ARPI Effect on PSMA Expression/Sensitivity

[lokibear0803]

From this article presented as in-progress update on the PSMAddition trial, from ESMO 2021:

urotoday.com/conference-hig...

…the statement is made that:

“…androgen receptor pathway inhibitors (ARPI) have been utilized in this disease space and metastatic hormone-sensitive prostate cancer (mHSPC) for many years. Notably, ARPI treatment may alter PSMA expression and radiosensitivity. ”

I have two questions:

1– am I correct that ARPI includes ENZ and ABI?

2– do we know what is the hypothesis here, i.e. when we say “alter PSMA expression and radiosensitity”, does this mean favorably or unfavorably?

Thanks for your thoughts.

[Tall_Allen]

1 - yes

2- increase temporarily then decrease

[lokibear0803 in reply to Tall_Allen]

Thanks TA!

[GP24]

This article reports that Enza increases the PSMA expression:

eurekalert.org/news-release...

This is currently tested in Australia in the ENZA-p trial:

ascopubs.org/doi/abs/10.120...

[lokibear0803 in reply to GP24]

Fantastic, thanks GP24.

OK, so Tall_Allen is suggesting the effect is to at first temporarily increase, but then decrease, PSMA expression/sensitivity.

The PSMAddition trial NCT04720157 allows up to 45 days of CYP17 or ARDT, by which I assume CYP17 = abiraterone and ARDT = either abiraterone or enzalutamide. This would be consistent with the presumed initial increase followed by a decrease in PSMA expression after some period of time…am I right so far?

Do we have a sense of just how long the enhancement would last before onset of PSMA expression decrease?

However the ASCO article from @GP24 excludes prior ENZ but not prior ABI. Then it must be that the trial referenced in the ASCO article has a different hypothesis: prior ABI will NOT reduce PSMA expression after time, while ENZ does (since they want no prior ENZ). Am I interpreting this part correctly?

Many thanks.

[GP24]

I think Tall Allan refers to this study: link.springer.com/article/1...

This is a retrospective study, a prospective study was done by Prof. Emmett: jnm.snmjournals.org/content...

I think it is difficult to get a simple conclusion from this. The PSMA flare begins quickly, in about a week or two, but I cannot tell how long it lasts. I am also not sure that it turns into a PSMA decrease later. Some doctors argue, the reason for the decline observed in the above studies could be that ADT makes the lesions shrink. Smaller lesions will then not be visible with a PSMA PET/CT and have less PSMA expression in general.

The researchers currently believe that an antiandrogen like enzalutamide has to be used to increase the PSMA expression, the androgen receptors have to be blocked for that. Therefore enzalutamide is excluded before the ENZA-p trial as the ASCO article mentions, because this is the drug which shall be used to create a flare. Abiraterone is no antiandrogen, it lowers testosterone and does not block the androgen receptors.

With ARDT Novartis means abiraterone, enzalutamide, darolutamide, or apalutamide, etc. novartis.com/clinicaltrials...

[lokibear0803 in reply to GP24]

Again, fantastic information, GP24 . I thank you very much.

Then the Emmett prospective comes close to what I’m trying to get to: the salivary glands showed no change from baseline regardless of androgen blockade (AB), while the PC lesions did show reduction in PSMA.

So, I (mistakenly?) generalize this from the salivary glands to other PSMA-expressing areas: although saliva glands, liver, kidney, brain, and etc. express PSMA, they do not show PSMA reduction with ADT…probably because they do not rely on androgens as do PC tumors.

If you believe I’m misreading, please let me know. Can’t thank you enough for those very useful links.