your post.

I respectfully disagree with your comment about hot flashes. Most data that I've seen says that hot flashes can be completely eliminated with supplemental estradiol.

Tamoxifen will likely counteract the positive effects of estradiol, leaving only radiation as the only means for treating gynecomastia.

Anyone considering using estradiol should get their BRCA 1/2 gene status tested because of an increased risk of breast cancer, especially with a family history. Try prostatecancerpromise.org for free genetic testing.

Seasid profile image
Seasid in reply tojanebob99

"Yes, tamoxifen is a Selective Estrogen Receptor Modulator (SERM). It acts as an estrogen receptor antagonist in some tissues, like the breast, but can act as an agonist in others, such as the bones and the uterus.

In the context of prostate cancer:

Tamoxifen is sometimes used to manage gynecomastia (breast enlargement) or breast pain, which can be side effects of androgen deprivation therapy (ADT), particularly when drugs like bicalutamide are used.

However, tamoxifen's effects on prostate cancer itself are less direct since it mainly targets estrogen receptors rather than androgen receptors. Its role in prostate cancer is not typically as a treatment for the cancer itself but for managing certain side effects of prostate cancer treatments.

Since tamoxifen modulates estrogen activity in various tissues, its impact on prostate cancer would depend on the balance of ERα and ERβ in the tumor, similar to the effects of estradiol."

ChatGPT explains. Use this information at your own risk.

janebob99 profile image
janebob99 in reply toGP24

I forgot to add this plot, that shows a serum estradiol (E2) level above 120 pg/ml can completely eliminate hot flashes in post-menopausal women. Men typically respond the same way as PM women. Ref: Steingold et al (1985).

Hot Flashes vs Serum E2 concentration
GP24 profile image
GP24 in reply tojanebob99

The result of the trial was: "patients using transdermal estradiol experienced less hot flushing (44% vs. 89%)". Therefore I wrote "hot flashes reduced in half". This surprised me as well but I had hot flashes with Bicalutamide which does not lower estradiol, rather increases it.

I used Tamoxifen with Bicalutamide and as far as I understand it works mainly on the breast tissue. It is also recommended for Enzalutamide monotherapy as used in the Embark trial.

janebob99 profile image
janebob99 in reply toGP24

Thank you for the clarification. Perhaps the raised E2 with biclautamide wasn't sufficiently large? Di you measure your serum E2 levels then?

GP24 profile image
GP24 in reply tojanebob99

I do not recall how often I had hot flushes while taking Bicalutamide but they were mild and short. The package insert for Bicalutamide mentions hot flushes as a side effect. The E2 levels were high in the PATCH trial and the patients still reported hot flushes. Apparently you cannot avoid these completely.

janebob99 profile image
janebob99 in reply toGP24

I agree.

Of course, there is a spectrum/distribution of severity and frequency of hot flashes. It's not a yes/no binary kind of thing. So, it's unclear to me how they determined that only 44% of men had hot flashes. 1 hot flash per hour? 1 per day? Dripping sweat or a red face? Temperature rise? What's the criteria? I think you could get any number depending on how you define it. Perhaps their formal paper will explain this in more detail when it is published later this year...

Seasid profile image
Seasid in reply toGP24

1. I am for more than 6 years on Degarelix and still don't know what are hot flashes.

2. I belive that the big advantage of the estradiol patches is that the bone mineral density is preserved! (sorry for the confusion, I even confused ChatGPT.)

3. The biggest worry is that if you have a BRCA mutation than you could get a Brest cancer easily therefore it would be advisable to test yourself for BRCA mutation before starting transdermal Estradiol. I am not a doctor therefore I am not sure would tamoxifen prevent breast cancer if you have a BRCA mutation? (ask your oncologist).

Seasid profile image
Seasid in reply toSeasid

Additional comments from ChatGPT.(use it at your own risk):

1. Hot Flashes: Hot flashes are a common side effect of androgen deprivation therapy (ADT) like Degarelix. They typically involve sudden feelings of warmth, especially in the face, neck, and chest, and can be accompanied by sweating and flushing. If you haven't experienced them, it's possible you're either not sensitive to this side effect or have managed to avoid it through other means.

3. BRCA Mutation and Breast Cancer: BRCA mutations increase the risk of developing breast cancer, and it's wise to discuss this with your oncologist. Transdermal estradiol may increase breast cancer risk, and BRCA mutation carriers might have an even higher risk. Tamoxifen can reduce breast cancer risk in some individuals, but its effectiveness might vary based on genetic factors. Your oncologist can provide personalized advice and might suggest genetic testing before starting any hormone therapy.

GP24 profile image
GP24 in reply toSeasid

Degarlix lowers testosterone and therefore estrogen. It does not preserve bone mineral density.

Seasid profile image
Seasid in reply toGP24

You are spot on. I am still using it and I am not going to take bone strengthening medication.

I would not change to estradiol patches at this stage of my disease.

Seasid profile image
Seasid in reply toSeasid

When and if I break a bone I will reconsider taking bone strengthening medication after my bone heal.

GP24 profile image
GP24 in reply toSeasid

This is not a good idea. These fractures reduce overall survival. If you do not want estradiol patches you should take Denosumab.

Seasid profile image
Seasid in reply toGP24

I have to first work on my dental health. That is my main problem. It will cost me 27000 A$ according to the dentist in my hospital. I definitely can't start denosumab now without big work on my teeth. Unfortunately that is how it is.

GP24 profile image
GP24 in reply toSeasid

Maybe you consult a different dentist. I heard a presentation about ONJ and the presenter said, most important is a professional teeth cleaning. ONJ primarily occurs when there is too much tartar.

Seasid profile image
Seasid in reply toGP24

I am doing a regular cleaning every six months and planning to go to do my next cleaning at "gum doctors" specialist for a periodontal health and gum disease specialist. I don't have any problems with my gum yet.

Derf4223 profile image
Derf4223 in reply toSeasid

@Seasid of course its our prerogative to not take a medicine, but with bones, once the osteoporesis genie is out of the bottle... ADT is so notorious for causing bone loss you can get a bone scan annually in the US (as opposed to one every two years.)

Bone breaks in elderly men have a good chance of causing subsequent painful deaths

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

Seasid profile image
Seasid in reply toDerf4223

I agree 👍

Derf4223 profile image
Derf4223 in reply toSeasid

"When and if I break a bone ..." That's like saying I won't wear a seat belt until I get ejected in a crash.

Seasid profile image
Seasid in reply toDerf4223

No if you break a bone and you are under bone medication your bones will have difficulties to heal. I am optimistic that I am careful and that I will be fine. Just because you are taking denosumab is not a guarantee that you will not break a bone. I can have yearly scans but I can't get a same operator therefore what's the point of having one? Maybe I change my mind if I could get the same operator like last time to do the bone density scan. I really feel great and I don't want to spoil it with denosumab side effects. I still hope that my bones are reasonable. I believe that taking denosumab only improve the chance of breaking the bone in your spine by only 5% or so. I should ask ChatGPT for opinion but I can tell you that only 8% of osteoporotic people are on bone medication and they are happy that they don't develop kidney problems etc. Of course you are welcome to take denosumab if you want.

Seasid profile image
Seasid in reply toSeasid

Ok, I am not on abiraterone and prednisolone plus I don't plan xofigo in the near future. My bone Mets are under control as a result of early docetaxel chemotherapy and the cancer in my bones are in a senescent state now. It means that the prostate cancer in my bone Mets are biologically alive but not multiplying and hopefully they stay that way for some time. Abiraterone would not benefit therefore I am now only on Degarelix and bicalutamide.

Seasid profile image
Seasid in reply toSeasid

If I develop a visible metastasis I will sbrt it with high precision MRI linac if it is feasible.

Proflac profile image
Proflac

Avery interesting trial and these latest results are also promising. Too late for us but if diagnosed now I would certainly be looking very seriously at this. Avoiding the awful QOL side effects of traditional testosterone lowering drugs would have been very welcome.

Maxone73 profile image
Maxone73 in reply toProflac

I don't think it's too late, I just wish I already had the results about OS. But nothing stops you from switching to estradiol.

janebob99 profile image
janebob99 in reply toProflac

It's important to remember that, in general, substituting tE2 for standard ADT will not eliminate some side effects due to low testosterone, such as loss of muscle mass, increased muscle weakness, and loss of libido.

Proflac profile image
Proflac in reply tojanebob99

Yes thanks, that's important to note though overall better QOL scores and the cardio risks are pretty good benefits.

janebob99 profile image
janebob99 in reply toProflac

Yes, those are huge benefits! Thanks for pointing that out. Plus, reduced costs from not having to use expensive anti-osteoporosis drugs like zolendronic acid and bisphosphinates, and no jaw necrosis.

pj1121 profile image
pj1121 in reply tojanebob99

Janebon99

After a year of ADT , Lupron Zytiga, I’ve had sudden onset of peripheral neuropathy in my feet. I am scrambling to find a clue as to the cause of this. Side effects from ADT have been pretty mild for me.

I thought a possible cause of my neuropathy could be my ultra low testosterone I was wondering if you had heard anything about estradiol possibly benefiting Neuropathy.

Thanks

Pj1121

janebob99 profile image
janebob99 in reply topj1121

Alas, you're the first person I've heard of this problem. I don't know if E2 would help you or not. Do you have diabetes?

Mascouche profile image
Mascouche in reply topj1121

Could be radiation related neuropathy

Seasid profile image
Seasid in reply topj1121

Comment generated by ChatGPT.(use it at your own risk) :

"Peripheral neuropathy can sometimes be a complication of cancer treatments, but it can also have a wide range of causes, including metabolic or hormonal changes. Since you've experienced neuropathy after a year of androgen deprivation therapy (ADT) with Lupron and Zytiga (abiraterone), it's possible that the hormonal imbalances could contribute.

While low testosterone itself isn't commonly linked directly to peripheral neuropathy, prolonged hormonal imbalances from ADT can have various effects on nerve function. There have been some discussions in the medical community about the role of estradiol in managing neuropathy, as estradiol has neuroprotective properties and can support nerve function in some contexts. Research has shown that estradiol might help protect against nerve damage, and in animal models, estradiol has been found to promote nerve regeneration and reduce inflammation in peripheral nerves.

However, the clinical application of estradiol for treating neuropathy, especially in men with prostate cancer, is still a subject of debate. For someone on ADT like yourself, any modification involving estradiol should be done cautiously, as estradiol can have complex effects on prostate cancer progression.

To explore the potential connection between your ADT and peripheral neuropathy, it would be good to rule out other common causes, such as:

Vitamin deficiencies (especially B12, B6, and folate)

Diabetes or other metabolic issues

Medication side effects (besides the ADT drugs)

In your case, I recommend discussing the possibility of using estradiol with your oncologist and possibly a neurologist to see if it's a viable option. Additionally, they may look into supportive treatments like nerve supplements, physical therapy, or other medications specifically designed to manage neuropathy symptoms."

Scout4answers profile image
Scout4answers

How do I find an MO who will prescribe estradiol?

janebob99 profile image
janebob99 in reply toScout4answers

You won't, because it's not standard of care yet. But, your GP or PCP will likely prescribe it off-label to treat side effects of ADT.

Seasid profile image
Seasid in reply toScout4answers

"Q. Does the prostate cancer has also estrogen receptors in addition or even parallel to the androgen receptors?

A. Yes, prostate cancer can express estrogen receptors (ERs) in addition to androgen receptors (ARs). There are two main types of estrogen receptors: ERα (alpha) and ERβ (beta). In prostate cancer:

ERβ is the more commonly expressed receptor in prostate tissue and plays a role in regulating cell proliferation and differentiation. It is often considered protective against prostate cancer progression.

ERα, on the other hand, is less commonly expressed in normal prostate tissue but may be upregulated in prostate cancer, especially in more aggressive or advanced stages. It is generally associated with promoting tumor growth.

The interaction between estrogen and androgen signaling is complex, and both can contribute to the development and progression of prostate cancer. This is why some therapies, like selective estrogen receptor modulators (SERMs), have been explored as potential treatments in specific prostate cancer cases, particularly when conventional androgen deprivation therapies are less effective.

Q. If estradiol patches are used could it contribute to the prostate cancer grow if estrogen receptors are also present in a prostate cancer?

A. Yes, using estradiol patches could potentially contribute to prostate cancer growth if estrogen receptors, particularly ERα, are present in the cancer cells. While estradiol can bind to both ERα and ERβ, its effects differ depending on which receptor is predominant in the tumor.

ERα is typically associated with cancer cell proliferation and tumor progression, so activating it with estradiol could promote growth in prostate cancer that expresses this receptor.

ERβ, on the other hand, is more protective, and its activation can have anti-proliferative effects in prostate cancer. However, its protective role can be overridden if ERα is also present and activated by estradiol.

The overall effect of estradiol would depend on the balance of ERα and ERβ expression in the cancer cells. In some advanced prostate cancer treatments, estrogens like estradiol have been used in hormone therapy to lower testosterone levels. However, this approach needs to be carefully evaluated to ensure that stimulating estrogen receptors does not inadvertently accelerate cancer progression, especially in those with significant ERα expression.

If estrogen receptor status in your case is unknown or concerning, it would be essential to discuss this therapy's risks and benefits with your oncologist."

ChatGPT explains.

Seasid profile image
Seasid in reply toSeasid

Yes, tamoxifen is a Selective Estrogen Receptor Modulator (SERM). It acts as an estrogen receptor antagonist in some tissues, like the breast, but can act as an agonist in others, such as the bones and the uterus.

In the context of prostate cancer:

Tamoxifen is sometimes used to manage gynecomastia (breast enlargement) or breast pain, which can be side effects of androgen deprivation therapy (ADT), particularly when drugs like bicalutamide are used.

However, tamoxifen's effects on prostate cancer itself are less direct since it mainly targets estrogen receptors rather than androgen receptors. Its role in prostate cancer is not typically as a treatment for the cancer itself but for managing certain side effects of prostate cancer treatments.

Since tamoxifen modulates estrogen activity in various tissues, its impact on prostate cancer would depend on the balance of ERα and ERβ in the tumor, similar to the effects of estradiol.

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