A look at the next generation of Androgen Receptor therapies--AR Degraders/PROTACS

[NPfisherman]

Greetings FPC members,

Recently, Cujoe the K9 Wonder asked me if ARV-110 might deserve a post and I confirmed that the next generation of AR drugs--the PROTACs / AR Degraders indeed deserve a serious look. What does one do when those second line AR drugs like abiraterone, TAK-700, enzalutamide, apalutamide, or darolutamide stop working.?? Today, people turn to things like Provenge, Xofigo, Lu-177 or Cabazitaxel, but in the future, these kind of drugs will be the answer also.

But... what is a PROTAC /AR Degrader?? A PROTAC causes breakdown of proteins by targeting a specific system (in this case--AR system in PCa cell lines) as opposed to being an androgen production blocker (abiraterone) or an AR binder inhibitor (enzalutamide). An explanation of PROTAC below:

en.wikipedia.org/wiki/Prote...

But why should this be any better than those second generation drugs ?? My response to you is that these drugs by degrading the AR receptor in prostate cancer cells have a greater ability to inhibit the wild AR type mutations and hold them in check, thus stopping progression or causing regression and buying time, especially for heavily treated patients. ( Our goals--QOL and Buying Time !!!)

ARV-110 is one of the AR Degraders and is already into Phase 2 trials. Some information about ARV-110 from Arvinas:

arvinas.com/pipeline-progra...

and the initial data release from Phase 1 trial:

ir.arvinas.com/news-release...

There are a number of AR Degraders in development currently and I have listed some information on the ones that I have found.

ARD-69

pubs.acs.org/doi/abs/10.102...

MTX-23

mct.aacrjournals.org/conten...

UT-34

clincancerres.aacrjournals....

With ARV-110 in Phase 2 trials, and bromodomain inhibitors like ZEN-3694 and CCS-1477in Phase 2 or headed into Phase 3, we should see some new classes of drugs on the treatment scene within 5 years. These will be added on in combo with other drugs and add years to PCa sufferers lives..

The Science is Coming !!! so keep them peepers open folks...

Don Pescado

[hansjd]

Dear Fish once again thanks so much for your ongoing research and your great posts. Peepers are definitely open. Lol G&J

[NPfisherman in reply to hansjd]

Glad you liked it... AR Degraders and bromodomain inhibitors will be game changers for PCa, especially for the heavily treated... there is a clinical trial now with Enzalutamide, ZEN 3694 and Keytruda at UCSF... an AR blocker, a bromodomain inhibitor, and a checkpoint inhibitor for MCRPC... combos... see below:

clinicaltrials.gov/ct2/show...

It is how overall survival will be changed... when I was diagnosed Stage 4 in 2018, the American Cancer Society said I had a 20% chance of surviving 5 years... (their statistics always lag behind)....recently, I saw another agency said 33%...

With other treatment trials like BAT, nanoparticles, CAR-T, BiTE, vaccines, and more, there is real hope for all of us...

Fish

[Hope59]

Great post, Fish!

[NPfisherman in reply to Hope59]

Thank you.... like everyone here, I am grateful for all the research that is going on and I try and do justice to the discoveries that will benefit so many...

Fish

[GreenStreet]

Great post. Thanks for all the research you bring to the site.👍

[NPfisherman in reply to GreenStreet]

You're welcome... I find the science fascinating.... ARV-110 will be a game changer for many and add years to lives... because it is a new class of drugs that addresses the problem of MCRPC, I believe it will be approved faster...

Fish

[TheTopBanana]

Thank you 🌹🌹🌹

[NPfisherman in reply to TheTopBanana]

You're welcome... the science just keeps on happening... BTW, love the Kermit picture....it ain't easy being green....LOL....

Fish

[TheTopBanana in reply to NPfisherman]

Do you think it could be useful for hormone sensitive patients?

[NPfisherman in reply to TheTopBanana]

I believe it could, but at this point, we have a study showing increased efficacy with the apalutamide and abiraterone combo... IMHO, it should be held for the castrate resistant crowd initially...

Fish