4th pBAT cycle results with Darolutamide questions

[Ichthus316]

Blood Test Results:

8-16-24, end of 4th hiT cycle, drawn 7 hours after 11th T injection:

PSA = 2.25 (similar to previous cycles)

E2 = 87 (should be <30, so have re-introduced the AI letrozole in ongoing 5th hiT cycle)

9-3-24, middle of loT cycle, drawn after 1 week @ full dose Nubeqa and 1 wk half dose:

PSA = 0.48

E2 = 21 (taking low dose E2 patch, .025 mg/d during all loT phases)

9-16-24, end of 4th loT cycle, drawn after 3 wks Nubeqa (2 wks @ half dose) + 6 day washout

T = 16 ng/dL (T reached a low while on Lupron ADT of <2.5 in May, 2023)

PSA = 0.14 (was 0.59 at end of 3rd loT cycle – good response to Nubeqa)

9-16-24 started 5th hiT cycle, planned for 26 days

10-12-24 projected start of 5th loT cycle

The results of the exBAT trial, which utilizes Daro (Nubeqa) during the loT phase of BAT, are still a year or two away, so I’m a bit nervous about using Daro every loT cycle.

What are the risks of taking Daro as above during every loT phase?

Should I be concerned about the development of resistance to this ARSI?

If so, can indomethacin (or something else) forestall resistance?

Can ARSIs eventually feed PCa growth?

[MateoBeach]

sorting out your pBAT Regimen looks like you are doing about one month of high-T alternating with one month of low T. Is that correct? And you add two weeks of darolutamide at front of low-T cycle to block ant residual testosterone that might be carried over. One week full dose and one week half dose. That is a very good plan IMO though I would be inclined the duration of high T to perhaps two months. Something to consider.

I presume you are also on some form of ADT as well. Without it the darolutamide may effectively block AR receptors but it can leave higher testosterone levels if the testicular axis is capable of responding. Unknown what effect this has with BAT. Personally I take Orgovyx during my low T month and also use darolutamide at half dose during the first two weeks.

I share your concern about developing resistance to darolutamide so that is why I also keep exposure brief. Like other ARSIs it can undergo antagonist to agonist mutations even though it is much less susceptible than for other ARSIs. MB

[Ichthus316 in reply to MateoBeach]

Thanks for the reply! I’ve been following your posts for a year or so and I value your experience and insights. I hope your recovery is going well.

You are correct about the length of my cycles. I’m currently adding 3 full weeks of daro during loT, the last 2 of those at half dose. Since starting BAT last spring, I’ve been extending hiT by 1 or 2 shots each cycle. I plan to continue doing so as long as my PSA at the end of hiT remains stable. I take Eligard shots every 12 weeks, so ADT is always running in the background. I wouldn’t mind switching to Orgovyx, though.

I’m leaning toward only adding Daro to my BAT regimen every other cycle, at least for now… due to possible resistance, mutations, and other unknown risks. However, since long periods without T presents its own risks, I may start adding Daro to additional loT cycles if the time to reach baseline PSA without it keeps growing. Sound reasonable?

[PCaWarrior in reply to Ichthus316]

Very reasonable. I use Daro until the last 5 days before high T. I use olaparib for a couple days prior to high T and then for 2 more days.

I use some form of ADT (orgovyx) Pretty much continuously. I'm thinking of adding some Zytiga to some of the low T pulses. I vary my cycle length. Long like Mateo, medium like the trials, and some very short ones (hours to days). PSA has gone down almost every time I've done a short cycle. Cell studies back this up.

And of course I use propionate. Denmeade told me the main reason he doesn't use it is because it isn't "trial worthy". I'm one guy and I want to live so I do what's best for me and my kids.

[PCaWarrior]

I don't know the answer to your resistance question. I think for now I'll kick that down the road. I have a few plans to try to reverse resistance. I don't have super high hopes for any of them. I suspect my best bet might be to rely on BAT to keep me HSPC.

[Ichthus316 in reply to PCaWarrior]

Since last August, my loT cycles have included 3 weeks of half dose darolutamide (I use a full loading dose for 2 or 3 days) and my hiT cycles have been getting longer. My next hiT cycle is planned for 8 weeks. Last loT cycle, my PSA dropped to .05 so it seems that a half dose of Daro is quite effective at this time. My hope is that using Daro only a third of the time at a reduced dose will forestall resistance to the ARSI. Another option I'm considering is the use of indomethacin. The guy from Norway in the FB group says it inhibits ACK1C3, thus development of ARV7. I think I have a paper on that somewhere in my files. I've discussed all this with my MO and he is willing to prescribe it when I'm ready to pull the trigger. Thoughts?

[PCaWarrior in reply to Ichthus316]

I've looked into indomethacin. I haven't found any solid data concerning it. I'm not going to use until I either see good data or as a last ditch effort.

24. Possible resensitization (indomethacin): AD1173402.pdf

apps.dtic.mil/sti/pdfs/AD11...

I use daro 2 out of 3 or 4 cycles. About the same as your use. I don't know the answer. I decided to use Zytiga on some lows. And combine daro and Zytiga on one out of 4 cycles.

something like this:

hiT

lowT nothing added

hiT

lowT daro

hiT

lowT zytiga

hiT

lowT daro and zytiga

Repeat

I have no idea what approach is best, and maybe some combination is best? So I hedge my bets for now.

I combine short, middle, and long cycles. Again, no real reason. Short is backed by some cell and animal studies. Middle matches clinical trials. Long..? If I had to get rid of one of them, it would be long. My PSA continues to go up as the high T environment is maintained. I'm not very comfortable with that. I can knock PSA down, but do long cycles give rise to mets? The short cycles (a day or hours) can be folded into a low T phase. I feel ok about them because I've done over a dozen, and my PSA drops almost every time (one time it went up, but I was in the middle of SBRT).

[Ichthus316 in reply to PCaWarrior]

Are you discounting the paper on indomethacin you linked because it was only a cell and mouse study or because it was restricted to enzalutamide? Or some other reason?

[PCaWarrior in reply to Ichthus316]

Mouse, cell, not a clinical trial. Plus it's the only study I've found. If something can really reverse CRPC I would think you'd have a LOT of interest in it. The government does trials on water!

[Ichthus316 in reply to PCaWarrior]

Here's a small clinical trial on the use of indomethacin in enza resistant CRPC. It is suggested in other studies that daro shares the same mechanisms of resistance as enza

ascopubs.org/doi/10.1200/JC...

[PCaWarrior in reply to Ichthus316]

Thanks. It'll probably make it to my backup plans. BAT followed by an ARSI (enza was trialed) looks very good too. 75%. But we already do that so I'm assuming if I go CRPC I'll need something other than an ARSI and BAT.

[Ichthus316]

I share your hope that BAT will keep us hormone sensitive indefinitely... if we continue learning, following the worldwide trials and working to maximize/refine our protocols and cycle lengths. The reason I brought up indomethacin is because I recall you writing in a post that you have reservations about using daro too often. Presumably this was due to the possibility of developing resistance... or was there another reason? This small but new trial (published in 2024) at least gives us a reason to further explore indo as a backup plan should we develop resistance. Or in my case, in an effort to forestall it. I've been responding so well to daro that I'm very hesitant to reduce my use of it.

A few mos back, MB wrote this about daro in one of his replies to this post:

"Like other ARSIs it can undergo antagonist to agonist mutations even though it is much less susceptible than for other ARSIs"

That's a bit worrisome if true! Have you read anything about that possibility?