I just came across a study (2019 International Journal of Pharmacology) that suggests that long-term use of ADT can cause neuroendicrine differentiation, leading to rapid spread and more aggressive spread. (the article was actually about the use of propanalol to counteract the effect of NED, but the thing that struck me was the long-term effect of ADT.
I've only been on Enza for 9 months - it has now failed - but before that I was on bicalutamide, and casodex , and the 3 monthly Zoladex injections. In total, 5 years of ADT. I'm about to go to Singapore and Australia on a work trip, my Onco is currently on vacation, so says carry on with Enza (even though PSA is doubling every 3 months - now standing at 3.3) before testing for Abiretarone when I get back. I get the theory of 'it may continue to rise, but it would rise a lot more if you stopped ADT altogether' but what if continuing with Enza/Xtandi was actually making it worse?
I'm hoping to get a consultation in Melbourne, because I'm now considering the Hail Mary option of Pluvicto sooner rather than later (I'm really reluctant to go down the chemo route unto all options are closed) But until then would consider Abiretarone.
So here's my questions:
1. Is this NED affect of long-term ADT common knowledge? If so, is it particular to Enza?
2. Has anyone ever just stopped ADT and, if so, what was the impact on their PSA?
3. Does anyone have any alternatives to Enza (I was already coming off it because of the horrible, exhausting SEs)?
Your advice as ever, is gratefully received!
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CrocodileShoes
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With any second generation androgen deprivation you have a risk that the tumor cells become castration-resistant by mutating to neuroendocrine-like cells. This is not fully neuroendocrine its called treatment-emergent neuroendocrine differenciation. You have to accept that risk and get second generation ADT otherwise your cancer will progress quickly and the PSA value will rise. ncbi.nlm.nih.gov/pmc/articl... This mutation is probably caused by the intense pressure the tumor gets from second generation ADT. It is not special to Enza.
The next step will be Abiraterone which will not work for long. You might as well get a chemo or better Pluvicto.
Is the reverse true GP24? With Abiraterone for example. And with treatment induced differentiation is PSA still the best indicator that the cells have mutated?
Thank you for all the well informed advice you provide. It is appreciated
When you start with Abiraterone, Enzalutamide will work for several months only. This is called cross-resistance. As far as I recall, there are studies that one or the other will work a bit better. They have different results.
To determine this differenciation, you will need a biopsy. Also, imaging will show progression at low PSA values.
Thank you. It hasn't been mentioned. MO said when Abi fails...expect after about 2 years then he'll have Lu 177. Pretty expensive option but if it does the trick.
He only lasted about six months on Enzalutamide as the side effects were totally debilitating to the point where he could hardly walk or function cognitively. Like a new man on Abi. Happy, active, virtually no side effects...to the contrary- given him a new lease on life. Don't think he'd be too keen to have another go on Xtandi again. I'll do a bit of research on chemo though now that you've mentioned it as the 'two year' mark is fast approaching and I like to be prepared .
I think I misunderstood your comment. I thought he was on Zytiga and about to start Xtandi.
In my humble opinion an ability to move onto Lu-177 after Xtandi and Zytiga fail to bring benefit is not a bad thing if your healthcare pays for it or most of it.
Nope it's ok. I knew what you meant and there's no guarantee that his MO won't recommend going back on Enza if Abi fails so it's good to have the knowledge about chemo up my sleeve....though I know that's not the best option for him.
Lu177 isn't not funded here (except if you're on a trial) like I think it might be in the States..it's probably about between 10K and 12K a treatment. But if it's the right option then that's the way we'll go.
I was on Zytiga for 3 1/2 years before it failed. I then went on xtandi and was on that for 4 years before it failed. And by the way years before I was on Zytiga, I was on Casodex for 5 years.
Many years of good quality life. Keep in mind everyone responds differently to drug therapies.
My question further down the thread is no longer relevant, Magnus. Sorry, I hadn't caught up on all the responses! Ignore it. 4 years on Xtandi....I got 7 months!
I stopped ADT once. PSA was undetectable before and after 9 months PSA was 1.0. Started ADT again and PSA only dropped to 0.17. Then PSA starting climbing, became castrate resistant and now have added abiraterone. PSA still climbing and have new mets. Looking at adding new treatments, I have already had chemo.
My question is always does ADT cause changes/differentiation or does it just allow the differentiated cells to out-compete the hormone sensitive cells. Excessive UV from too much sun can cause mutations and cancer. I don't think it lets underlying UV-resistant cells to out-compete with UV-sensitive cells. Of course, our DNA is not passive. Some changes in the cell (e.g. from no testosterone and the no T chemical cascade from that) has been shown to activate different genes (if I remember right). That would fall under the category (in my view) of actively changing cells and not simply allowing cells that are already differentiated via built-in mutations.
A huge number of our genes are never expressed, but can be caused to be expressed under certain stimuli, which would include the removal of some "stimuli". The DNA has not actually mutated it is just changing how it is "used". I guess that is splitting hairs but it is part of my ongoing internal dialogue as to the details of the disease/therapy progression.
I'm overwhelmed by the responses to my question. Many thanks, although some seem overly dramatic. To reassure everyone, I never had any intention of simply stopping all treatment! In fact, I resume Xtandi (half dose) tonight, after a 2-week vacation. My body just needed a break. I feel much more like my old self, so now I can go back to feeling awful again! And do bear in mind, folks that, a quarter dose of Xtandi saw better numbers than the full dose - in my case. And I've been reassured over the NED chances. I'll stay on half dose Xtandi, as I seemed to tolerate that slightly better, while I'm away for the next 6 weeks. After that, my onco is back, and we'll re-evaluate. I'll probably give Abi a try, get some genetic profiling done and when the Abi fails, fly to Heidelberg, or Perth , or Melbourne to try Pluvicto.
If you search this forum for neuroendocrine or NED there are some posts that have blood markers you can keep an eye on during your quarterly blood tests.
I just recently asked by MO at MGH “How do we know if my cancer is growing as a neuroendocrine type?” He said tests We keep an eye on are rising LDH, ASP, rapid weight loss all this without PSA rise.
The most common markers are chromogranin A, CD56, synaptophysin, and neuron-specific enolase, with synaptophysin being the most sensitive and chromogranin A being the most specific marker. Elevated expression levels of chromogranin A are associated with higher disease burden and poorer prognosis of prostatic carcinoma.Oct 3, 2022
I think of it differently. The tumor is always mutating. When you take away testosterone, cells that can go in the absence of testosterone grow. It is not causing the mutation just creating an environment where it can outcompete other forms. The alternative is to allow your prostate cancer to grow so fast that it wins the competition. In this scenario you lose faster.
I stopped Xtandi 3 years ago and I am still here. My PSA is rising but still asymptomatic. I have been on first and second generation ADT drugs for 20 years. I don't know what the future holds at this point, but I have had a lot of good quality life.
As always, as I have told many on the this forum, everyone responds differently to treatments. I can only tell you what my experience has been. I have had a lot hind site and wished that I knew 30 years ago, what I know now.
I have never had chemo. I think it has a benefit for some. Has I have always tied to tell the members here, everyone responds differently to treatments. Other factor of health prevent me from risking chemo. I may in extreme circumstances.
It sounds like Magnus didn't need chemo....wow, quite impressive can-kicking, Magnus! I've still got a lot of the othe 'mides' to try (Darolutamide, Dutestaride, Apalutamide, Finisteride, etc) I presume, Magnus, you've gone through this, or have you had exceptionally good luck with Enza only? For me, chemo is going to stay at the end of the road.....
Croc shoes, like Magnus says we all respond differently so you have to go with your own educated gut feeling. I personally had pretty good luck with zytiga especially hearing all the horror stories from x, though they say it happens 1 in 5, that’s just what they know of, probably higher if more people came forward.Also ivermectin has shown to kill off crpc n allow the 2nd gen drugs to work again if your sold on the continuous use. Pluvicto is hard to come by now days w the Novartis misstep shortage. Should be up in running at full strength in six months as a second company is starting to make the drug as well n is very promising, they’re just trying to fine tune the dose.Last n not least they’re working on an mRNA vaccine 💉 that’s having great results w lymphomas n should be out in two years and don’t quote me on it but word is out pca vaccine is to follow, hopefully in two-five years. So there are a lot of things in the works, let’s just try n stay alive long enough to see them. 😁😇😍🥰Mad love to you all…God bless…
Croc shoes, like Magnus says we all respond differently so you have to go with your own educated gut feeling. I personally had pretty good luck with zytiga especially hearing all the horror stories from x, though they say it happens 1 in 5, that’s just what they know of, probably higher if more people came forward.
Also ivermectin has shown to kill off crpc n allow the 2nd gen drugs to work again if your sold on the continuous use. Pluvicto is hard to come by now days w the Novartis misstep shortage. Should be up in running at full strength in six months as a second company is starting to make the drug as well n is very promising, they’re just trying to fine tune the dose.
Last n not least they’re working on an mRNA vaccine 💉 that’s having great results w lymphomas n should be out in two years and don’t quote me on it but word is out pca vaccine is to follow, hopefully in two-five years. So there are a lot of things in the works, let’s just try n stay alive long enough to see them. 😁😇😍🥰Mad love to you all…God bless…
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