A case to push for darolutamide.

[KocoPr]

out of 68 known Variants that escaped treatment darolutamide is effective against all but one. This article is from june 2021.

it is a invitro study so it needs vitro study, then insilico AI to further confirm but it is still important.

And even shows resistant variants to abiraterone, corticosteroids, estrodiol, all the lutamides.

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

Evaluation of Darolutamide (ODM201) Efficiency on Androgen Receptor Mutants Reported to Date in Prostate Cancer Patients

In summary, out of 68 experimentally evaluated AR mutants (24 reported in the previous works and 44 presented in the current study), 25 demonstrated enhanced activation by DHT, 17 by progesterone, 12 by estradiol and 6 by hydrocortisone, compared to the wild-type receptor (Figure 4). The first-generation bicalutamide behaved as a partial or complete agonist for the majority, 43 out of 68, of studied AR mutants (63% of mutants). The second-generation antiandrogen, enzalutamide, demonstrated full or partial activation of eight mutant variants, while the structurally distinct and most recently approved darolutamide demonstrated significant activation in only one mutant at concentrations up to 25 µM [21], which identifies a sequencing opportunity for this drug in men with progressive CRPC with a gain-of-function mutation in the AR under selective pressure of first-line ARPIs. 

5. ConclusionsEmergent AR mutations in men with advanced PCa treated with ARPI promote CRPC progression. The incidence of AR mutations was estimated to be around 15% for CRPC patients [4] and the availability of circulating tumour DNA assays now provide a sensitive method to serially detect (and treat) the emergence of resistant AR mutants. This current work expanded the list of experimentally evaluated AR mutants with 44 additional examples (bringing the total to 68) and quantified their response to four major endogenous steroids and three clinically used AR antagonists, including darolutomide. Among these, only darolutamide demonstrated complete inhibition of 67 out of the 68 studied AR mutant variants, with no significant signs of partial of full activation at even higher concentrations.

[Spyder54]

Thank you KokoPr. Saved. On Lupron/Zytiga now. Will inquire about switch to Darulutamide. Mike

[dhccpa]

Is darolutimide expensive? It's only for non-metastatic patients?

[KocoPr in reply to dhccpa]

It is expensive but if you are being seen at a really good hospital that does clinical trials they have a lot of pull with the pharmaceutical companies. You can also go to the patient assistance program of any drug company and fill out the forms, but much better if the hospital pharmacy fills most of it out then they will mail the unfinished form for you to sign and put in a few things.I have stage 4 hormone sensitive PCa with mets in pelvic and in chest and shoulder.

So all you can do is ask your OC and do some research.

[dhccpa in reply to KocoPr]

Thanks

[Spyder54]

Surprised you didn’t see more comments on this study Koko? It seems half of us are on Zytiga/Abiraterone. Mike

[MateoBeach]

This is astonishingly valuable information. Thank you for posting it and your summary KocoPR. Justifies switch to Darolutamide after resistance has developed (failure) on abiraterone and/or enzalutamide, etc. So effective do not need to do AR mutation analysis for oneself, though one day that may become widely available. For now, we’ll worth trying and this provides justification. A keeper.

[Shorehousejam]

Hi, is this your post? A case for

[KocoPr in reply to Shorehousejam]

yes, how did you find it. Thank you

[Shorehousejam in reply to KocoPr]

I put in search “ a case for ….”

[Shorehousejam]

My husband was diagnosed in July 2022, all information in profile and it was fda approved for hormone sensitive men, as a first line of treatment instead of zytiga and prednisone…

But I think I found the answer, I think Nubeqa does Not stop adrenal gland testosterone…

[KocoPr]

why go through a 1st generation drug which will create many serious mutations when you can get a second generation drug that only has one mutation? I know what the pat answer is “lets keep that in our back pocket as a tool for when you fail abiraterone”. Couple thoughts for me is daro doesn’t cross the blood brain barrier, plus you don’t have to take another damaging drig with it like prednisone?

[KocoPr]

Zytiga was patented in 1995 and Apoved in 2011, where Daro was patented in 2011 and approved in 2019. So where talking 15 years in advancement. So the word generation isn’t scientific it’s nothing.

Here is the purpose of the study.

Of course it is about treatment induced mutations thats the point! Daro only has one AR mutations failure. Compared to many failure points for Aby.

The aim of this study is to characterize the responses of 44 AR mutants, derived from PCa patients, to available steroids that activate the receptor as well as to various treatments currently used in the clinic. This work will help create a tool to guide the medical team in selecting the best personalized treatment option for each patient.

Oh and why wouldn’t you not be able to go to aby when daro fails?

I see absolutely no reason not to choose darolutamide.

Also much less side effects. No need for prednisone nor does it cross the blood brain barrier.

Another thing is the lupron is blocking production of testosterone so why take another upstream drug like aby blocking CYP17 enzyme when you can take a down stream drug (darolutamide) that actually blocks the androgen receptor.

Again very few side effect compared to abiraterone

[KocoPr]

The only trial was the Aresens trial that also combined docetaxel for HSPC.

The thing about darolutamide is it blocks the androgen receptors thus preventing translocation to the nucleus thus preventing transcription.

I’ll grant you it is very expensive but you can certainly get financing relief or in my case a grant from a well funded major hospital.

Im actually on lupron and darolutamides low volume but 5 locations including two above diaphragm. Doc said Chemo for me is not necessary at this time but we’ll hold it in our back pocket.

CONCLUSIONS: In this trial involving patients with metastatic, hormone-sensitive prostate cancer, overall survival was significantly longer with the combination of darolutamide, androgen-deprivation therapy, and docetaxel than with placebo plus androgen-deprivation therapy and docetaxel, and the addition of darolutamide led to improvement in key secondary end points. The frequency of adverse events was similar in the two groups. ARASENS ClinicalTrials.gov number, NCT02799602.