Worrying study on long-term ADT (esp Enza)

[CrocodileShoes]

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.

The reference is: scialert.net/fulltext/?doi=...

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!

[GP24]

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.

[marnieg46 in reply to GP24]

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

[GP24 in reply to marnieg46]

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.

[CAMPSOUPS in reply to marnieg46]

Chemo in between Zytiga and Xtandi can sometimes bring some extra benefit time on Xtandi.

[marnieg46 in reply to CAMPSOUPS]

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 .

[CAMPSOUPS in reply to marnieg46]

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.

[marnieg46 in reply to CAMPSOUPS]

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.

Anyway ....Happy Easter..

[Magnus1964]

I was on xtandi for 4 years. Three years later my PSA is rising. No side effects just rising PSA.

If you are nervous about xtandi, switch to zytiga if you haven't be on it before.

[Benkaymel in reply to Magnus1964]

Interesting that you say no side effects. Did you not at least get any hot flashes or fatigue from Xtandi? Most get that and worse.

[Magnus1964 in reply to Benkaymel]

The first few days I had hot flashes and night sweats. That past within a week.

[Benkaymel in reply to Magnus1964]

Wow, you were very lucky. I'm still getting hot flushes and fatigue 6 months into having Xtandi.

[Magnus1964 in reply to Benkaymel]

I probably didn't suffer long term side effects because I had been on ADT drugs since 1999.

[KocoPr in reply to Magnus1964]

your a true warrior brother being on adt for 24 years and counting , and 31 years with prostate cancer. Your amazing

[GSDF in reply to Magnus1964]

Mag, can we go onto zytiga once Xtandi fails? Or if one fails, both are now ineffective?

[Magnus1964 in reply to GSDF]

If xtandi fails you can go onto zytiga. Failing one ADT drug doesn't mean you automatically failed all.

Magnus

[GSDF in reply to Magnus1964]

🙂👍

[Magnus1964 in reply to GSDF]

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.

Magnus

[GSDF in reply to Magnus1964]

You're amazing Mag... Very inspiring....Thank you brother! 🙂

[CrocodileShoes in reply to Magnus1964]

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!

[Tall_Allen]

1. Yes, it is common knowledge. But the increase in survival from continuing is much greater than the small risk of NEPC.

2. That would be like cutting off your nose to spite your face.

3. Apalutamide, abiraterone, and darolutamide are substitutes in various situations.

[rsgdmd in reply to Tall_Allen]

Would you not expect to see NE differentiation with apalutemide & daralutemide? Similar drugs to enzalutemide, just haven't been around as long.

[Tall_Allen in reply to rsgdmd]

I wouldn't expect NE differentiation with any second generation drugs. It is the exception (less than 1 in 5) rather than the rule.

[CrocodileShoes in reply to Tall_Allen]

Thanks. Duly noted.

[Farmhand]

look into BAT (Bipoplar Androgen Therapy) as another option….also search this site for info on Adaptive therapy

[Islandboy2021]

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.

[maggiedrum]

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.

[Stevecavill]

the long term side effect of stopping ADT is death from prostate cancer.

[Nfler in reply to Stevecavill]

yes probably true but the long term effects of adt is also death from prostate cancer…!

[CrocodileShoes]

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.

Thanks for all your concern

[KocoPr in reply to CrocodileShoes]

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.

frontiersin.org/articles/10...

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

[Grandpa4]

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.

[Magnus1964]

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.

Magnus

[Ian99 in reply to Magnus1964]

Hi Magnus. During all that time why were you never prescribed chemo ?

[Magnus1964 in reply to Ian99]

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.

[Ian99 in reply to Magnus1964]

Thanks. Your long run is an inspiration to read. Continued good luck.

[CrocodileShoes]

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.....

[Nfler in reply to CrocodileShoes]

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…

[Nfler]

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…