Zytiga + Statins + CRPC

[pjoshea13]

New study below [1].

"Statins are safe and inexpensive, and may synergize with novel antiandrogen agents abiraterone via pharmacokinetic interactions and decrease substrate availability for de novo androgen biosynthesis."

Interpretation: Solid cancer cells contain high levels of cholesterol. If PCa cells can't get enough, they will make it. ADT generally fails (CRPC) when PCa finds alternative androgen sources. The ultimate solution is for the cells to make their own, with cholesterol as the starting point (steroidogenesis).

I contend that statins should be part of any protocol for CRPC. And that other men who are on ADT & considering Zytiga, say, should logically be thinking about statins too. Statins limit escape options for non-CRPC PCa.

In the Zytiga study:

"Statin use was a significant prognostic factor for longer {overall survival} in univariable (hazard ratio [HR] 0.51 ...) and multivariable analysis (HR 0.40 ...) and was significantly associated with PSA declines (>50% decline at 12 wk: 72.1% in statin users vs 38.5% in non-users ...)."

"We assessed the effects of statin use in patients with advanced prostate cancer receiving abiraterone. Patients treated with a statin plus abiraterone appeared to live longer than those treated with abiraterone only. Since no negative drug-drug interaction is known and statins are widely used and inexpensive, further studies assessing the use of abiraterone plus statins are warranted."

"The mechanism of this interaction warrants elucidation ..."

Apart from blocking steroidogenesis, there is another benefit of statin use. It has been known for a century that solid cancers (not just PCa) accumulate cholesterol. Denying cancer cells access to unlimited cholesterol, limits cholesterol being used for proliferation unrelated to androgen production.

This is from another paper published this month [2]: "Modulating cancer cell survival by targeting intracellular cholesterol transport." "Demand for cholesterol is high in certain cancers making them potentially sensitive to therapeutic strategies targeting cellular cholesterol homoeostasis." - i.e. targeting cholesterol has value in many cancer types.

And from May [3]: "The cholesterol metabolite 27-hydroxycholesterol stimulates cell proliferation via ERβ in prostate cancer cells." i.e. the cholesterol metabolite is an estrogen receptor [ER] agonist & triggers proliferation via ER activation.

Also from this month [4]: "... preoperative hypercholesterolemia is associated with a diagnosis of high-risk PC which is negatively influenced by statin intake."

But hypercholesterolemia isn't really the point. Men on ADT who have low cholesterol levels, are in danger of having PCa cells manufacture their own cholesterol.

I have been using Simvastatin as a PCa drug for 6(?) years. My circulating cholesterol level is irrelevant to my purpose.

-Patrick

[1] ncbi.nlm.nih.gov/pubmed/287...

Eur Urol Focus. 2017 Apr 8. pii: S2405-4569(17)30083-4. doi: 10.1016/j.euf.2017.03.015. [Epub ahead of print]

Statin Use and Survival in Patients with Metastatic Castration-resistant Prostate Cancer Treated with Abiraterone Acetate.

Di Lorenzo G1, Sonpavde G2, Pond G3, Lucarelli G4, Rossetti S5, Facchini G5, Scagliarini S6, Cartenì G6, Federico P7, Daniele B8, Morelli F9, Bellelli T10, Ferro M11, De Placido S11, Buonerba C12.

Author information

Abstract

BACKGROUND:

Although statin use has been associated with favorable effects in various solid malignancies, no conclusive evidence is available at present. Statins are safe and inexpensive, and may synergize with novel antiandrogen agents abiraterone via pharmacokinetic interactions and decrease substrate availability for de novo androgen biosynthesis.

OBJECTIVE:

To determine whether statin use affects survival in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with abiraterone.

DESIGN, SETTING, AND PARTICIPANTS:

Medical records of patients with documented mCRPC between September 2011 and August 2016 were reviewed at multiple participating centers. This research was conducted in ten institutions, including both referral centers and local hospitals. A total of 187 patients receiving abiraterone for mCRPC between September 2011 and August 2016 were eligible for inclusion in this retrospective study.

OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS:

Patients were assessed for overall survival (OS), statin use at the time of treatment initiation, prostate-specific antigen (PSA) variations, and other variables of interest. Univariable and multivariable analysis was used to explore the association of variables of interest with OS and PSA declines.

RESULTS AND LIMITATIONS:

Statin use was a significant prognostic factor for longer OS in univariable (hazard ratio [HR] 0.51, 95% confidence interval [CI] 0.37-0.72; p<0.001) and multivariable analysis (HR 0.40, 95% CI 0.27-0.59; p<0.001) and was significantly associated with PSA declines (>50% decline at 12 wk: 72.1% in statin users vs 38.5% in non-users; p<0.001).

CONCLUSIONS:

Our study suggests a prognostic impact of statin use in patients receiving abiraterone for mCRPC. The mechanism of this interaction warrants elucidation, but may include enhancement of the antitumor activity of abiraterone as well as cardioprotective effects.

PATIENT SUMMARY:

We assessed the effects of statin use in patients with advanced prostate cancer receiving abiraterone. Patients treated with a statin plus abiraterone appeared to live longer than those treated with abiraterone only. Since no negative drug-drug interaction is known and statins are widely used and inexpensive, further studies assessing the use of abiraterone plus statins are warranted.

Copyright © 2017. Published by Elsevier B.V.

KEYWORDS:

Abiraterone; Prostate cancer; Statins

PMID: 28753882 DOI: 10.1016/j.euf.2017.03.015

[2] ncbi.nlm.nih.gov/pubmed/286...

[3] ncbi.nlm.nih.gov/pubmed/285...

[4] ncbi.nlm.nih.gov/pubmed/284...

[BigRich]

Patrick,

Very valuable information; thank you.

Rich

[Dr_WHO]

Thank you so much for the information! I have been on Lipitor for about six years (well b/f I was diagnosed with advanced cancer). I am glad that the statin may be helping with the Lupron and Zytiga I am now on!

[Break60]

As a Gleason 9, I've been using Crestor for as long as I can remember. Way before getting PCa . My RO insisted that I stay on it and added metformin . I'm on my third round of ADT after three recurrences post RP. Although I've had mets to lymph nodes and femur (both treated with RT and ADT) , ADT is apparently still working as my PSA was reduced to undetectable the first two recurrences and this time ( after a lesion on femur) went from 2.3 to .3 in two months. I'm hoping that the combo of drugs I'm taking and RT is helping.

Bob

[pjoshea13 in reply to Break60]

Hi Bob,

The PCa research tends to favor the lipophilic statins (e.g. atorvastatin, lovastatin, and simvastatin) rather than the more hydrophilic (e.g. pravastatin, rosuvastatin (Crestor), and fluvastatin). But it isn't a yes/no situation:

"In terms of lipophilic nature, lovastatin and simvastatin are the most lipophilic, followed by atorvastatin, fluvastatin, and pravastatin. Rosuvastatin {Crestor} is a relatively new statin, having a polar methane sulfonamide group, and it can be placed between fluvastatin and pravastatin." [1] (2005).

Use of any statin will be beneficial.

I chose Simvastatin based on the few studies available some years back. It might no longer be the best option, but there are no definitive survival studies.

In a 2012 cell study: "Statins act directly on PC-3 cells with atorvastatin, mevastatin, simvastatin (1 μM) and rosuvastatin (5 μM), but not pravastatin, significantly reducing invasion towards BMS {Bone marrow stroma} by an average of 66.68% ... and significantly reducing both number ...) and size ... of colonies formed within BMS." [2]

So Crestor was effective, but at a much higher dose.

-Patrick

[1] pharmacytimes.com/publicati...

[2] ncbi.nlm.nih.gov/pubmed/225...

[Break60 in reply to pjoshea13]

Patrick

I'm taking 40 mg daily of rosuvastatin . Is that a high enough dose ?

Bob

[pjoshea13 in reply to Break60]

Bob,

I believe 40mg is the highest approved dose, although off-label 80mg has been reported.

My concern with Simvastatin is that 80 mg used to be the highest dose in the U.S. (it remains so in some countries). When the FDA reduced the highest dose to 40 mg (why not to 60 mg?) they allowed those already on 80 mg to continue on that dose. Bad timing on my part.

PCa studies report a dose-related response to statins. The highest dose is always better. When comparing statins, the lipophilic nature of the drug is important, but the maximum dose one can obtain is also important when figuring out which is the most potent in practice.

For someone like myself, who wants to use a statin only for PCa, 40mg Simvastatin is a far better option than 40mg Rosuvastatin (due to preferential uptake by PCa cells). But for control of LDL-cholesterol the reverse is true. So for someone like yourself, the ideal choice isn't so obvious.

Best, -Patrick

[herb1]

I'm going to try to slip in a somewhat related question; for some reason my email didn't make it to the site.

Often men are on statin BECAUSE there is some heart problem or concern. I've just had triple bypass, will that make Zytiga a no-no? (My cardiologist did increase my statin, Lipitor, from 10 mg/day to 40). Coincidental with the surgery, my psa has stopped going down on ADT3 (casodex) and is stuck at 1.4.

Herb

[pjoshea13 in reply to herb1]

Herb,

This might help answer your question:

accessdata.fda.gov/drugsatf...

I'll paste in two extracts below. -Patrick

"Use ZYTIGA with caution in patients with a history of cardiovascular disease. ZYTIGA may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition [see Adverse Reactions (6) and Clinical Pharmacology (12.1)]. Co-administration of a corticosteroid suppresses adrenocorticotropic hormone (ACTH) drive, resulting in a reduction in the incidence and severity of these adverse reactions. Use caution when treating patients whose underlying medical conditions might be compromised by increases in blood pressure, hypokalemia or fluid retention, e.g., those with heart failure, recent myocardial infarction or ventricular arrhythmia. The safety of ZYTIGA in patients with left ventricular ejection fraction <50% or NYHA Class III or IV heart failure has not been established because these patients were excluded from the randomized clinical trial. Monitor patients for hypertension, hypokalemia,

3 and fluid retention at least once a month. Control hypertension and correct hypokalemia before and during treatment with ZYTIGA"

"Cardiovascular adverse reactions in the phase 3 trial are shown in Table 1. The majority of arrhythmias were grade 1 or 2. Grade 3-4 arrhythmias occurred at similar rates in the two arms. There was one death associated with arrhythmia and one patient with sudden death in the ZYTIGA arm. No patients had sudden death or arrhythmia associated with death in the placebo arm. Cardiac ischemia or myocardial infarction led to death in 2 patients in the placebo arm and 1 death in the ZYTIGA arm. Cardiac failure resulting in death occurred in 1 patient on both arms."

[herb1 in reply to pjoshea13]

Patrick, thanks. I was aware of the concerns/warnings but my oncologist and urologist had failed to answer each time I asked. I guess it will still be a question when it comes time. I will bet they go right to Xtandi.

herb

[Sisira]

I am already taking Atorvastatin - a daily dose of 10mg to keep my bad cholesterol under control. In case I have to take treatment for CRPC, what should be the minimum daily dose of Atorvastatin that should be combined with the primary treatment for gaining the additional survival benefits?

Thank you for the useful information.

Sisira

[pjoshea13 in reply to Sisira]

Sisira,

You are taking a lipophilic statin, so that is good, but at the lowest dose.

Approved doses: 10 mg ; 20 mg ; 40 mg ; 80 mg.

The PCa studies indicate that higher doses are better. Don't expect to find a study that quantifies the benefit of each step-up for the major statins, or any statin in particular.

If a time comes when you want to increase the dose, you could do it gradually. COQ10 might prevent muscle ache. If you can't tolerate 80mg, 40mg is still a significant dose.

You mention CRPC, but the time to start is while on ADT, to delay CRPC, IMO.

-Patrick

[Sisira in reply to pjoshea13]

Thanks Patrick. I got your point that the time to start Statins is while on ADT. Now according to your advice, to be of any appreciable effect on PCa the dose should be either 40mg or 80mg ( much better ). I also read in a reply given by you today to another that regardless of his LDL-C level that he should consider a high dose lipophilic statin for PCa.

Well, I have been taking 10mg ( the lowest dose ) to keep my bad cholesterol under control for the last 5 years and my purpose there is to prevent cardio vascular decease ( I had a slightly high level in the past ). My latest Lipid Profile readings are given below and for the whole period the variations have remained almost in the same ranges.

Normal Range

Serum Cholesterol 148 150 - 200 mg/dl

HDL - Cholesterol 55 40 - 60 mg/dl

LDL - Cholesterol 68 0 - 160 mg/dl

Triglycerides 70 50 - 150 mg/dl

So if I were to increase my dose to 40mg from 10mg, with a view to getting the desired Pca treatment benefits, is it not going to affect the above healthy position drastically and create other metabolic problems?

I also can discuss about this with my physician ( Endocrinologist ) who checks my blood markers and the vital metabolic functions regularly but I equally value your opinions too.

Sisira

[pjoshea13 in reply to Sisira]

Sisira,

I wonder how many PCa doctors are familiar with the statin literature, or understand the risk of de novo cholesterol in PCa cells & steroidogenesis while on ADT? How many even prescribe statins?

& how many endocrinologists appreciate the role of cholesterol in cancer?

My own GP had no problem prescribing high-dose Simvastatin. Your guy might be disinclined, based on your numbers. I wonder how they might change on 40mg? BigPharma would say "only for the better", I suppose.

Good luck, -Patrick

[Sisira in reply to pjoshea13]

Patrick I fully agree with you,

When I first mentioned about Metformin and Statins to my oncologist, bluntly he said he has never herd of them and nonsensical for cancer treatment! In fact my Endocrinologist is not at all concerned with my PCa. I use him to maintain my vital metabolic functions in order, based on various blood tests. He only knows that I am a PCa patient. My question is not directed to the poor attitudes of these physicians. The focal point is :

In my situation can overdosing of Statins to 40mg/dl or 80mg/dl lower my cholesterol levels too much and create some metabolic issues? ( Leave aside its positive impact on PCa treatment ).

Appreciate your time in further clarifications.

Regards

Sisira

[pjoshea13 in reply to Sisira]

Sisira,

As I mentioned, my doctor was not concerned about starting me on the high dose. In fact, he apologized for not being able to give me 80mg Simvastatin.

There is a feeling amongst those who blame cholesterol for CVD, that cholesterol can never be too low. Strange attitude - but when more than half of Americans of my age are on statins, it's clear that safety issues must be minor.

However, recognizing your concern, I suggest that you try 20mg for a month & retest. If OK, repeat for 40 mg.

I doubt that the increased doses would have an extraordinary effect on LDL or create metabolic issues, but that's not expert opinion.

On the other hand, there might be significant PCa survival benefits with a higher dose.

-Patrick

[Sisira in reply to pjoshea13]

Thank you so much Patrick. I will follow your advice and increase the dose gradually and watch the effect on my lipid profile.

Sisira

[Abiathar in reply to pjoshea13]

The higher dose would continue to decrease your LDL but not much. There should be no appreciable disadvantage in regards to your lipids to increase the dose. The question I would have would be how much additional cancer benefit you would obtain.

Thanks

Abiathar

[Hidden]

Don’t know if it is relevant but had PSA of 5.16 in August, and was put on Crestor for cholesterol level. Was diagnosed with PCa in October. Surgery scheduled this month. In January had another PSA and it was at 2.87.

To my naive mind it suggests there is at least something going on. Uro Cancer doctor didn’t seem to think much of it but he may have been carefully measuring his words to keep me from attaching too much significance. I don’t know.

[pjoshea13 in reply to Hidden]

Something often overlooked is that statins lower inflammation. It may partly explain their benefit.

-Patrick