Extreme responses to immune checkpoint blockade following bipolar androgen therapy and enzalutamide in patients with mcrp cancer.

[p3d1]

“Priming the pump” seems to be worth investigating if you have a DNA repair gene mutation ( BRCA2, ATM etc.)

This was highlighted in a previous post but this article includes the NCT trial number which takes it to the next level

ncbi.nlm.nih.gov/pmc/articl...

[Tall_Allen]

The clinical trial ended and results were reported. The major results, reported in my article were:

(update January 2021) In the COMBAT trial, 44 heavily-pretreated men who were mCRPC and who have progressed on either Zytiga or Xtandi, received BAT followed by Opdivo (nivolumab - an immune checkpoint inhibitor).

• ⅔ had at least some PSA reduction

• half had a PSA reduction ≥ 50%

• 5-6 patients had a complete PSA response

• However, in 27% PSA got much worse after BAT

• Almost half (46%) had a reduction in their cancer

• BAT seems to inhibit MYC - a genetic driver of prostate cancer

This trial suggests that BAT may prime prostate cancer cells so that they are more sensitive to checkpoint inhibitors.

It adds to the conundrum of identifying patients who seem to improve from those who will get much worse. N-MYC is a common mutation in heavily-pretreated PC patients - why do only some of them respond?

[p3d1 in reply to Tall_Allen]

Thank for the quick reporting. This seems to be an important trial. Half had a 50% reduction in PSA

Half saw their cancer shrink

Nearly 12% had a complete response.

If this was a big pharma trial it would be making headline news. The fact that it is repurposing or sequencing is not so newsworthy.

Not being cynical but who will pay for the phase 3 trial?

[Tall_Allen in reply to p3d1]

It was a Big Pharma trial - what do you think Opdivo is? But a trial in 44 men that had equivocal results is not what I would call an "important trial," although I hope it is pursued further. You ignored that: " in 27% PSA got much worse after BAT." There is no clue that the improvement in PSA in some will result in a metastasis-free survival or overall survival improvement. It is not "repurposing," which is a term used for generic drugs approved for other, non-cancer, purposes. Sequencing trials do make big news (e.g., Jevtana as third). Opdivo is a proprietary immunotherapy approved for some cancers. Bristol Myers Squibb would probably fund an expanded trial if they think it is worth pursuing. Perhaps the manufacturers of the other approved checkpoint blockers (Keytruda or Tecentriq) will take an interest.

[p3d1 in reply to Tall_Allen]

Not going to argue over terminology, taking Xtandi whose main approved purpose was ADT treatment and now using it as a priming tool is kinda repurposing. But you are correct that 27% saw an increase in PSA after BAT is part of the unknown in cancer treatment. When they look closer at the 5-6 complete responses perhaps they will narrow down a biomarker. And I do hope the other PD1 / PDL1 checkpoint blockers take notice.

[Tall_Allen in reply to p3d1]

Xtandi is still under patent too. I'm sure Pfizer/Astellas would love to find a new indication that would extend their patent.

Biomarkers have so far proved elusive.The responders had mutated n-MYC, but so did many non-responders. The lack of biomarkers isn't from want of sleuthing. Johns Hopkins has always been a key player in finding them. I suspect the key is in mathematical modeling rather than in biomarkers.

[Hidden in reply to Tall_Allen]

Actually, researchers have found BAT super responders had TP53, BRCA2 (but for some reason not BRCA1), and/or ATM mutations. Research continues but they have certainly identified biomarkers that respond to high dose T.Here is a quick 3 min video explaining: youtu.be/soHNul0GOpY(Not working as expected?)

It is the info p3d1 refers to in his original post above.

[Tall_Allen in reply to Hidden]

Those, like n-MYC, are the most common mutations found in metastatic PC patients - true of responders and non-responders alike. What is required are biomarkers that are true of responders but not of non-responders. So far, there is nothing.

[Hidden in reply to Tall_Allen]

From Foundation One:"FREQUENCY & PROGNOSIS

TP53 mutations have been reported in 18-40% of prostate cancers. Overexpression of p53, which is indicative of TP53 dysregulation, has been reported to be significantly more common in late-stage and hormone-refractory prostate cancers and has been found to be associated with prostate-specific antigen (PSA) recurrence in low and intermediate-grade prostate cancer. TP53 loss has been found to be associated with prostate cancer-specific mortality in univariate analysis."

So if you are that ^^^ guy--in 2021-- with late stage refractory prostate cancer and a TP53 mutation (among others) which usually has a worse outcome, and you hear BAT can actually work better if you have that mutation, what are you going to do? Wait until they figure out exactly who will or will not respond (which probably won't happen in any of our lifetimes since cancer has so many moving parts and is always working to mutate), or do BAT?

I know what my husband chose.

[Tall_Allen in reply to Hidden]

tp53 is one of the more common somatic mutations, add in RB1, ROS1,N-MYC, and BRCA2, you've pretty well covered many of the most common somatic mutations found in prostate cancer metastases. Yet many with those same mutations don't respond or get worse when given testosterone. What we have to find are (1) differences that differentiate responders from non-responders (i.e. heterogeneous between) and (2) traits that responders have in common (i.e., homogeneous within). TP53 does not fit the bill because mutations are as common among responders as among non-responders.

As you can see in Table 1 showing the mutations of the 3 top responders:

Patient 1: BRCA2, ROS1

Patient 2: ATM, DNMT3A,ERBB2, KMT2A, POLD1, RB1, TSC1, AR, FGFR1, MYC

Patient3: BRCA2 (diff. from Patient 1), DNMT3A (diff. from Patient 2),JAK2, NTRK2, TP53

ncbi.nlm.nih.gov/pmc/articl...

As you can see, there were no mutations that the top responders had in common (even the genes that were in common had different mutations in those genes). So there is nothing that is heterogeneous between and nothing that is homogeneous within. So we are left without genomic candidates.

It's possible that Johns Hopkins missed some good candidates, but knowing their excellent reputation in genomics, that's not likely. That's why I think the answer will be found outside of genomics, by mathematical modeling.

[podsart in reply to Tall_Allen]

I see that patient 2 has a ERBB2 mutation; what do we know about this mutation?

[Balsam01 in reply to Hidden]

May I ask how your husband is doing?

[Hidden in reply to Balsam01]

He's actually doing pretty good! On BAT, he says his thinking is clearer and his mind is sharper, he has gained a better sense of smell, he can walk farther, and now has to shave every day for the first time in years because his facial hair is growing again.. It basically got him off the couch where he spent most of his time with constant fatigue. We still don't have psa results to see what happened after the 3rd round (psa started at 30, went to 34, then dropped to 25 after the first 2 cycles) and I'm sure scans are in the future, but overall he feels better than he has in a long time. He is totally fine if all goes haywire and the T hastens his death. He wants quality over quantity. All the studies in the world can't top getting out of bed and actually feeling good during the day.

[p3d1]

I remember your post “priming the pump”. Hopefully your research PCA MO can shed more light on the way forward. It looks promising.

[pete-ginger]

I get a 400 bad request error with this link. Would you re-post the full link or give me the article title? Many thanks.

[Hidden in reply to pete-ginger]

Here you go:youtu.be/soHNul0GOpYl(Not working as expected?)

Title is "Characterization of PSA responses to bipolar androgen therapy in mCRPC" on the VJOncology channel if that one doesn't work.

[NOCanceros]

Shalom Nalaktras If you do not mind which kind of treatment and medecine you are taking,i want to know in case if i reach that point.

Thnx

George

[Cooolone]

Of course the issue revolves around identifying which markers when present will lend to favorable responses when whatever method is used to treat a particular condition. This is further compounded the fact there are many somatic mutations present when metastatic lesions are present. Add to it this is different for every patient and the difficulty in results showing high probability for effectiveness gets complicated.

Let's talk about checkpoint inhibitors... And why when it's a "genetic" characteristic, it's use is approved when the disease becomes castrate resistant which has absolutely nothing at all to do with the function of the checkpoint inhibitors. Or let's say, MMR Gene's like BRCA! Same deal... mCRPC has nothing to do with the fact this gene, whether it be BRCA1 or BRCA2 deletion, that this approval be based upon castrate resistance! Yes, the trials were used with patients in these classifications, but the condition is not associated with those conditions other than they being present. The gene mutation and or it's fix, does not impact castrate resistance!

Something that just befuddles my thinking and a pet peeve of mine. Personal yes, because obviously this directly impacts what I want to do, but fall subject to the SOC options. Anyways...

It's all good stuff!

BAT is very interesting and obviously like most therapies, is not quite correct for everyone. Finding the foot for the glass slipper is the trick and until they identify and associate the best fit for an aligning diagnosis, we will endlessly debate it. And personal opinion is that it's one thing when something doesn't work, but another entirely if it accelerates progression. Again, how do we get to determine or know who best would benefit? Simple group classifications are too old school anymore and the INDIVIDUAL must become more the norm for diagnosis and treatment methodology IMO.

Best Regards

[MateoBeach in reply to Cooolone]

Agree. And also one of my pet concerns. (Why can I not get Provenge until castrate resistant???)To determine if the glass slipper is going to fit sometimes you actually have to try it on the foot! I don’t have my summary of the COMBAT trial just now, (on the road to visit Lulu77) but I recall that when those 27% who had greatly accelerated PSA were taken off the protocol, the vast majority of them had their PSA promptly decline again. And I believe that scans showed no metastatic progression. Was that not so?

[p3d1]

That would be an interesting fact, if it is so.