Darolutamide & Simvastatin?

[pjoshea13]

New cell study from Japan below (1).

It has been known for a century that solid tumor cells have an increased uptake of cholesterol.

In PCa, higher cellular cholesterol levels are associated with a poorer prognosis.

From 2004: "Involvement of cholesterol-rich lipid rafts in interleukin-6-induced neuroendocrine differentiation of LNCaP prostate cancer cells" [2].

PCa cells may manufacture cholesterol even if blood levels are plentiful. Perhaps that has something to do with the makeup of LDL-chol. VLDL (very low density lipoprotein)-chol has a better chance of being taken up by cells.

Cholesterol is the starting point for the creation of the sex hormones.

ADT, by restricting access to androgens, may select for cells that make androgen from cholesterol - and, if necessary, make cholesterol itself.

With that in mind I asked my doctor for high-dose Simvastatin over a decade ago. I was somewhat out of luck since the FDA had just restricted access to the 80 mg dose. I had to make do with 40 mg.

Simvastatin is fat soluble. I wasn't concerned with liver uptake - only with PCa uptake. I still take it every night. Others might be able to state the case for a different statin. The important thing is that the statin must be able to prevent the creation of cholesterol in PCa cells. Reducing available LDL-chol is of secondary importance.

We all know that ADT leads to CRPC. There are escape pathways that facilitate that. It's a good idea to close all of the barn doors once one is commited to long-term ADT.

Another escape pathway is the manufacture of DHT (dihydrotestosterone) via the alternate pathway that does not require testosterone, Avodart will inhibit that.

Anyway, the new study explores the idea that:

"One of the growth mechanisms of castration-resistant prostate cancer (CRPC) is de novo androgen synthesis from intracellular cholesterol, and statins may be able to inhibit this mechanism."

"Simvastatin alters the expression of many genes involved in the cell cycle in CRPC cells. Thus, the combination of novel AR antagonists (darolutamide) and simvastatin can potentially affect CRPC growth through both androgen-dependent and androgen-independent mechanisms."

Obviously, the authors are a long way from proving efficacy in men with advanced PCa, but it's good to see them restate the basis for statin use in PCa.

Of note from 2018 [3]:

"Inhibition of cholesterol biosynthesis overcomes enzalutamide resistance in castration-resistant prostate cancer (CRPC)"

"Enzalutamide, a nonsteroidal second-generation antiandrogen, has been recently approved for the management of castration-resistant prostate cancer (CRPC). Although patients can benefit from enzalutamide at the beginning of this therapy, acquired enzalutamide resistance usually occurs within a short period. This motivated us to investigate the mechanism involved and possible approaches for overcoming enzalutamide resistance in CRPC. In the present study, we found that 3-hydroxy-3-methyl-glutaryl–CoA reductase (HMGCR), a crucial enzyme in the mevalonate pathway for sterol biosynthesis, is elevated in enzalutamide-resistant prostate cancer cell lines. HMGCR knockdown could resensitize these cells to the drug, and HMGCR overexpression conferred resistance to it, suggesting that aberrant HMGCR expression is an important enzalutamide-resistance mechanism in prostate cancer cells. Furthermore, enzalutamide-resistant prostate cancer cells were more sensitive to statins, which are HMGCR inhibitors. Of note, a combination of simvastatin and enzalutamide significantly inhibited the growth of enzalutamide-resistant prostate cancer cells in vitro and tumors in vivo. Mechanistically, simvastatin decreased protein levels of the androgen receptor (AR), which was further reduced in combination with enzalutamide. We observed that the decrease in AR may occur through simvastatin-mediated inhibition of the mTOR pathway, whose activation was associated with increased HMGCR and AR expression. These results indicate that simvastatin enhances the efficacy of enzalutamide-based therapy, highlighting the therapeutic potential of statins to overcome enzalutamide resistance in CRPC."

-Patrick

[1] pubmed.ncbi.nlm.nih.gov/348...

Prostate. 2021 Nov 29. doi: 10.1002/pros.24274. Online ahead of print.

Combination therapy with novel androgen receptor antagonists and statin for castration-resistant prostate cancer

Hiroshi Nakayama 1 , Yoshitaka Sekine 1 , Daisuke Oka 1 , Yoshiyuki Miyazawa 1 , Seiji Arai 1 , Hidekazu Koike 1 , Hiroshi Matsui 1 , Yasuhiro Shibata 1 , Kazuhiro Suzuki 1

Affiliations collapse

Affiliation

1 Department of Urology, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan.

PMID: 34843630 DOI: 10.1002/pros.24274

Abstract

Background: One of the growth mechanisms of castration-resistant prostate cancer (CRPC) is de novo androgen synthesis from intracellular cholesterol, and statins may be able to inhibit this mechanism. In addition, statins have been reported to suppress the expression of androgen receptors (ARs) in prostate cancer cell lines. In this study, we investigated a combination therapy of novel AR antagonists and statin, simvastatin, for CRPC.

Methods: LNCaP, 22Rv1, and PC-3 human prostate cancer cell lines were used. We developed androgen-independent LNCaP cells (LNCaP-LA). Microarray analysis was performed, followed by pathway analysis, and mRNA and protein expression was evaluated by quantitative real-time polymerase chain reaction and Western blot analysis, respectively. Cell viability was determined by MTS assay and cell counts. All evaluations were performed on cells treated with simvastatin and with or without AR antagonists (enzalutamide, apalutamide, and darolutamide).

Results: The combination of darolutamide and simvastatin most significantly suppressed proliferation in LNCaP-LA and 22Rv1 cells. In a 22Rv1-derived mouse xenograft model, the combination of darolutamide and simvastatin enhanced the inhibition of cell proliferation. In LNCaP-LA cells, the combination of darolutamide and simvastatin led to reduction in the mRNA expression of the androgen-stimulated genes, KLK2 and PSA; however, this reduction in expression did not occur in 22Rv1 cells. The microarray data and pathway analyses showed that the number of differentially expressed genes in the darolutamide and simvastatin-treated 22Rv1 cells was the highest in the pathway termed "role of cell cycle." Consequently, we focused our efforts on the cell cycle regulator polo-like kinase 1 (PLK1), cyclin-dependent kinase 2 (CDK2), and cell cycle division 25C (CDC25C). In 22Rv1 cells, the combination of darolutamide and simvastatin suppressed the mRNA and protein expression of these three genes. In addition, in PC-3 cells (which lack AR expression), the combination of simvastatin and darolutamide enhanced the suppression of cell proliferation and expression of these genes.

Conclusions: Simvastatin alters the expression of many genes involved in the cell cycle in CRPC cells. Thus, the combination of novel AR antagonists (darolutamide) and simvastatin can potentially affect CRPC growth through both androgen-dependent and androgen-independent mechanisms.

Keywords: androgen receptor; cell cycle; darolutamide; prostate cancer; statin.

© 2021 Wiley Periodicals LLC.

References

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[2] pubmed.ncbi.nlm.nih.gov/145...

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[3] ncbi.nlm.nih.gov/pmc/articl...

[johnscats]

Hi ok interesting article what dose are you taking going to run it by my onc thanks again for the research

[pjoshea13 in reply to johnscats]

I'm on 40 mg Simvastatin, since it is the highest dose allowed in the U.S. PCa benefit is dose-dependent.

Here is a statin dosage equivalency chart that might interest some:

mqic.org/pdf/UMHS_Statin_Do...

"Hydrophilic or Lipophilic Statins?" A recent paper:

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

"The predominantly lipophilic statins (simvastatin, fluvastatin, pitavastatin, lovastatin and atorvastatin) can easily enter cells, whereas hydrophilic statins (rosuvastatin and pravastatin) present greater hepatoselectivity. "

-Patrick

[GeorgeGlass in reply to pjoshea13]

Patrick, thanks.

So, even though 20mg of rosuvastatin is a higher potency than simvastatin, you think that the 40mg of sim is more effective at preventing CRPC? I read an article three years ago that said Cresor (rosu.) was one of the top three in terms of effectiveness against PCx. I'd be willing to switch, if the Sim. is better. Any more data/studies?

And about Avodart - Are some doctors or studies recommending Avodart for the pathway inhibition you mentioned? When I mentioned it to my docs, they pu-pu'd it away, saying it didn't help.

George

[pjoshea13 in reply to GeorgeGlass]

George,

Statins & survival (ignore prevention stats.) I think we need more intervention studies. As with Metformin-diabetes, it's the intervention studies that count (unless you actually have a need for those drugs. LOL) And we need to know the profile of the subset who benefit most, IMO.

Avodart while on ADT is only important if DHT is being produced via the alternative pathway. A small percentage of men do this "naturally" - which is why Dr. Myers always tested for T & DHT. However, when this happens within PCa cells in response to ADT, a blood test will not show it. What percentage of CRPC cases involve DHT? I don't know. Small, but Avodart is insurance. Of course, one could wait for CRPC & give Avodart a try. So, for the majority of cases, Avodart isn't needed & most docs will pooh-pooh the idea.

-Patrick

[GeorgeGlass in reply to pjoshea13]

I'll ask about a DHT test and talk to my cardiologists to see if they like the simvastatin change idea or not. They never seem to like anything unless it's their own dogma. I might ask them also about the nitric oxide patch. J-O-H-N said he got a bang out of it.

[Hidden]

Avodart blocks DHT. Finasteride isn't nearly as efficient. But combining them has been shown to be better at blocking. Avodart doesn't lend itself to ADT. But finasteride can be useful since it has a short half-life (Avodart takes months for elimination).

[Kuanyin]

Hi Patrick,Thanks for the helpful post. I guess exogenous sources cholesterol aren't relevant: limiting one's intake of fats are not that relevant?

--K

[pjoshea13 in reply to Kuanyin]

Hi Kuanyin,

The gist of my preamble is that PCa is driven by its own cholesterol agenda & I doubt that a 4-egg omelet will make the critter more aggressive. It will readily make what it needs. Fortunately, statins, which inhibit liver production, will also inhibit PCa cell synthesis - if the statin can get into the cel (hence lipophilic)..

Best, -Patrick

[Explorer08 in reply to pjoshea13]

Regarding your mention of the four egg omelet: it’s my understanding that egg whites are the better choice since egg yolks contain choline and PCa cells are avid for choline. I’ve read that choline can exacerbate existing PCa, possibly making it more aggressive.

[pjoshea13 in reply to Explorer08]

I contend that most of us are not in danger of overdoing choline. True, an egg might give you a quarter of the 550 mg daily requirement, but that's about what you might get from a serving of cod.

The American diet, on average, contains more eggs in baked goods, etc, than on the breakfast plate. I don't eat that sort of stuff, so a daily egg wouldn't be a big deal for me.

The downside of choline insufficiency is nonalcoholic fatty liver disease and muscle damage, so it wouldn't be wise to cut out foods containing choline - but that would be difficult, since choline is everywhere.

I would be cautious of liver - a serving might give you two-thirds of the daily need. But who eats liver these days. LOL

-Patrick

[Scout4answers]

Thanks for the informative post Patrick and for the equivalency chart. I am currently taking 20 mg. of Atorvastatin which looks like it is equivalent to 40 Mg of Simvastatin. Is there any meaningful difference that should make me want to switch to Simvastatin?(Currently taking Lupron and Zytiga)

[pjoshea13 in reply to Scout4answers]

Off-hand, I can't give you a strong reason to switch.

"lovastatin and simvastatin are the most lipophilic, followed by atorvastatin, fluvastatin, and pravastatin", but I can't quantify the effect on PCa uptake.

Best, -Patrick

[Seasid]

Interactions EditCombined P-glycoprotein and strong or moderate CYP3A4 inducers such as rifampicin may decrease exposure to darolutamide, while combined P-glycoprotein and strong CYP3A4 inhibitors such as itraconazole may increase exposure to darolutamide.[2] Darolutamide is an inhibitor of the breast cancer resistance protein (BCRP) transporter and can increase exposure to substrates for this protein such as rosuvastatin.[2] It has been found to increase exposure to rosuvastatin by approximately 5-fold.[2]

This information is from Wikipedia.

István

[pjoshea13 in reply to Seasid]

2019 - Neal Shore [1]:

"These analyses suggest the pharmacokinetic profile of darolutamide is not affected by a number of commonly administered drugs in patients with nmCRPC. Although pharmacokinetic data have indicated that darolutamide has the potential to interact with rosuvastatin, used to assess DDI in these studies, this finding did not seem to translate into increased AEs due to statin use in the ARAMIS trial."

-Patrick

[1] pubmed.ncbi.nlm.nih.gov/315...

[GeorgeGlass in reply to pjoshea13]

Based on this, would simvastatin be the best choice? Or have they not studied all of them? I go to this doctor again in a few weeks. I told him I wanted to go with Darolutamide and not chemo and zytiga like he recommended six months ago. I am taking rosuvastatin for the last five years.

[pjoshea13 in reply to GeorgeGlass]

George,

It would be prudent to switch in that case.

You ask: "have they not studied all of them?"

Such connections are probably made via chance observations, but I'm sure that would lead to an examination of the entire class of drug.

-Patrick

[Muffin2019]

A friend has been taking 80 of the statin for years and can still get it in the US.

[pjoshea13 in reply to Muffin2019]

Yes, the FDA had a grandfather provision for those who were already at that dose.

So annoying that the dose was cut in half for everyone else.

-Patrick

[Hidden]

I had to stop taking simvastatin and switch to atorvastatin. I have GERD from a hiatal hernia and take omeprazole to reduce stomach acid production. The simvastatin seemed to completely counteract the omeprazole and leave me with heartburn. Atorvastatin didn't cause that problem. I managed to get my doctor to increase dosage from 10 mg to 20 mg atorvastatin. Not sure if I should try to go higher.

[GeorgeGlass in reply to Hidden]

I highly recommend trying natural supplements and probiotcs for your GERD. Omeprazole just made my GERD much worse. It also can cause heart disease and cancer in some people. It's bad stuff. I used probiotics, marshmallow root, slippery elm and Cardamom and totally resolved the GERD 2-3 years ago. Cardamom is good for fighting prostate cancer as well. Once you use these to resolve your GERD, then cut back on the probiotics, which usually promote folate and B-12, and eat foot that is probiotic in nature.

[Hidden in reply to GeorgeGlass]

I'll have to look into that. Omeprazole and similar acid reducers have recently been implicated in contributing to dementia. I don't know if that is because they reduce B12 absorption and produce a deficiency or some other mechanism. My problem is that you could drive a truck through my hiatal hernia. It ain't small.

[GeorgeGlass in reply to Hidden]

the PPIs remove the acid/bile, which is exactly what we need to digest our food. Like many medicines, it's a temporary treatment that causes long term problems, and it can screwup your system, so it stops producing the enzymes you need for a healthy gut. there are tons of articles and some studies on this. Just search for it. There is also a group about stomach problems on certain websites. I used them when I had problems. In the end, I solved my problem as described above. I think the probiotics were the most important of the supplements.

[Justfor_ in reply to GeorgeGlass]

Probably purely coincidental, but my PSA seven months after RP being stable at 0.02 started rising 1-2 months after taking a proton inhibitor.

[pjoshea13 in reply to GeorgeGlass]

PPIs are linked to C-Diff, which is difficult to treat - as I discovered myself.

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

-Patrick

[j-o-h-n]

Ok C.B. Stat in wrap....

Good Luck, Good Health and Good Humor.

j-o-h-n Wednesday 12/01/2021 11:10 PM EST

[GeorgeGlass]

Patrick - I'm trying to make some important treatment decisions right now. I have a few important questions that you might be able to answer for me, if you don't mind:

1. When they came up with this result and Conclusions that the study mentioned above, did they compare the different types of statins against each other, when they were used with darolutimide? I didn't see Livalo/pitivistatin mentioned (I know you had problems with it, but many people don't) - Results: The combination of darolutamide and simvastatin most significantly suppressed proliferation in LNCaP-LA and 22Rv1 cells.

2. So, these lipophilic statins are probably more effective at blocking the AR and having a longer effectiveness in slowing the cancer growth? "The predominantly lipophilic statins (simvastatin, fluvastatin, pitavastatin, lovastatin and atorvastatin) can easily enter cells, whereas hydrophilic statins (rosuvastatin and pravastatin) present greater hepatoselectivity. "

3. Here's what it says about Livalo on their website: "LIVALO, with a solubility partition coefficient of 1.5, is a lipophilic statin that has both lipophilic and hydrophilic properties; it is sparingly soluble in a lipid medium and very slightly soluble in water1,9" Do you think the simvastatin would be more effective than Livalo against prostate cancer, due to it having both lipophilic and hydrophilic properties? or would that make Livalo even more effective than simvastatin?

thanks,

George

[RugbyVLS]

Wondering if anyone currently takes Nubeqa with Simvistatin. If so, what is your dose for simvastatin? Any adverse effects? I am concerned about the studies that show Nubeqa can magnify the concentration of rosuvastatin. Thanks!