Current Understanding of Resistance to Abiraterone and Enzalutamide in Advanced PCa

[pjoshea13]

Emmanuel S. Antonarakis, Johns Hopkins, below [1].

Mentions 14 ongoing clinical trials, including this:

"Another approach that we have begun to test here at Johns Hopkins is the use of high-dose testosterone in patients with CRPC that has become resistant to abiraterone or enzalutamide (NCT02090114). Preclinical work has supported the idea that exposing CRPC cells to very high doses of testosterone can induce cell death by causing double-strand breaks in DNA as well as by preventing DNA relicensing during the cell cycle. The first of these studies, which was published by Schweizer and colleagues in Science Translational Medicine in 2015, found that monthly intramuscular injections of high-dose testosterone produced significant clinical responses in approximately half of the patients with CRPC. One of our emerging hypotheses is that high-dose testosterone therapy may also work by eliminating AR splice variants."

-Patrick

[1] urotoday.com/recent-abstrac...

hematologyandoncology.net/f...

[savingdaddy]

Wow! I wonder what the ‘preclinical work’ entailed?

[cesanon]

Sartor at Tulane participated in the bipolar testosterone trials, and appears willing to treat using this approach as well.

He treated someone on this forum with this, but it apparently didn't work in that case. But in that case it appeared that he didn't really use really high doses of testosterone. Just androgen instead of injections.

[EdBar in reply to cesanon]

Yes, during my last visit with him (Sartor) when we were discussing what the next step would be when the day comes that Xtandi stops working for me he mentioned rechallenging with T - BAT as one option.

Ed

[kmack57]

Boy, I ‘d love to have my T back!

[Break60 in reply to kmack57]

We all would ! Them was the days🥴!

[j-o-h-n in reply to Break60]

I traded my T for two T's (TITS).

Good Luck, Good Health and Good Humor.

j-o-h-n Monday 03/25/2019 7:00 PM DST (Greek Independence day)

[Break60 in reply to j-o-h-n]

Haha me too ! If I had the nerve I’d send a pic but check out the next issue of penthouse!

[j-o-h-n in reply to Break60]

LOL Cover or Centerfold?

Good Luck, Good Health and Good Humor.

j-o-h-n Monday 03/25/2019 8:03 PM DST (Greek Independence day)

[Adam10]

I too would like my testosterone back but looks like I’m in the intermediate group at this stage - Gleeson 7 but PSA 4.6 after the HIFU. So looking at next stage if treatment. But urologist is ruling out any TRT as it’s the and I androgen devil.

[Schwah]

Clearly for some percentage of patients the high dose T can help. I can’t find out however what happpens to the rest. Do they simply stay castrate resistant or do their cancers progress much faster because of the extra T? Anyone know ?

Schwah

[pjoshea13 in reply to Schwah]

There are many ways in which PCa deals with the problem of ultra-low androgen. A common one involves over-expression of the androgen receptor [AR]. This is reversed when T is restored. Another involves amplification of the AR. This is where the AR has repeats of transcription instructions. T restoration will not be effective in such cases. Less commonly, there are AR mutations, which I can't comment on.

T is normally quickly cleared from the body. However, that isn't true for T cypionate injected into muscle. T patches would provide better control for changing direction should T restoration lead to a shorter PSA doubling time.

-Patrick

[henukit]

Let's hope the body of evidence grows to give a better picture. One of my docs (very prominent one in oncology) has an extremely cautious (or conservative) opinion on this subject.

[zenbee13]

So Maybe this is why I'm doing a bone scan and going off all meds if clear? Onc said it was to give me some quality of life since I'm 7 years solid on androgen blockers and 10 years into my fight with this beast with no metastasis to date. Bone scan Thursday and when clear I drop all meds on Friday this week!

What a crazy ride this is...

Bees

[COOP8]

My husband’s oncologist offered this treatment option to us through a clinical trial/research study. Unfortunately he was experiencing pain from bone mets and she felt the high dose testosterone could exacerbate his pain. She did say that many men are happy to receive the testosterone and the benefits it provides.

As an alternative she suggested a different research study, and as part of that he’s currently undergoing 4 rounds of chemo followed by rucaparib (PARP inhibitor).

[pjoshea13 in reply to COOP8]

Has he tested positive for BRCA2, e.g.? -Patrick

[COOP8 in reply to pjoshea13]

Yes, he is BRCA2 positive

[pjoshea13 in reply to COOP8]

OK, so the Rucaparib study is a good fit.

But maybe afterwards, BAT might be reconsidered? While a trial is preferable, a number of men have used BAT outside of that context. BAT is basically continuation of ADT with a periodic testosterone shock. It's easy to administer & easy to monitor. And T can be stopped at any time.

Best, -Patrick

[COOP8 in reply to pjoshea13]

Thank you for that info! We had thought it might be a possibility later on, so it’s good to hear more info about that.