High Risk/Recurrent/Advanced Reminder Reader Comments

[Rick Davis]

Hello Folks …

One of our regular particpants has asked if we can set up a Forum for comments on our Reminder.
His wish is our command!!!
Let’s try this for the next couple of months and if it proves popular, we’ll continue this Forum feature.

O&U, rd

[notsdr]

Thanks Rick. I was able to register!

Notsdr

[John]

ok good

[John]

Liked the link to the acupuncture article, in fact the whole Cancer today site

[alllanh]

Easy to register. Hope the forum proves helpful. Alan

[notsdr]

Thanks Rick for posting the articles on cognitive effects of second line ARSIs. While I had the same reaction as you did to the meta analysis of adverse cognitive effects of using these ARSI’s (“no sh — sherlock”), I did learn something by reading Dr. Morgan’s DEAR study. I had always thought that daralutamide did not pass the blood brain barrier thereby preventing decline in cognitive function. However, she states that daralutamide “has a distinct structure with low blood-brain barrier penetration which may lead to a lower risk of central nervous system-related adverse events and minimal risk of adverse events commonly associated with ARIs”. So “low”, not “no” penetration. And in fact, she reports that 1.6 % of patients using daralutamide in the DEAR study had a cognitive disorder, while
1.8 % and 1.6% of the patients using enzalutamide and apalutamide, respectively, had a cognitive disorder. I don’t know whether these differences are statistically significant, but the odds of having a cognitive disorder from using daralutamide is very close to the other ARSIs, and is certainly not zero.

[Rick Davis]

I noticed the cognitive numbers for enz and apa too and questioned them! I haven’t had the time to check them out – my gut tells me there is more to it. There has to be more…

• This reply was modified 11 months, 2 weeks ago by Rick Davis.

[Len Sierra]

Those stats for the DEAR study were misquoted. The actual numbers Morgans reported were for cognitive disorder were:
Daro – 1.1%
Enza – 1.8%
Apa – 1.6%
In this DEAR study, the median age of participants was 80. And 27% were over 85! It seems to me that age alone could account for cognitive disorder, leveling things out among the three lutamides.
Also, in this Antonarakis pub: (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6816030/) he reports: “darolutamide has negligible blood-brain barrier penetration… of about 2% compared to 25% for enzalutamide”
That’s quite a difference. Finally, in the DEAR study, daro had significantly fewer patients discontinuing therapy compared to enza and apa, and the most likely reason would be less cognitive disorder with daro because progression to mCRPC was lowest in patients taking daro. Ideally, they would have asked the patients why they discontinued therapy, so that’s quite a weakness of this “retrospective chart review.”

[notsdr]

Len, sorry I did mistype the daralutamide percentage and thank you for pointing that out. 1.1% is correct. My comment was based on the correct percentage. I didn’t think there was much difference between 1.1%, 1.8%, and 1.6%. And I thought it would be much higher for apa and enza.

[Len Sierra]

I’m not a statistician, but the difference between 1.1% (daro) and 1.8% (enza) is actually quite large — the HR for cognitive disorder for enza compared to daro would be 1.6 — that’s huge.

[Rick Davis]

I’d agree with Steve that the absolute numbers look low based on anecdotal experience.
Ido think the factors Len outlines may explain that

[Rick Davis]

I’d agree with Steve that the absolute numbers look low based on anecdotal experience.
Ido think the factors Len outlines may explain that

[notsdr]

Thanks Len for your follow up on darolutamide, and I was glad to hear on the video that your drug holiday is going very well!

Perhaps the misconception that darolutamide does not penetrate the blood-brain barrier (as opposed to minimal penetration)can be traced to this 2021 Pubmed Article:
https://pubmed.ncbi.nlm.nih.gov/32881669/
All of the other Articles I could find clearly state there is minimal blood brain barrier penetration, not none.

That said, and cost aside, why would an oncologist prescribe enza or apa instead of darolutamide? If cost is a consideration, is it reasonable for a patient to accept a prescription of one of the other ARSIs? That is, are efficacy and side effect profiles of enza, apa, and daro sufficiently similar to make out of pocket cost (e.g., $1,200/mo. vs. 0.00/mo.)the primary determinant of which ARSI a patient should choose? Thanks.

[Rick Davis]

@notsdr ….. I don’t think it is approved for mHSPC alone unless accompanying chemo. Len can correct me. So it has to be offered off-label and that makes life complicated.

[Len Sierra]

Yes, Rick has it right — the way the original darolutamide trial was designed, it limited the approval to just nmCRPC which we now know to be an erroneous disease stage since it is highly likely that if a patient is CRPC, they are probably already micrometastatic. And PSMA-PET scans are proving this to be true. If someone is struggling with cognitive issues on enza or apa and their medonc refuses to switch them to daro, we suggest they find another medonc, assuming their insurance allows for that.

[tjacobsen]

Hi Rick,
Not sure if this is the right place to post, but anyway, I saw in your chat log for the 6-19-23 meeting that there was a mention of Venlafaxine, which I’m curious about. I wasn’t able to attend, but could you please fill me in on the context of this discussion. Thanks.

[Rick Davis]

Hello Tom … venlafaxine (Effexor) can be prescribed to prevent hot flashes. It is primarily used as an anti-depressant (SNRI). For some men, including one in the meeting on Monday, it may be an antidote for hot flashes.
O&U

[Rick Davis]

Hello Tom … venlafaxine (Effexor) can be prescribed to prevent hot flashes. It is primarily used as an anti-depressant (SNRI). For some men, including one in the meeting on Monday, it may be an antidote for hot flashes.
O&U

[notsdr]

Rick,

Your post today on the PARPi combo approval and Committee hearing was a great follow up to the webinar you, Len and Dr. John moderated the other night. It really leaves the non-BRCAm mCRPC patient wondering, despite FDA approval, whether it is worth the risk to try it out. I personally will not try a PARPi because I do not have a BRACm, even though I have the ATM mutation. As the Committee representative stated at about 2:20:00 of the Committee video, there was insufficient proof of stratification of non-BRCAm participants in the trial (and I am unclear whether the non-BRCAm patients had any other mutations, such as ATM), and there were serious toxicities related to PARPi use (as you and Dr. Munster also point out). Most importantly, the Committee representative claimed that rPFS of Olaparib + AA+P was 0.95 and not statistically significant compared to AA + P + placebo. Who should the patient believe and rely on: Pfizer, which has the overwhelming approval of the FDA, or the Committee representative? Thank you.

[Rick Davis]

ATM is a tricky HRR mutation from what I know @notsdr. It was what pulled us into this in the first place back in 2020 because it was considered actionable in Jake’s GRHS FMI report. Len will correct me if I am mistaken, but ATM had some response to PARP’s in the PROfound trial but not enough to make it significant.

W.r.t. to the BRCA question in PROpel, all participants were tested for germline. I addition I think most were tested somatically but many on old tissue – for example from a former RP. There was a complaint from AZ (inc Shore and George) that testing bone was unreliable due to the maceration process. And that many docs did not order somatic tests. No one, including the FDA, suggested ordering both liquid and solid tests, that you can do. Dr. E did that for Steve Saft z”l. There are some quirks but it can be done.
I believe AZ ran numbers for all the HRR variants. I recall it being said there were not enough of some of the lesser variants to be significant. I’d have to go through again to find more… but feel free to write to Neal Shore and ask him about ATM in PROpel.
Worse than the poor rPFS for all comers, the OS was 1.07 with olaparib and abi. That says, you are MORE likely to live shorter than the control arm.
You ask:
Who should the patient believe and rely on: Pfizer, which has the overwhelming approval of the FDA, or the Committee representative?
Did you just switch gears to speak about Talapro2 and the Talzenna + Xtandi approval? It’s a good question that I have pondered. Why have they approved talazoparib + enz for all HRR mutations and not just BRCA mutations?
Well, the non-BRCA HRR Hazard Ratio was 0.72. What I don’t know is the split between HRR mutations, but I feel sure Pfizer/the researchers do. I can’t find it released publicly but Dr. Fizazi mentions it in his clip below.
I was hoping we would get into that in the webinar but Shore split early although not before clearly stating that anyone who wants a PARP should be allowed to try it. So we know where he stands.There is likely some synergy from the two drugs. But there is also significant toxicity.
Listen to Dr. Fizazi https://www.urologytimes.com/view/dr-fizazi-on-pivotal-talapro-2-trial-of-talazoparib-enzalutamide-in-hrr-gene-mutated-mcrpc. He states that CDK12 does well, while ATM and CHK2 do not! He also suggests the FDA may return to narrow its approval.

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