Abiraterone and Enzalutamide Raise Metabolic, Cardiovascular Adverse Event Risks

[Scout4answers]

Abiraterone was significantly associated with an 84% and 37% increased risk for a major or minor diabetic event, respectively, and a 91% and 75% increased risk for a major or minor cardiovascular event, respectively.

Not sure why any of us are using this drug!!!

July 6, 2022

Abiraterone and Enzalutamide Raise Metabolic, Cardiovascular Adverse Event Risks

Abiraterone and enzalutamide treatment were significantly associated with a 77% and 22% increased risk, respectively, of a major metabolic or cardiovascular adverse event. Source: Getty Images

Older men with advanced prostate cancer receiving abiraterone or enzalutamide have increased risks for metabolic and cardiovascular adverse events, a new study finds.

“With continued expansion of the indications for abiraterone and enzalutamide to earlier stages of the disease continuum, increasing numbers of men will be receiving these therapies for longer periods of time,” Lillian Y. Lai, MD, MS, of the University of Michigan in Ann Arbor and colleagues reported in the Journal of the National Cancer Institute. “This will potentially amplify the scope of men affected and increase the magnitude of the risks of adverse events, making careful attention to management of these issues crucial.”

Among 56,230 patients with advanced prostate cancer receiving Medicare (mean age 76-78 years), 2736 were treated with abiraterone, an androgen synthesis inhibitor, and 2466 with enzalutamide, a nonsteroidal androgen receptor antagonist, along with androgen deprivation therapy. The primary composite outcome was a major metabolic or cardiovascular adverse event, defined as an emergency room visit or hospitalization associated with diabetes, hypertension, or cardiovascular disease while on treatment with abiraterone or enzalutamide. The secondary endpoint was a minor metabolic or cardiovascular adverse event resulting in an outpatient visit while on treatment with these drugs.

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Abiraterone treatment was significantly associated with a 77% increased risk of a major composite adverse event and a 24% increased risk of a minor composite adverse event, compared with androgen deprivation therapy alone, Dr Lai’s team reported. By component, abiraterone was significantly associated with an 84% and 37% increased risk for a major or minor diabetic event, respectively, and a 91% and 75% increased risk for a major or minor cardiovascular event, respectively. The investigators noted that abiraterone is taken with a glucocorticoid, which in itself has metabolic and cardiovascular consequences.

Enzalutamide treatment was significantly associated with a 22% increased risk of a major composite adverse event but not a minor composite adverse event, according to the investigators. Abiraterone and enzalutamide did not increase the risk of hypertensive adverse events.

“As hypothesized, men receiving abiraterone with androgen deprivation were at a significantly increased risk of metabolic and cardiovascular adverse events necessitating emergency room visits and hospitalizations compared with those only on androgen deprivation,” the authors wrote. “Though also statistically significant, the evidence supporting the risks of enzalutamide was weaker, with a smaller magnitude of effect size compared with that associated with abiraterone use.”

Reference

Lai LY, Oerline MK, Caram MEV, Tsao PA, Kaufman SR, Hollenbeck BK, Shahinian VB. Risk of metabolic and cardiovascular adverse events with abiraterone or enzalutamide among men with advanced prostate cancer. J Natl Cancer Inst. Published online April 13, 2022. doi:10.1093/jnci/djac081

This article originally appeared on Renal and Urology News

[Tall_Allen]

Please learn how to read a study before posting "shocking news." 3 hints: (1) association is not causation (2) 124% of 1%= 1.24% (3) Risk increases with history

[Scout4answers in reply to Tall_Allen]

Allen... it is your reply that is Shocking... Perhaps you should take it up with Darryl @ Male Care as I copied that article directly from his Male Care Newsletter. You are saying the heart attack risk of anyone taking Abiraterone is less that 2% ???

[Tall_Allen in reply to Scout4answers]

Thanks, and I will take it up with Darryl. Media thrives on construing results so as to make headlines. In the trial that got Zytiga approved, the adverse event of "Cardiac failure" occured in 2.3% of men taking Zytiga and 1.0% of those taking placebo, a difference of 1.3% attributable to Zytiga.

[dhccpa in reply to Tall_Allen]

Cardiac failure is the most extreme. I wasn't sure that's what the article implied.

[Scout4answers in reply to Tall_Allen]

So this conclusion is just plain wrong?

“As hypothesized, men receiving abiraterone with androgen deprivation were at a significantly increased risk of metabolic and cardiovascular adverse events necessitating emergency room visits and hospitalizations compared with those only on androgen deprivation,” the authors wrote. “Though also statistically significant, the evidence supporting the risks of enzalutamide was weaker, with a smaller magnitude of effect size compared with that associated with abiraterone use.”

[Tall_Allen in reply to Scout4answers]

The statement isn't wrong, but you are misinterpreting it.

[Scout4answers in reply to Tall_Allen]

Where do you get these #s? 124% of 1%= 1.24%

[EdBacon in reply to Scout4answers]

Think about it this way:

You have a very low chance of the winning the Powerball. The odds are 1 in 292,201,338. But if you buy 2 Powerball tickets, you are 100% more likely to win. So although you are twice as likely to win, the odds are still very low.

[Tall_Allen in reply to Scout4answers]

"24% increased risk of a minor composite adverse event" 24% increase = 1.24 x 1.0% =1.24%

[EdBacon]

You said "Not sure why any of us are using this drug!!!"

I'm 100% sure why I'm using these drugs.

youtube.com/watch?v=I_izvAb...(Not working as expected?)

[j-o-h-n in reply to EdBacon]

B G scared the shit outa me........... but loved it..... all alone so ended up dancing with a broom...Thanks...

Saw a great remark by someone who played it:

"Played this at my uncle's funeral. He drove us home afterwards".

Good Luck, Good Health and Good Humor.

j-o-h-n Tuesday 07/12/2022 6:14 PM DST

[Alturia]

I am taking abiraterone because both my MO and I believe that the benefits are worth the relatively small risks associated with the drug. All drugs involve a risk reward calculation.

[Vangogh1961 in reply to Alturia]

I'm taking because I'm hoping to live long enough to have a cardiac event.

[Djangler in reply to Vangogh1961]

Funny. When I met with a RO he said there were risks of adverse effects 20 years down the road. I told him I hope I'm able to have those side effects. He didn't get the joke.

[LearnAll]

We can argue about extent of risk . But it is certainly true that Abiraterone does increase blood pressure and blood sugar and tends to exacerbate metabolic syndrome. The extent of damage to heart and worsening of diabetes depends on many other individual factors such as personal and family history of High BP and Diabetes, Body weight, smoking, lack of regular aerobic exercise and so on. Lutamides tend to have less cardiac and Blood sugar problems compared to abiraterone but they also worsen blood pressure and Blood sugar.

At the same time, I would say that Abiraterone is a very effective drug for PCa. I am taking it at lower dose 250 mg/day with fatty meal. Side effects are tiredness sometimes lethargy and low motivation which are mitigated by my 5 mile daily walks and antioxidant ,anti-inflammatory foods and supplements.

[marnieg46 in reply to LearnAll]

Could I ask the reason why you are taking it with a fatty meal? The instructions say take on an empty stomach either one hour before breakfast or two hours after a meal. Just wondering?

[LearnAll in reply to marnieg46]

When Abiraterone was brand name (Zytiga) and was being sold for $12000 for one month supply...the drug company came out with recommendation of taking 1000 mg empty stomach.Once it became generic and price dropped dramatically University of Chicago researchers published data that when taken along with fatty meal, the absorption and bioavailability becomes 4 to 6 times. In other words, taking 250 mg with fatty meal...works just as good as 1000 mg empty stomach. I take 250 mg with fatty meal and my total T is 3 (three) and free T is 0.3. So it is doing its job.

[marnieg46 in reply to LearnAll]

Thank you for the explanation...but just a couple more questions...so if 500mg is what has been prescribed 2x day is it then better to stick to taking it on an empty stomach?

Also, has 250mg taken with a fatty meal become SOC in US based on the data from the research or has that remained at 1000mg? Just curious...

[Concerned-wife in reply to marnieg46]

When I last looked, The low dose with food is now in the NCCN guidelines as well as the regular dose. Here is a reference to it. cancerletter.com/guest-edit...

Please note that you do not reduce side effects with the lower dose…other than the hit to your wallet and swallowing fewer pills.

[dhccpa in reply to Concerned-wife]

Thanks for posting. Those hits to the wallet can be damned devastating!

[marnieg46 in reply to Concerned-wife]

Thank you. Your answer appreciated. I'm encouraged that you note that regardless a lower dose doesn't seem to change the side effects.

I'm just curious as my husband is moving from Enza after less than 12 months due to side effects that not only obliterated any QOL but left him at serious risk of becoming immobile and at danger from increasing falls. He's unlikely, at least at this stage to deviate from MO's recommendation, so I guess I'll have to see how he goes on the full dose using the 'take on an empty stomach' advice on the web.

Cost isn't an issue for us because of our national health care. His heart specialist has advised that she is unconcerned about any risks of a cardiac event due to the change to Abi. So we'll see. Probably like most medications the effect on individuals seems to be almost person specific.. at least to some degree.

[marc_andersun in reply to LearnAll]

Any idea how much fat is needed in the meal? I usually do 40ml of olive oil in my keto meals....

[Concerned-wife in reply to marc_andersun]

healthsystem.osumc.edu/pted...

[LearnAll in reply to marc_andersun]

Honestly I do not count fat every day. In my dinner meal, I use approx. 2 tsf (10 ml) of liquified Butter, known as GHEE. This amount seems good as my T drops to below 5.

[dhccpa in reply to LearnAll]

Sensible analysis.

[jazj]

This is an area I'm a bit clueless on as I'm not at that point but am curious to better understand. Maybe someone can give me the skinny? Is not the benefit from all these drugs derived from starving prostate cancer from using Testosterone to fuel its progression? My loose understanding is different drugs have different ways of doing that I think some stop production of Testosterone some stop the cancer cell receptors from using Testosterone - or are their mechanisms of action very similar as are their side effect profiles (on average): abiraterone, enzalutamide, darolutamide, and bicalutamide. Seems like those are the 4 references 95% of the time. I'm not sure why Relugolix (Orovyx) is not mentioned more often recently as my understanding is at has less cardiovascular risks, lowers T faster, T comes back quicker, and it's a pill you can take instead of going in for a shot. My guess is it being new is the main reason and thereby more expensive and thereby denied by many insurance plans in favor of the older drugs?

This is an area I would make sure I have an expert Oncologist and just go with their recommendation assuming they are in the know regarding all the trial results for all the available drugs and/or combinations thereof.

[Concerned-wife in reply to jazj]

Relugolix is an alternative to Lupron, not these drugs, which are prescribed in addition.

[KocoPr]

Shouldn’t you be taking prednisone with aby to prevent these cardio events and metabolic disease?

[LearnAll in reply to KocoPr]

Yes. prednisone itself has lots of serious side effects. Review list of side effects of steroids, list is 10 meter long..

[KocoPr in reply to LearnAll]

Thanks for pointing that out, researching,,, going down another rabbit hole! Jeez when will these rabbit holes end!

[j-o-h-n in reply to KocoPr]

That's a question Mr. Hare never wants answered....

Good Luck, Good Health and Good Humor.

j-o-h-n Tuesday 07/12/2022 6:17 PM DST

[Schwah]

Studies can scare you with % increases. If 1% of people have a cardio vascular event before the drug and that goes up 77%, less than 1% more men have a cardio event than otherwise would have. Now if 20% more are alive from adding the drug, and less than 1% more are dead from a heart attack, you have your answer as to “why any of us are using this drug”.

[dhccpa in reply to Schwah]

I suspect they'll start writing the articles in that way after seeing this thread. We'll see.

[Brianne07]

if you have pre existing medical conditions it is very important to have stress tests ,echogram ,ultra sound of the heart and checked by a heart professor.Also walk daily ,light weights and a very good diet. Regards Brian

[London441 in reply to Brianne07]

Light weights? Why ‘light’ weights?

[jazj]

Incidentally, I was clearing a scratch pad (notepad) on my PC I always have open and a note I pasted a month or two ago from an article that I have no idea where it came from tied into this thread. Had to google one of the sentences and found it was from here:

tandfonline.com/doi/full/10...

This was from 2015, 7 years ago. I would assume many users who have done deep dives into this type of information (and/or their Oncologists) are well aware of a lot of this information? My first question to my Oncologist when beginning ADT would be, what has been concluded/confirmed since this retrospective study? I found the study referenced (Phase 2 PRINT clinical trial):

clinicaltrials.gov/ct2/show...

Apparently no results yet? Is cycling AR inhibitors standard of care now?

"Retrospective data from patients with mCRPC suggest the possibility of cross-resistance among different AR signaling inhibitors and between hormone agents and chemotherapy as well as reduced activity when agents are used in sequence [72–74]. The praecox and longterm use of potent AR inhibitors can induce adaptive phenotypes in cancer cells through the activation of both AR-dependent and AR-independent survival pathways [15,16]. Histological dedifferentiation and lineage alterations, such as treatment-induced neuroendocrine prostate cancer (t-NEPC) and treatment-induced epithelial-to-mesenchymal transition (tEMT), can result in rapid disease progression and resistance to both hormone agents and chemotherapy [75]. A study confirmed that use of abiraterone acetate and enzalutamide increases the percentage of t-NEPC, which are found in 17% of metastatic biopsies obtained from patients with mCRPC [76]. This aggressive form of PCa is associated with shortened survival and shows near-mutual exclusivity with the presence of DNA repair mutations [76]. Strategies to prevent the treatment-induced lineage crisis might include rapid drug cycling with collateral sensitivity, innovative drug combinations, intermittent therapy and bipolar androgen therapy [57,77,78]. The phase 2 PRINT clinical trial is ongoing to assess the feasibility for cycling therapies to prevent resistance in patients with mCRPC [79,80]. This study might provide valuable data to test this approach also in the

setting of nmCRPC."

[dhccpa]

Any signs of a generic enzalutamide coming to the USA market?

[Break60]

Nobody is getting out of here alive!

[j-o-h-n in reply to Break60]

Now you tell us.....................emmmm

Good Luck, Good Health and Good Humor.

j-o-h-n Tuesday 07/12/2022 6:18 PM DST

[Boywonder56]

I know for fact that adt causes a1c to rise....and i had to add actose to my metformin to lower it....i would have rather stopped adt.....but me grandaughter smiled at me and i lost my inclinattion......its amazing hows sum of use can beat percenatages to bits...you must of been the nerds with pocket protectors.....just take ur meds and live life...we could of got small cell lung cancer or worse.....

[j-o-h-n in reply to Boywonder56]

Yes, like getting bitten on your Johnson by a black mamba..............at your bachelor party....just before your lap dance..... (you know the punch line - you're gonna die)....

Good Luck, Good Health and Good Humor.

j-o-h-n Tuesday 07/12/2022 6:28 PM DST

[dmt1121]

I think these links may help put these studies in perspective regarding comorbidities thelancet.com/journals/ecli... practiceupdate.com/content/...

Personally, I was also concerned about some of the articles and studies on this subject because I don't understand how to interpret the statistical information. I shared a recent article with my primary care doctor to see if I needed monitoring by a cardiologist. Her response was that my medical history and current health did not show a need for this level of care.

There is a lot of information out there that can be scary when we don't know what is really being said. I think Tall Allen's response is helpful. Maybe on future posts, we can ask the question about how to interpret such data in articles and studies and our resident experts on this forum can explain them...without derision.

I think it is important that the panic we sometimes feel that leads to posts that may be unintentionally misrepresenting the findings be corrected in a way that is respectful and understanding. I know this may be annoying to constantly respond to posts that may cause alarm to correct the posting but we need to keep in mind that we are here to learn and support each other.

Both you and Tall Allen are sincere in wanting to help those on this forum but some of us are much more knowledgeable and in a mentorship and educational role. We greatly appreciate those of you who share your knowledge with us. It is literally a life saver.

[EdBacon]

The problem for us stage 4 guys is that we are in a "damned if we do, damned if we don't" kind of situation when it comes to the risks associated with some of the meds we are taking.

We understand that there are risks, side effects, etc. with anything we take, but we often have to choose between the lesser of evils so to say in order to get whatever life extension we can. We can't let the perfect become the enemy of good as the saying goes.

That said, I've gotten over 5 years out of Zytiga and Xtandi so can't complain. 😀

[Benkaymel in reply to EdBacon]

Ed, which one (Zytiga or Xtandi) did you have the worst side effects from?

[EdBacon in reply to Benkaymel]

I didn't really have side effects from either. I wasn't on Xtandi as long as Zytiga though.

[Benkaymel in reply to EdBacon]

Wow, just goes to show that everyone is different!