BCR May Not Be a Strong Surrogate End Point for Prostate Cancer Survival

[pca2004]

A new study, below [1] & [2].

In 2004 I came across old studies that showed that ADT promotes changes to the androgen receptor [AR] environment. At diagnosis, the AR is invariably "wild type". When ADT failed, AR gene amplification was common. True mutations were rare.

{This was sufficient for me to delay Lupron as long as I could (I still haven't used it, but I do use DES [Diethylstilbestrol]) and to develop the hypothesis that periodic testosterone replacement might be useful during ADT, to reverse adaptations.}

The irony is that the AR - normal at diagnosis - remains the ultimate target of AR-axis therapies - even though success is short-lived imo.

With more aggressive AR-axis treatments, AR splice variants such as ARV7 have became common.

The ultimate response to very aggressive AR-axis therapies, is a retreat into a stem cell-like state (i.e. without AR). And neuroendocrine PCa [NEPC] has thus become more common.

In castrate-resistant [CRPC] intervention studies, and even those involving hormone-sensitive metastatic cases, there is little need for a surrogate for overall survival. But in local hormone-sensitive PCa, overall survival times can be lengthy. The "time to biochemical recurrence" [TTBCR] has been used as a surrogate. The idea being that if a treatment is effective for a longer period, overall survival will be correspondingly longer.

My problem with this is that treatment itself results in treatment-emergent states that tend to reduce post-treatment survival. The cost of increasing treatment-effective durations is the creation of a more aggressive disease. Therefore, one must be careful when using "time to biochemical recurrence" as a surrogate for increased survival time.

"In a recent study published in the Journal of Clinical Oncology, researchers found that biochemical recurrence (BCR) was not a reliable surrogate end point for overall survival (OS) in patients with localized prostate cancer(PCa)." [2]

"Individual patient data from 11 trials evaluating radiotherapy dose escalation, androgen deprivation therapy (ADT) use, and ADT prolongation were obtained." [1]

"TTBCR was measured as the time from random assignment to BCR or the onset of ADT without recurrence or any cancer-specific death. Biochemical recurrence-free survival (BCRFS) was defined as the time from random assignment to BCR or death of any kind. OS refers to the time from random assignment to death." [2]

"Although BCRFS and TTBCR are prognostic, neither measure successfully met the surrogacy criteria. ...

“Overall, these results strongly suggest that BCR-based end points should not be the primary end point of any randomized trial in localized PCa.”"

-Patrick

[1] ascopubs.org/doi/10.1200/JC...

[2] ajmc.com/view/while-prognos...

[MateoBeach]

Well Patrick, you have certainly summarized the "Catch 22" problem of early androgen axis treatments including ADT and survival. Certainly "kicks the can down the road" for a time, while also creating the circumstances for castrate resistance and failure. Most studies of advanced PC compare ADT with, or without, some other treatment and mostly in mCRPC. So difficult to impossible to extrapolate that to approaches to early treatment, such as BCR after failure of primary curative-intent treatments.

I also have chosen to avoid sustained ADT at all costs. Having used only short ADT duration adjuvant to SBRT (4-6 months) and use Orgovyx with Nubequa for only one month out of 4 with my modified BAT program. A small informal seeries of HSPC patients on BAT programs suggests it works even better in this setting than in mCRPC. Remains to be tested formally but of course we cannot wait for that! Paul

[Scout4answers in reply to MateoBeach]

Most interesting discussion as I am having emotional mood swings that I attribute to lack of Testosterone in my system, I have been on Lupron now for 24 months and my PSA is now 0.01 .

I have been contemplating taking a vacation. Is there any way to determined if my treatment has created stem cell-like critters (i.e. without AR). or neuroendocrine PCa [NEPC]?

Can I reasonably assume that since My PSA is undetectable that the transformation has not yet occurred.

[MateoBeach in reply to Scout4answers]

I concur with Patrick, Scout.

That your PSA is .01 on Lupron after 24 months means that it has not yet become castrate resistant (not dependent on extrinsic androgens for growth). However, if you persist with continuous ADT you can expect that you will become castrate resistant. "When" cannot be predicted and is variable but averages 24 months. NEPC transformation cannot be followed by PSA levels as it often does not produce any. Best followed by scans. However, NEPC arises in established CRPC so you are not there yet.

I agree that ADT "vacation" without testosterone recovery is no vacation at all. Decision to undertake BAT programs while still HSPC is a personal one. However, it can be monitored with PSA and occasional scans to see if it is working or not. Suggest you read Russ Hollyer's book on Bipolar Androgen Therapy on Amazon/Kindle if you want to consider it further.

[Scout4answers in reply to MateoBeach]

Thanks Paul I have been following Russ since I joined here. I did read an early version but will go to facebook and get up to speed. Actually of all the versions of BAT I have been watching yours is the one that appeals to me most. It seems to be closer to Gattenby's Adaptive Theory. I like the Idea of T for longer and ADT shorter. Keep the critters guessing.

[Scout4answers]

Does DES [Diethylstilbestrol] block Testosterone?

Your opinion on my question to Paul below would be appreciated.

[pca2004 in reply to Scout4answers]

Hi Scout,

Before Lupron there was DES. Diethylstilbestrol is a synthetic estrogen. It suppresses testosterone production.

It differs from Lupron & the like, as follows:

a) it does not cause bone loss

b) aside from blocking T production it has anti-PCa properties

c) it is inexpensive, but prescriptions have to be filled in the US at a compounding pharmacy

d) at the onset of covid it was convenient to be taking a daily cap (no office visits for shots)

e) as an oral estrogen, it increases the chance of a blood clot - however, nattokinase plus D-dimer monitoring eliminates the risk

***

You have been on Lupron for 24 months. That's a long time. For most men, Lupron monotherapy lasts 18-24 months, although some men are able to use it for much longer.

After 24 months, T will not recover quickly & probably never to previous highs. If you want a vacation, you will remain castrate for many months imo. I have always thought that T should be restored during IADT vacations. Not to ~350 ng/dL, but to ~1,000 ng/dL.

You do not have CRPC, but you might be interested in Denmeade's BAT protocol. Best to find a doctor who has interest & experience.

For non-standard BAT, what works for me, or Paul, might not be so good for you.

In the past, I avoided being heavily treated by alternating between 3 months of T restoration & 3 months of castration. It gave me years of a high QoL - very easy to tolerate. A very good protocol when starting ADT, imo. But after 24 months continuous ADT?

-Patrick

[maley2711 in reply to pca2004]

so, when men with Gleason 8-10 select radiation as the initial treatment, 18-28 months of ADT is prescribed, and studies show lower PCa-specific mortality with the longer ADT durations. So, what to do for such men after initial diagnosis of local PCa?

Should we follow PCa mortality or overall mortality?

[pca2004 in reply to maley2711]

"PCa mortality or overall mortality?"

Years ago, I had a difference of opinion with "he who must not be named". He had posted the results of a clinical trial that showed that, compared to a certain treatment, a more aggressive version reduced the risk of PCa death even further.

However, overall mortality remained the same.

I pointed out that the men with improved PCa mortality had been subjected to the morbidity of the more aggressive treatment - without any overall mortality advantage. The aggressive treatment increased the likelihood of death from other causes. (Whatever happened to "First do no harm"?)

His response: Yes, but who wants to die from prostate cancer?

That might resonate with some.

It took me a while to buy into "Heart healthy is prostate healthy.", but it makes sense to me. And the PREDIMED trial is the only trial where a dietary intervention reduced the risk of further cardiovascular events. It's a Mediterranean-style diet (40% fat). I have never suffered a CVD event - maybe I can avoid them altogether?

So, now that I have seemingly reduced the risk of prostate & heart related mortality, should I be worried about Alzheimers? I have the gene associated with increased risk. (I'd sooner die from PCa.)

Of course, by decreasing the probability of CVD mortality - a major competing cause of death for men with PCa, I may have made a PCa death more likely.

In 5+months, it will be 20 years since my failed surgery. Having reached the age of 75, I now do not dwell on death.

-Patrick

[Scout4answers]

Thanks for the informative response.

I was told by Szmalawitz an MO at U of Chicago who worked with Denmeade that they will not prescribe BAT to HSPC men

CRPC means that you now have stem cell-like critters (i.e. without AR). or neuroendocrine PCa [NEPC]?

How would I get a prescription to DES ?

Does DES have any advantage over Estradiol?

[KocoPr]

Hi Scout, neither DHES nor E2 will raise your T. I assume you want a vacation to restore vitality and such.

Read Russ’s updated book.

I have just finished 3rd cycle of pBAT and today i stop my darolutamide and after 5 day washout i will start my 4th high T cycle.

I feel so much better even during my ADT phase and have restored my E2 levels by not taking letrozole (aromatase inhibitor) nor Orgovyx on last high T cycle.

I will shut down the E2 production this time and measure.

One thing about pBAT is i fill my prescriptions of T-propianate and letrozole over seas with no prescription needed.

The medicine goes a long way but expect 1 month for delivery.

[Nfler in reply to KocoPr]

Wow that’s great, at what point did you start the pbat protocol n which pharmacy do you trust w the cypionate n letrozole if you don’t mind me asking…

[KocoPr in reply to Nfler]

I was 17 months into ADT (5 mos on lupron alone then 1 year on both Orgovyx and darolutamide)

I use propianate not cyp.

I sent you a chat