PARP or immuno for BRCA2+ and NED - Advanced Prostate...

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PARP or immuno for BRCA2+ and NED

Purple-Bike profile image
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Being BRCA2+, I am considering a PARP inhibitor (olaparib) in the hope of killing my (presently undetectable) cancer, despite having No Evidence of Disease since last May when my only met detectable by PSMA was zapped.

I quit ADT two months ago, after 10 months use. Will start abiraterone for four months possibly followed by olaparib for a relatively limited time, if side effects are tolerable

The alternative is immunotherapy. Trying to figure out which is best to use (first).

These treatments are approved for cancer at an advanced stage. I am acting on the assumption they may be more effective when NED.

Any comments appreciated, need to decide now.

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Purple-Bike
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tango65 profile image
tango65

The problem is to get the drugs outside a clinical trial. Olaparib has been approved for:Prostate cancer

• for the treatment of adult patients with deleterious or suspected

deleterious germline or somatic homologous recombination repair

(HRR) gene-mutated metastatic castration-resistant prostate cancer

(mCRPC) who have progressed following prior treatment with enzalutamide or abiraterone.

accessdata.fda.gov/drugsatf...

These are trials for Olaparib:

clinicaltrials.gov/ct2/resu...

These are trials for Rucaparib:

clinicaltrials.gov/ct2/resu...

Perhaps there is one which could fit your situation. You do have metastatic prostate cancer even when there is NED at the present time.

Purple-Bike profile image
Purple-Bike in reply totango65

Thanks for the effort, but I am visiting a country where I can get olaparib without a prescription. It would be self-managed outside a trial.

tango65 profile image
tango65 in reply toPurple-Bike

Great. Best of luck.

Tall_Allen profile image
Tall_Allen

PARP inhibitors are VERY toxic. They are approved for use in CRPC only. I can't even imagine what use it is if metastases are inactive (they stop repair of active cancer DNA).

Purple-Bike profile image
Purple-Bike in reply toTall_Allen

Why would a PARP inhibitor not be able to kill small cancer clones and micrometastasis that have survived the onslaught from hormonal therapies?

Granted, PARPi can be quite toxic but many fare rather well on it.

tango65 profile image
tango65 in reply toPurple-Bike

Less toxic than dying from the cancer.

Tall_Allen profile image
Tall_Allen in reply toPurple-Bike

Because that's not what PARP inhibitors do. PARP is a protein that repairs damaged DNA. If the DNA isn't yet damaged, the PARP inhibitor is wasted.

Purple-Bike profile image
Purple-Bike in reply toTall_Allen

I would think that at least some of the micrometastasis is active, non-senescenct and vulnerable to PARPi.

But I believe we can assume that some is indeed senescent and, taking in what you have written, thus invulnerable to PARPi, is that correct?

That said, do you have any view on using immunotherapy for possibly eliminating cancer when NED after zapping a met?

Tall_Allen profile image
Tall_Allen in reply toPurple-Bike

I agree that there is likely a mix of cells in different states. Aside from toxicity. the problem with PARPi when cells aren't actively dividing or mutating is that we know resistance occurs. If one gets one shot at a PARPi, I would think one would want to use it when it is likely to maximize cell kill.

I doubt that anything we have now can reliably eliminate metastatic prostate cancer, but combining tumor radiation with immunotherapy seems to be helpful:

prostatecancer.news/2016/08...

europeanurology.com/article...

journals.sagepub.com/doi/fu...

Purple-Bike profile image
Purple-Bike in reply toTall_Allen

TA, do you think the following combination might have a (long-shot?) chance of curing BRCA2+ NED metastatic PC?

1 An array of hoped for senolytics, including Dasatinib+Quercetin with small clinical trials indicating efficacy, to wipe out the senescent PC cells.

2 Olaparib to kill the active micrometastatic PC cells, only for a few months in the hope this will suffice since the cancer volume is so low. Thus limiting toxicity and the risk of resistance, so if needed it can be used layer.

3 Olaparib is preceeded by four months of abiraterone -previously only ADT - and possibly succeeded by immunotherapy to further improve the odds.

Purple-Bike profile image
Purple-Bike in reply toPurple-Bike

Any comment, or suggestion for an improvement of the regimen, would be appreciated.

Tall_Allen profile image
Tall_Allen in reply toPurple-Bike

I wanted to say, first off, that I am very sympathetic to what you are trying to do. I don't think it's possible to completely rid yourself of all prostate cancer cells. I compare them to the mycelium of a fungus plant - and metastasis-directed therapy is just plucking a few mushrooms when they get big enough. But I also know that going after the"mycelium" with early systemic medicines has a greater net impact than the selective pressure of using those agents. But there will always be some selective pressure - resistant variants will survive and eventually form the bulk of the population.

There are many resistance pathways other than senescence. Almost all therapies are ineffective against cancer stem cells, and therefore select for them.

(1) I know that Snuffy Myers was very big on dasatanib (Sprycel). Dasatanib is a member of the class of "src pathway inhibitors." Unfortunately, it was one of the many times he was wrong (bless him for trying!). It did not have any activity against prostate cancer alone or when combined with a powerful VEGF inhibitor. In clinical trials, none of the src pathway inhibitors and none of the VEGF inhibitors, or their combination have had any activity against prostate cancer.

As an aside, preclinical studies suggest that dasatanib may extend the effectiveness of PARPi in men who are BRCA+:

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

Does the combination of dasatanib+quercetin do anything in humans with cancer? I don't know and nether does anyone else. You say that there are clinical studies, but I have not seen them. Do you have any? I only have seen this which is about senescent cells in fat cells, not those induced by cancer therapy:

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

(2 & 3) PARPis do exactly the opposite of what you are trying to achieve- they trigger senescence:

"We found that DNA damage inducers like irradiation and poly (ADP-ribose) polymerase1 (PARP) inhibitors triggered a stable PCa-TIS independent of the p53 status."

mdpi.com/2073-4409/9/7/1593...

More importantly, olaparib actually preserves what you are trying to kill. As you can read there, in castrate-resistant cells, they also trigger cell death (Section 3.2). But in hormone-sensitive cells, they do not (Section 3.1).

in reply toTall_Allen

Expressed with a gentleness I appreciate. Hope keeps many of us afloat ❤️

Purple-Bike profile image
Purple-Bike in reply toTall_Allen

I greatly appreciate the invaluable advice I am getting from you and that you take the time to do this.

I was influenced by a study exploring the rolle of a PARP inhibitor in arresting MHSPC clinicaltrials.gov/ct2/show...

But the results will only be published next year.

The study you linked to, with actual results indicating that PARPi induces senescence in active HSPC, may be beneficial in other contexts but is indeed not what I want.

Abandoning PARPi at this stage, my plan B to kill and ideally eliminate active micromets is to take, in sequence but uncertain in which order

- abiraterone

- docetaxel (or cabazitaxel) + carboplatin

- possibly a dendritic cell enhancer, Provenge.

Assuming that less is needed for the low cancer volume in

micromets remaining after ADT and radiation and when NED, I guess that abi and chemo can be short, maybe four months and three cycles respectively.

As for killing the senescent PC cells, two small open-label clinical trials tentatively indicate evidence of Dasatinib + Quercetin reducing senescent cell burden in general. This presumably includes PC senescence although the studies targeted two other diseases; senolytic action specifically targeting cancer is tested and shown only in preclinical studies. For an overview see

onlinelibrary.wiley.com/doi...

onlinelibrary.wiley.com/doi...

in which references are given to the two studies. “Thus, as in mice, D+Q can successfully decrease senescent cell burden in humans”. Again, this is tentative.

I am not technically able to copy the links to the two studies but here is a reference to one of them:

Senolytics decrease senescent cells in humans: Preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease - EBioMedicine (thelancet.com)

with a corrigendum of the latter largely confirming the results with the main conclusion unchanged: a decrease in cells with markers of senescence and a reduction in senescent cell burden.

Advice and comments are welcome.

Tall_Allen profile image
Tall_Allen in reply toPurple-Bike

The one about D+Q in diabetics was the one I linked. They only looked at fat cells. I have seen nothing about its use in clinical studies in cancer patients. I'm not at all sure it is the same animal. The word "senescence" seems to be used to describe non-replicating cells in general, but in cancer, senescent cells also signal other cells to replicate. It seems to be a different phenotype.

Be careful with dasatanib - it is very toxic. So are PARP inhibitors.

Chemo has been found to have no effect when there are no detectable metastases. It is controversial whether it is effective at all when the metastatic burden is low (I suspect it is). It only works against actively replicating cells, so I really don't see why you would take it now:

prostatecancer.news/2019/02...

BTW- even if you can find a doctor willing to prescribe these drugs off-label to you, insurance probably won't cover it. If you are wealthy, I guess it is no problem.

Purple-Bike profile image
Purple-Bike in reply toTall_Allen

Thanks again, TA. My ammunition is rapidly evaporating ;) but I am grateful not to be barking up the wrong tree.

However, I do believe you will agree that Zytiga is a safe bet in my case, even if the shown survival benefit concerns the newly metastatic whereas my dx was six months ago. Please tell me if you disagree.

I didn't realize you were referring to the same study on Dasatinib + Quercetin since I couldn't open the link. Dr Kirkland refers to the senolytic action of D+Q in the diabetes study in the same vein as he refers to their action on cancer in preclinical studies and I find no mention of different phenotypes, but I will certainly read up as thoroughly as I can to see if I should reassess my use of Dasatinib. D can indeed be toxic but three days a month or bi-monthly, as the highly informal guidelines signal, should greatly limit the danger.

Tall_Allen profile image
Tall_Allen in reply toPurple-Bike

The latin term de novo metastatic (which I often mis-translate as "newly diagnosed") really means that when the patient was diagnosed, he already had metastases. So you fall into that category. An open question is whether the patient has distant metastases (stage M1) on a bone scan/CT or on a PET scan. However, a recent STAMPEDE analysis proved abiraterone was even effective in patients who were M0 with N1 or very high risk features and regardless of whether they had prostate radiation.

Rolphs profile image
Rolphs in reply toTall_Allen

Thanks TA. I’m on Xtandi and when my PC turns to CRPC my MO will likely put me on Olarparib. Have CHEK2 mutation, PSA 27. It is helpful to know what is ahead. Thanks PB and others who contributed

tango65 profile image
tango65 in reply toPurple-Bike

I believe if you have a germline BRCA mutation the DNA is already damaged. If the cell in the micro metastases are not senescent, and they are dividing to become bigger mets, then the Olaparib may work.

2dee profile image
2dee

I started Lynparza 2 months ago after Xtandi failing after 1.5 years. Still on Lupron 3 years but it is slowly failing as well. The last two weeks have been the best of the last 3 years for ME. Pain reduced, BM regular due to less pain meds, brain mush mostly gone, no side effects beyond normal fatigue but it is less than before. PSA dropping every month. Right now I am really pleased. See my profile for my history.The tech text notes that if you so much as physically touch the pills you have to wash hands immediately. So I use a shot glass to administer the pills. Sounds scary to put stuff in your mouth that you can't touch? So I guess they are quite toxic.

I expect to get some more time with my family that looked unlikely a couple of months ago.

Read, research, ask questions here, and make your own decision.

2Dee

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Tall_Allen profile image