How long to Castrate Resistance: ADT+/- ARSI

[MateoBeach]

Further discussion on details of EMBARK study on another HU forum bears restating here (IMO). For high risk BCR (and beyond) ADT combined with ARSI (in this case enzalutamide) is clearly superior to either monotherapy. However, development of castrate resistance between ADT + Enza vs. Enz monotherapy which can be FOLLOWED by ADT when Enza fails is not answered in this study. Longer term follow up of the subgroups is needed. Here is my analysis:

"Yes, if they had an undetectable PSA at week 36 then they could go onto suspended treatment ("vacation"). 91% in the ADT + Enza group suspended for a mean of 20.2 months and were "on" the treatment or 32.4 mo. 44% did not receive Tx for 24 months.

For ADT mono only 68% qualified for suspension which averaged 16.8 months (On treatment 35.4 mo. 32% did not receive Tx for 24 months.

Eza mono was again intermediate: 86% qualified for treatment suspension which averaged 11.1 months. 20.4% did not receive treatment for 24 months. So they had the longest time-on-treatment of 45.9 mo average.

But the other question is how did these hormonal treatments affect emergence of castrate resistance? They formally report this as 3.9% (14/355) for ADT+ E vs 34% for ADT mono. (!) They cannot report it for Enza mono as they could always add Lupron, and these had supra-physiologic Testosterone levels, so do not meet criteria for CR. It is an additional unmeasured possible advantage of ARSI monotherapy as it could be followed with ADT when monotherapy fails.

Another measure is PSA progression which is available for all groups as a proxy for regimen failure: This is 2.3% (8/355) for ADT+E combo; 26% (93/358) for ADT mono; and 10% (37/355) for Enzalutamide monotherapy.

Paul/MateoBeach

[swwags]

Can SSE equate to failure? ncbi.nlm.nih.gov/pmc/articl...

[Scout4answers]

Not sure I totally understand what the implications are...

One should seek out Enza as a mono therapy and when it fails use Lupron as a mono therapy?

One should seek out ADT + Enza and when it fails switch to Enza Mono?

[MateoBeach in reply to Scout4answers]

Or vice versa in my view. At least possibly. CR is a one way street so far.

[Scout4answers in reply to MateoBeach]

Since it is too late for me to change what has been done are you saying that one should continue with ADT + Abi and when it fails switch to Enza or Abi Mono? or better yet switch to an ARSI mono before ADT+ Abi fail.

Right now it looks like a 3rd generation ARSI (which have been mentioned here recently ,now in trials) may be the best move if and when they become available. If I remember correctly they block the protein which PCa needs to metastasize.

[MateoBeach in reply to Scout4answers]

ADT with Abi or ADT with an ARSI I a fine way to go Scout vs mono therapy. I’m just trying to consider options beyond that might extend total time to CR (unknown). I have kept my time on ADT to a minimum, even now on long-cycle BAT. I remain HS with undetectable PSA 16 years since diagnosis and 14 since BCR. N=1 🤷‍♂️

[Tall_Allen]

It is pure nonsense to believe that hormone therapy speeds up the occurrence of castration resistance, when ALL of the trial results (and there is a huge amount of it) say exactly the opposite.It is also pure fiction that taking ADT vacations delays castration resistance. Stick to the science instead of imagining how you would like it to work.

[MateoBeach in reply to Tall_Allen]

Bs. The trials compared ADT as SOC to ADT plus. It is ADT that selects for castrate resistance. The other factor is replication rates and hence mutations, which is why ADT plus an ARSI is superior. The question I posed remains unanswered regarding sequencing. That is also consist with why ADT mono therapy is inferior.

[Tall_Allen in reply to MateoBeach]

HT extends survival - castration resistance is beside the point. SWOG-S9364 proved that intermittent ADT extends neither, decreasing survival by 10%. Antiandrogen monotherapy has always proved inferior because it doesn't prevent and block androgens as well as the combo. This is not controversial.

[Schwah in reply to Tall_Allen]

You are usually very careful TA to have science to back up Your statements. Here I think you have your own confirmation bias against intermittent ADT may have lead to you overstating what’s proven or not about intermittent ADT. I’ve discussed this in detail with Dr. Scholz. First, the IADT VS CADT studies did not prove a 10% decrease in survival. The study results showed no difference in survival that was statistically significant. The studies also were done on ADT alone vs ADT plus any of the newer drugs like Zytega. Finally these studies had very high thresholds to go off IADT which may have been too high. I believe a more accurate statement on the subject would be that “there are currently no studies that show a statistical difference between IADT and CADT. And no one has yet studied IADT with ADT plus Zytega etc.” Anyway you know this stuff better than I do let me know if I’m way off base here

Schwah

[Tall_Allen in reply to Schwah]

It certainly DID show a 10% decrease in survival with intermittent ADT. Your understanding of statistical significance is very wrong. It was a non-inferiority trial, which means that beforehand they set up a 20% decrease in survival threshhold to call intermittent ADT "inferior." It only decreased survival by 10% - but the 90% confidence interval included a decrease in survival by 23% and only 1% had a survival increase. They could "not rule out" a 20% decrease in survival with intermittent ADT.

Because of the lower-than-expected death rate in both groups (as often happens because patients in clinical trials get such great care), the study was "underpowered" to get a smaller confidence interval, but the best guess is the median, which is a 10% decrease in survival. Because this was set-up with a threshhold of 20%, it is "statistically inconclusive," which is very different from "statistically insignificant."

The statistics that most patients can relate to is that median survival was 5.8 years in the continuous-therapy group and 5.1 years in the intermittent-therapy group

I suggest you and Scholz call Maha Hussain to explain this. (I asked her about it at the last GU Conference.) It seems straightforward to me, but I spent 20 years with statistics, and most doctors have not.

I agree that newer ARSis may help, but that remains to be proven.

Finally, I disagree that she set the end-of-vacation PSA too high (20 ng/ml or 10 ng/ml at the doctor's discretion). What is the point of a vacation if one's ADT-symptoms do not get better? Trials that look at non-metastatic patient groups usually use a much lower PSA threshold for ending the vacation (typically 4 ng/ml). Now with PSMA PET scans, one can use metastatic growth as a signal.

[MateoBeach in reply to Tall_Allen]

I was not discussing the IADT Trial. You went off the rails there but I hope you feel better. The enzalutamide mono therapy group had supraphysiologic testosterone as was reported. Their suspended treatment was entirely different. What we don’t know from this is if when they ultimately fail enzalutamide mono therapy could they then go on ADT and further extend time to castrate resistance? I don’t have that answer and don’t expect one from you unless you have that from some study I am not aware of. And any personal attack is unwelcome. Thank you

[Tall_Allen in reply to MateoBeach]

The post above was in response to Schwah's post, not yours.

What you misunderstand is that testosterone accumulates when all androgen receptors are blocked. But that can have no physiologic effect because the androgen receptors are blocked. We further learned that blocking androgen receptors is inferior to the combination with GnRH agonists because the effect on number of cancer cells is greater than any effect on survival of clones.

[StayingOptimistic in reply to Tall_Allen]

TA, I am on Erleada and Firmagon. My current psa is .02. Does your statement above means that the androgen receptors are not all blocked since my psa is not .00?

[Tall_Allen in reply to StayingOptimistic]

0.02 is essentially complete response.

[StayingOptimistic in reply to Tall_Allen]

Do you think it’s safe or somewhat safe to take a vacation for 6 months and monitor psa? Thanks

[Tall_Allen in reply to StayingOptimistic]

Only you can answer if it's worth the risk to you.

[StayingOptimistic in reply to Tall_Allen]

I am sorry, I am not arguing. I am just trying to understand the disease. What is the risk? I will be monitoring the psa and once it’s gone to .05, I will start ADT and Erleada back. Please tell me what is the risk so I can try to avoid it.

[Tall_Allen in reply to StayingOptimistic]

What is the point of a vacation to 0.05?

[StayingOptimistic in reply to Tall_Allen]

1)Improved quality of life

2) Reduced risk of long-term side effects.

3)Improved cancer control (I always have the fear that cancer might change to a more complicated type like Neuroendocrine type.) If I stayed too long on it

4)Improved bone health

I was just thinking to stop for about 6-9 months or so

Thanks

[Tall_Allen in reply to StayingOptimistic]

I guarantee that you will not experience any of those benefits if you go back on ADT when your PSA reaches 0.05. But, by easing up on the pressure, you may select for more virulent types of prostate cancer.

[StayingOptimistic in reply to Tall_Allen]

“by easing up on the pressure, you may select for more virulent types of prostate cancer.”

WOW, I thought it was the other way around.

[Tall_Allen in reply to StayingOptimistic]

Think of it this way: When you stop taking an antibiotic too soon, you select for strains most resistant to antibiotics.

[StayingOptimistic in reply to Tall_Allen]

That is absolutely true but then sometimes I think of it in a different way like years ago when I used to have muscle pain, I used to take a couple of Advil and the pain is gone , now as I got older, it does not work for me as good. Isn’t that considered “ resistance “? does the same happens with ADT drugs?

[Tall_Allen in reply to StayingOptimistic]

That's not resistance - it means your pain is worse. It doesn't matter how you "think" about any of it - it only matters what the empirical facts are.

[Justfor_ in reply to StayingOptimistic]

The risk is that you will increase the load to your medical system. More frequent labs, queries that can't be answered by your docs (like the one you just posed), less consumption of drugs affecting the pharmaceuticals turnover. Do we want any of this?

[Nfler in reply to MateoBeach]

Matt that was great “I was not discussing the iadt trial. You went off the rails there but I hope you feel better.”

😂

We’ve had problems w his condescending ways and inaccuracy before, nice to see you stand up to him like that, much encouraged as he has people walking on egg shells when all they’re trying to do is learn about this dreaded disease…

[Nfler in reply to Schwah]

Dr Scholz is a medical oncologist actively treating patients and a good one at that. Ta is a statistics guy, hence that’s why he doesn’t have Dr attached, so I would stick w what Dr. Scholz says hands down…

[mrscruffy in reply to Tall_Allen]

Ya my 7+ years on ADT show that for me this was the correct choice

[JWPMP in reply to Tall_Allen]

I'm not sure what all this means. Every three months starting January this year, they have offered to Jim to take a "vacation". Dr Borno at UCSF said last week since Jim is tolerating treatment so well, it is more of a personal QOL decision and would not be "clinically significant " because they would take action at 0.2 Jim still declined. Thinking Jim is making the correct decision??

[Tall_Allen in reply to JWPMP]

That was one of the findings of the intermittent ADT clinical trial - that even when the vacation lasted until PSA reached 20 ng/ml, most men did not regain enough QOL to justify the loss in survival.

[JWPMP in reply to Tall_Allen]

And if there's no gain at 20, there certainly won't be at 0.2 I would think. And if they could guarantee a couple years of "vacation", just the "mental" break from pills & shots might be worth the gamble. But it could be as little as a mere couple months I'm thinking. Where's the upside of that?

[ImDD]

Not sure what all this means. Eventually, all prostate cancers become castrate resistant?

[Radars in reply to ImDD]

I have been on intermittent ht since 2016,psa check every 6months still undetectable 0.03.

[MakeItRainbows in reply to Radars]

Can someone help me understand if there is any practical difference between the statements:

* PSA is undetectable

* PSA is extremely low (0.03)

* PSA is <=0.1

I guess I'm asking because if PSA is truly "undetectable", why do some people cite their PSA?

Not a criticism. Truly trying to understand.

[Radars in reply to MakeItRainbows]

psa 0.03 and 0.1l is undetectable meaning zero prostate cancer

[Justfor_ in reply to MakeItRainbows]

No, there is no practical difference between them. If spoken by a medical professional all of them are synonymous to: "There is no change in your current treatment or the lack of it thereof." BSing in a pseudo-scientific format.

[maley2711]

well, apparently we have a disagreement?

[Mechizadek in reply to maley2711]

Perhaps the issue is that the treatments (ADT etc) do not cause the mutations. The mutations are continually arising and the treatments work until a mutation gains the upper hand that is not managed by the treatments. Then it is time to change the treatments.

[Nfler in reply to maley2711]

😂

[j-o-h-n]

How can those smart little bastards be inside of a dumbass like me?

Good Luck, Good Health and Good Humor.

j-o-h-n Tuesday 10/24/2023 9:23 PM DST

[Bestdays in reply to j-o-h-n]

Good question lol

[j-o-h-n in reply to Bestdays]

LOL that's why I asked..............

Good Luck, Good Health and Good Humor.

j-o-h-n Wednesday 10/25/2023 12:00 PM DST

[Seasid]

I am missing the point of this discussion. Some people just simply live long on ADT alone. I had an early chemotherapy and was supposed to be on IADT but I was too scared from it therefore I am on continuous ADT.

I am enjoying that I am still alive after 5.5 years after diagnosis as multymetastatic in my spine and neck etc.

I believe people on this forum believe that stopping ADT is like asking for trouble. If it keeps you alive why would you expeiment with yourself? I am on firmagon injections.

The median life expectancy with my diagnosis is 2 to 3 years.

[j-o-h-n]

If you hear a sound like lots of marbles rolling around on a tiled bathroom floor, don't fret, it's only the sound of my head spinning around, cause I don't understand the question (or would understand the answer). But knew that anyway...

Good Luck, Good Health and Good Humor.

j-o-h-n Wednesday 10/25/2023 10:02 PM DST