No intensification - is doc too laid back?

[Purple-Bike]

With a BRCA 2 mutation, Gleason 9, low PSA and intraductal cancer, I was preparing for “Total Combat” with a sharp intensification of my medication, which is now limited to ADT in the form of transdermal estrogen. “Hit the cancer hard and early”.

To my surprise, doc suggests no added medication at all because of

- My low blood tumor mutational burden, 4 Muts/Mb according to the Foundation One test. Doc says that the burden may not even include live cancer cells (don´t recall his exact wording).

- Non-detectable PSA (PSA it was at its highest 2.9 before starting ADT 7 months ago, after that it receded rapidly so despite my cancer being low-PSA type he says the zero PSA is still a very positive marker and that I should still be hormone sensitive).

- No new mets. DX last September, my first PSMA PET/CT in November showed three suspected mets. A second PSMA in April confirmed just one of them, in my iliac bone, shrunk, and now zapped.

- Markers are within the reference range LDH at 196 U/l ref range 0 - 250.

- No possible actionable mutations or other known mutations of importance, apart from BRCA 2.

- I had a very high and increasing cf-DNA, but it is on its way down now and he believes it is/was caused by a strong infection I recently had not related to the cancer, just like the CRP was going up then down.

- Chromogranin A at 2.0 nmol/l just within the reference range 0 - 2.09 but doc says no danger of neuroendocrine cancer. (None of the clinical features of NE listed in a post on this Forum is present healthunlocked.com/advanced...

In addition, I took a separate test showing no indication of any circulating tumor cells in 7,5 ml blood according to the Cell search system.

With all markers being so benign, doc says added medication is not called for since there will be nothing to measure progress against.

I can understand this in terms of immunotherapy like PD-1 and PD-L1 checkpoint inhibitors, which apparently require a higher mutational burden than my 4 Muts/Mb to have an effect (although my thinking was "why not try immuno anyway better safe than sorry").

But for the PARP inhibitors, which also hold particular promise for the BRCA 2 mutations, I don´t find clearcut evidence of this kind of lack of efficacy when tumor burden is low. Nor for treatments like docetaxel plus carboplatin, with the latter also holding particular promise for the BRCA 2 mutations. Or why not go for the promising combo which refers to what was precisely my condition when diagnosed prostatecancer.news/2021/05...

However, just about everything I find – from studies and from messages and stories on this forum – indicate that these medications in practice are taken when there is indeed PSA expressed, often failed ADT, castration resistance and/or ongoing metastasis. All studies measure progress against PSA reduction or radiographic improvements and the like.

In my case there is almost nothing to improve upon, almost nothing to measure against.

On the other hand, my cancer has all these aggressive features, which mean shorter expected time to castration resistance and less sensitivity of ADT. Should I, despite the benign current markers, persuade doc to go for treatment intensification – PARP inhibitor, chemo+abiraterone, or whatever?

Is there any reasonable chance of delaying time to castration resistance and new mets by doing this?

Can such treatments hit undetected micrometastasis around the single confirmed and zapped met or in other parts of my bones?

Doc even suggested I could quit ADT and not take any medication at all for the time being only relying on frequent monitoring, but readily agreed to continue prescribing estrogen when I told him I wanted this . Quitting the ADT just seems too radical.

Since doc is the head of the prostate cancer clinic with the best reputation in this part of the world I am inclined to go with his judgement, despite initial severe misgivings. I don´t mind not having the side effects of the drugs! But I welcome any comments for or against. It is a challenge to find evidence to help decide which way to go.

[Hidden]

I think the bottom line is your cancer is under control right now with the current treatments you are on and your disease burden sounds low so I can't see why you would add anything. Adding additonal treatments for no proven benefit just adds side effects and toxicity. Good to have them for future use if/when needed.

[Tall_Allen]

I've noticed the "neuroendocrine fear" that a few posters perpetrate on this site. That's because of their very limited knowledge of PC subtypes. There are many more prevalent subtypes of PC that you show some signs of - low PSA is a danger sign. A blood test for Chromogranin A is hardly dispositive. You also only got a cell-free Foundation One test it seems. What I believe you need is some better diagnosis (not a silly list someone posted on this forum).

(1) FDG PET may show metastases that do not express PSMA, as many low PSA do not. You also did not mention whether your bone metastases are sclerotic or lytic. If nothing shows up on FDG, you are probably safe to just keep doing what you are doing.

(2) Histology of a biopsied met and IHC analysis. The IHC would ideally include:

AR (androgen receptor), PSA, PSMA, MSH2, MSH6, PD-L1,chromogranin A (CGA), neuron-specific enolase (NSE), synaptophysin (SYP), DLL-3, CD56, Somatostatin (SST)

Your pathologist may not have all those stains, but get what you can,

PARP inhibitors are very effective in mCRPC men who are BRCA+. It has nothing to do with mutational burden - that's a sign that immunotherapy may be effective. An interesting coincidence is that a taxane+carboplatin seems to be effective in patients in whom PARP inhibitors are effective. If you can't qualify for a PARP inhibitor, maybe you can still get the adjuvant carboplatin.

[Purple-Bike in reply to Tall_Allen]

I suggested FDG PET but doc said it was no use it would not show anything.My single met was not possible to biopsy.

[Tall_Allen in reply to Purple-Bike]

He is usually right, but it seems to be a reasonable precaution. If it doesn't show anything, you're good to go, and you can feel more confident that your treatment is working just fine.

[Purple-Bike in reply to Tall_Allen]

Thank you. To my understanding, FDG does not show up until at a late stage when prostate cancer shifts from fat to glucose metabolism which is when PSMA often disappears. From one of your newsletters "About 90-95% of metastatic men express at least some PSMA on their prostate cancer cells. At some point, however, as genomic breakdown continues, PSMA is no longer expressed by metastases".

Dx only in September last year, and with my by PSMA PET single confirmed met zapped last month, I believe this is the reason doc thinks it highly unlikely there will be any cancer shown by FDG.

I suppose this assumption is reinforced by the fact that no circulating tumor cells per 7,5 ml of blood were detected by the Cellsearch method.

However, you write that low PSA cancer - which is my type - often does not express PSMA and that FDG PET may show metastasis not seen in PSMA PET in this type. I understand this means that the highly unlikely will be somewhat less unlikely. I will bring up this with doc; if you happen to know any article or study indicating this please let me have it.

[cesces]

Get a second opinion. That's always a good policy.

Make sure you are getting monthly PSA tests, at least for a while.

Make sure the tests are the ultra sensitive type.

Oh, and don't forget to follow Tall Allen's advice.

[EdBar]

Agree with cesces, get an ultra sensitive PSA test monthly and as long as it remains undetectable just stay the course is my opinion, that worked for me for about 6 years, only lately has it become barely detectable again so our plan is to monitor PSA progression and get a PSMA scan once they are available in my area. Then we will see what we are dealing with and go from there.I’ve taken the kitchen sink approach per Snuffy Myers since being dx, but once my PSA became undetectable we just stayed the course. My current PCa MO is Oliver Sartor, that’s been his approach over the last few years.

Ed

[Purple-Bike in reply to EdBar]

From your profile I see you too have Gleason 9 and that staying the course - with undetectable PSA and no apparent cancer activity - in your case meant Xtandi, in addition to ADT. Contrary to what my doc says to me, with just ADT.

[EdBar in reply to Purple-Bike]

Yes, I personally consider Xtandi as part of ADT, Snuffy Myers prescribed it for me to replace Casodex early on in my treatment. It was part of the kitchen sink approach. But seeing that you are able to reach an undetectable level on your current treatment regimen you may want to hold off on the Xtandi if possible. It has a pretty strong SE profile and limited time of viability in a lot of guys. If it were me I’d ride the horse your are on while monitoring your PSA closely, then if you become detectable again knock it back down with Xtandi. That is my unprofessional opinion knowing what I know from personal experience and having a couple of top notch PCa MO’s.

Ed

[Chugach]

When in doubt get a second opinion. It’s not a marriage, you can have a second MO.

[TeleGuy]

To employ an overused metaphor, I think you have to look at this as a marathon, not a sprint. It's easy to think that you need to throw everything at this all at once. But each treatment that you use will filter out part of the population that is sensitive to that treatment, giving you a challenge when the remaining population grows and presents a different mutation that you need to treat. If you use all the tools now, then you don't have them to use later. Save the big guns (and the side effects) for when you need them to control the cancer. Right now you have it under control with a low tumor burden, so enjoy!

I have not been following the estrogen vs. regular ADT debates and wonder if you would benefit from regular ADT possibly plus Abiraterone.

I think you're overthinking the fat/glucose metabolism and FDG PET. I have a low tumor burden and my first FDG PET several months after surgery showed a bunch of stuff. My most aggressive met showed up on a PSMA scan a couple of months earlier than that. It's not necessarily "late stage." Or at least I hope not! I'm still alive and doing well 6 years later at this point!

[Purple-Bike]

Thank you, TeleGuy. Did the FDG PET show you important stuff that your PSMA scan did not?I do believe transdermal estrogen probably is as beneficial as conventional ADT minus some of its side effects.

[TeleGuy in reply to Purple-Bike]

Yes, the FDG PET showed more, but that is probably for two unrelated reasons: the PSMA tracer was an experimental one that didn't make the cut; and my PSA was probably too low for it to show much. My first FDG PET was with a higher PSA that allowed it to show more. The vast majority of my imaging has been FDG PET because it is easy to get.