Your thoughts on getting off ADT while staying on AR inhibitor?

[KocoPr]

I often wonder why am i taking Orgovyx AND darolutamide especially since daro has the strongest binding to the androgen receptors than any of the other ari’s.

What or how would normal T help if im blocking the Andro receptor anyway ?

The only three things i can think of is:

1) Since darolutamide doesn’t cross the blood brain barrier does my brain health benefit?

2) Maybe my estrogen would return to normal (addendum; My estrodiol is normal so far) thus bone and brain health. Any thoughts on this?

3) Would having normal T while on Darolutamide keep my cancer androgen dependent thus not becoming castrate resistant?

Presently I have been on both daro and Orgovyx for a year now.

I am also taking a risk because im taking 10mg of both Osterine and Carderine daily. (Started at same time as daro and orgo)

The only side effects I have are minor in my mind. I don’t have as much drive for anymore big projects and of course no sexual drive, my energy is about 60% of peak before ADT. ( maybe my pitty puppy is tiring me out which is a great thing as she pushes like a trainer would) I have BIG plans for outdoor activities this summer.

I think if I was on any of the other inhibitors it would be even more risky.

[KocoPr]

Believe me,,, im not getting off of ADT at this time but I may in the future.

A recent great popular post broached this subject on “Why do we stop treatment” and it was mostly focused on fellow warriors experience with mostly failures. I did not want to take away from that specific and important subject.

I am mostly looking for the technical reasons like, well like my questions asked above.

[GP24]

The Embark trial tested Enzalutamide monotherapy with good results. One can assume that this would also be the case with Darolutamide and Apalutamide. Here is my post about the Embark trial:

healthunlocked.com/advanced...

[Brysonal in reply to GP24]

it was your thread that prompted the planned convo I am due to have with my MO this week and my follow of Prof Tombal on Twitter so thank you.

[KocoPr in reply to Brysonal]

Hi Brysonal!

Did you have that follow up convo with you MO and prof Tombal?

[Tall_Allen]

The problem is that so far it has only been tested in humans who are also taking a GnRH agonist. So it may effectively block T and DHT when they are both at very low levels. But what about when both T and DHT are elevated? There are no clinical data. It can take several years for any disadvantage to become apparent.

There are a couple of clinical trials testing that hypothesis:

clinicaltrials.gov/ct2/show...

clinicaltrials.gov/ct2/show...

[Brysonal in reply to Tall_Allen]

EMBARK had an Enza monotheraoy cohort which is causing the debate was my understanding?

But yes these things take time and discussion re patient selection is b interesting.

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[FinnO]

Great question! Was just wondering the same thing. I am on similar therapy (Daro+Orgo) after finishing a second salvage (pelvic) round of IMRT. I wonder about a middle ground:  Full strength Daro but "reduced" Orgo (of some sort) to maintain a low, but not zero T (e.g. testosterone saturation theory).

[KocoPr in reply to FinnO]

Reading your bio you stayed on top of your PSA exams I presume as you caught your cancer at PSA4. I also was doing PSA and DRE exams for 10 years every year then getting on androderm to boost my T which at age 53 was 330. Within 30 days PSA jumped to 5.6 and that’s how I got diagnosed.

Your bio has no genetic testing done. I would definitely get that done on your prostate immediately before the slides are degraded like happened to mine after 5 years. Also get the germline genetics done.

What do you mean by Testosterone Saturation Theory? Do you mean Supraphysiologic T used with BAT? If so you would get off the darolutamide ARi , and the Orgovyx for sure and pulse them but we can’t do the SOC BAT as we are not castrate resistant YET. Its to bad the SOC doesn’t include hormone sensitive.

[FinnO in reply to KocoPr]

Yes I was a “good soldier” and did annual DRE and PSA for the better part of 20yrs. I wish "hey your prostate feels big and misshapen go see a uro" would replace >= 4 PSA as SoC. I would have gotten a 10yr jump on treatment. Thanks for the note I updated my bio with genetics. My Decipher was .38 and somatic+germline testing showed no known mutations. My next treatment decision is when to come off ADT/Nub and more importantly how. The “quit ADT cold turkey” SoC doesn’t appeal to me although I'd be tempted to try BAT if/when mCRPC and less to lose. Maybe it’s the plumber/electrician/engineer in me that was taught never to turn crap on/off abruptly. And 24mos ADT is getting scrutinized, rightly so, as a one-size-fits-all SoC due to long term SEs. I have multi-Onco recommendations for how long to stay on ADT therapy ranging from 6-14 mos. 6mos feels too soon so I am hovering around 12-14mos. 24mos is not on my radar screen at this time. I mentioned the TST (wchh.onlinelibrary.wiley.co... as I research alternatives (e.g. ramp down ADT gradually, stay on Nub if already on it and eventually ramp that down as well until both gone). Looking for data, studies along these lines.

[KocoPr in reply to FinnO]

This is an interesting post by Patrick on C-MYC, SPT,

healthunlocked.com/fight-pr...

and further down hPatrick quoted a paper stating that ADT failure relates to a high c-MYC expression.

”From a 2021 paper [2]:

“… findings demonstrate an intricate balance between AR and MYC, and indicate that increased MYC in response to androgen deprivation contributes to castration-resistant PCa, while decreased MYC may contribute to responses to supraphysiological androgen therapy.”

“In support of the physiological significance of this MYC repression, we found DHT (dihydrotestosterone) treatment of CRPC xenografts could rapidly suppress MYC, a response that may contribute to the efficacy of supraphysiological androgen therapy in CRPC. Conversely, androgen deprivation in vitro and castration in vivo led to rapid and persistent increases in MYC. The expression of MYC and of MYC-regulated genes is also increased in CRPC, including in clinical samples without MYC gene amplification. This indicates that decreased AR activity in CRPC can be compensated by increased MYC, and that this may contribute to progression to CRPC after androgen deprivation therapy” ”

[KocoPr in reply to FinnO]

Hi FinnO! Did you get off Daro or Orgo?

Any details of response?

[FinnO]

Hi KP,

My apologies for the late reply. Trying to stay on top of all the nuances of this disease is overwhelming so I am focusing on my last shot at a cure and will cross the mCRPC bridge if I come to it. As for my current state I have not updated my bio in a bit but here is the skinny. I am still on Orgovyx and Daro, 12 and 10 months respectively. I do monthly blood tests so I have good trend data. I have had increasing neutropenia since finishing up my whole pelvic salvage 9mos ago. Latest ANC is 800 (should be at least 1500) and consensus from Uro, MO, Hema is that it is an SE of the Daro. All other WBC and RBC components are good. Just this week we dropped the Daro to 50% for the next month for cause/effect. Fingers crossed in case it’s not the Daro. Otherwise I am tolerating it well and have had no infections, colds, etc. The Orgo is doing its job well which sucks. Latest Dexa shows growing osteopenia so I started Fosamax week. The plan (based in part on latest EMBARK results) is to stop the Orgo at 18mos and continue Daro mono therapy to 24mos. Thought is to try to get my T factory (and libido) started back up while still having an effective AR blocker. MO fairly firm on not going past 24mos. As for muscle mass I lift regularly and have been able to maintain pre-ADT strength but there are days when I’d swear there’s an extra plate on the bar.

[KocoPr]

Thanks for the update.

For your radiation damage you might be interested in hyperbaric oxygen therapy.

ncbi.nlm.nih.gov/books/NBK5...

Isn’t Fosomax a permanent treatment?

You should ask the group either advanced prostate cancer or Fight Prostate Cancer group for advice on some of your issues like low white blood count, neutropenia etc…

Daro and Orgo are the best ADT drugs out there.

I intermix mine with BAT pBAT p=propionate.

Trying to improve QOL and delay Castrate Resistant.

All the best

[FinnO in reply to KocoPr]

Sure thing. My radiation induced GI issues are clearing up but I am keeping my head down and fingers crossed on having no long term chronic GI effects especially after two rounds of salvage. Timing suggests Daro and it’s the easiest to get cause/effect results so trying to confirm/deny suspects one at a time. Hopefully Daro is it because that’s a temporary problem for my plan and/or there are substitutes. I am happy with the Org + Daro choice. BAT is interesting and definitely something I would explore if needed. All the best!