second generation anti-androgens associated with cognitive and functional toxic effects

[Graham49]

This study of 12 randomized clinical trials comprising 13 524 participants observed an increased risk of cognitive toxic effects, fatigue, and falls among individuals treated with second-generation AAs (abiraterone, apalutamide, darolutamide, or enzalutamide).

A Systematic Review and Meta-analysis

Malgorzata K. Nowakowska, BS1; Rachel M. Ortega, MSA1; Mackenzie R. Wehner, MD, MPhil2,3; et al Kevin T. Nead, MD, MPhil4,5

JAMA Oncol. 2023;9(7):930-937. doi:10.1001/jamaoncol.2023.0998

”Main Outcomes and Measures Risk ratios (RRs) and SEs were calculated for cognitive toxic effects, asthenic toxic effects, and falls. Because fatigue was the asthenic toxic effect extracted from all studies, data on fatigue are specified in the results. Meta-analysis and meta-regression were used to generate summary statistics.

Results The systematic review included 12 studies comprising 13 524 participants. Included studies had a low risk of bias. An increased risk of cognitive toxic effects (RR, 2.10; 95% CI, 1.30-3.38; P = .002) and fatigue (RR, 1.34; 95% CI, 1.16-1.54; P < .001) was noted among individuals treated with second-generation AAs vs those in the control arms. The findings were consistent in studies that included traditional hormone therapy in both treatment arms for cognitive toxic effects (RR, 1.77; 95% CI, 1.12-2.79; P = .01) and fatigue (RR, 1.32; 95% CI, 1.10-1.58; P = .003). Meta-regression supported that, across studies, increased age was associated with a greater risk of fatigue with second-generation AAs (coefficient, 0.75; 95% CI, 0.04-0.12; P < .001). In addition, the use of second-generation AAs was associated with an increased risk of falls (RR, 1.87; 95% CI, 1.27-2.75; P = .001).

Conclusions and Relevance The findings of this systematic review and meta-analysis suggest that second-generation AAs carry an increased risk of cognitive and functional toxic effects, including when added to traditional forms of hormone therapy.”

[JohnInTheMiddle]

Yikes! Okay the reference was in July 2023.

pubmed.ncbi.nlm.nih.gov/372...

Here's a short more recent journalistic article on the same topic:

dailynews.ascopubs.org/do/m...

This is a developing area of research that would be good to know more about.

[Justfor_]

Good old Bicalutamide is priced too low to allow kickbacks. So, docs and their parrots bad mouth it as not potent enough. Follow the money potency.

[Tinkudi in reply to Justfor_]

Where there no comparative trials done ?

[Graham49 in reply to Tinkudi]

No comparison in this study. They say

"Fourth, there was an insufficient number of studies to stratify by type and mechanism of second-generation AA."

[Tinkudi in reply to Graham49]

Graham , what I meant to ask was between bicalutamide and later ARSis

[Justfor_ in reply to Tinkudi]

The pharmaceutical industry that spends their money into clinical trials would be sawing the branch they are sitting on by sponsoring such a trial. The price amplification of 2nd gen ARSIs vs Bicalutamide is approx 100:1. A trial concluding that, say 2% or more of patient cases could give equivalent results with Bicalutsmide, would be a financial disaster for the sponsors. Do you think they are that idiotic to take that gamble?

[Tinkudi in reply to Justfor_]

What does the poor patient do. In the face of a life threatening illness , not to follow soc seems so scary 😟

[Justfor_ in reply to Tinkudi]

Following SoC is good for your Lithium battery life (State of Charge 20%-80% preferably) because battery life is shortened when over charged or fully drained. Humans can be "overcharged" and this is considered advantageus by silly docs and their naive patients.

[Graham49 in reply to Tinkudi]

This “network meta analysis” found the second generation ARIs superior and all ARIs “generally well tolerated”

”Conclusion

The current network meta-analysis indicated that the second-generation ARIs were superior to the conventional ARI, bicalutamide. The three second-generation ARIs showed incomplete equivalence on CRPC treatment. The darolutamide was slightly less effective compared with enzalutamide and apalutamide. The adverse events of apalutamide were worse than the others, but no statistical significance was observed among these vital AEs. All ARIs were generally well-tolerated. These results may provide reference to clinical decision and further direct comparison trials.”

doi: 10.3389/fendo.2023.1131033

PMCID: PMC9950258PMID: 36843606

The efficacy and adverse events of conventional and second-generation androgen receptor inhibitors for castration-resistant prostate cancer: A network meta-analysis

[Justfor_ in reply to Graham49]

Check Figure 2:

AEs (Adverse Events) related to death (risk ratios - lower is better)

Placebo 0.33

Bica 0.28

Enza 0.49

Daro 1.0

Apa 2.3

Severe AEs

Placebo 0.82

Bica 0.82

Enza 0.96

Daro 1.0

Apa 0.88

And for those that don't like numbers:

"3.3.5 AE-related mortality

Meta-analysis showed that there was no statistical difference in AE-related mortality between placebo and bicalutamide as well as darolutamide (HR: 0.86, 95% CI: 0.34–2.11 HR: 3.03, 95% CI: 0.38– 85.13). Apalutamide and enzalutamide (HR: 6.73, 95% CI: 1.1–183.14; HR: 1.49, 95% CI: 1.03–2.20) increased the risk of AE-related mortality with statistical significance compared with placebo, and the risk in apalutamide group was the highest."

[Mascouche in reply to Justfor_]

I understand that Bicalutamide/Casodex is generally safer but there are exceptions. 50Mg/day was the highest dosage I could take without shedding my weight at a rate of 0.5 to 1 lbs a day and getting breathing issue. At 100Mg or 150 Mg it was killing me. And it was not even stopping my PSA from rising. Thankfully once I stopped taking it, I got better in a matter of days. But I am glad that it works for you Justfor_

[Justfor_ in reply to Mascouche]

I have posted that before but in the original paper the standard dose of 50 mg/day created 1:10+ blood concentrations in 114(?) men that tried it. It is evident that your sensitivity to the drug is in the higher numbers. It wasn't the drug at fault, it was your doc who didn't adapt the dose on you. We need docs that give their grey cells a whirl, not just memorize (magic) numbers from the SOC cookbook.

[Mascouche in reply to Justfor_]

My doc at the time was fresh out of school. He actually thought that my worsening condition was due to the cancer becoming more aggressive rather than me not tolerating that drug. Thankfully I document my weight and blood pressure as well as what I take and do every day in a spreadsheet so I was able to associate my new symptoms to the time when I upped the dosage to 100Mg. That gave me the fortitude to tell the doctor, you are wrong and I am correct on this one. When everything went back to normal after I stopped taking Bicalutamide, I was a little wise-cracking on my next appointment with him and told him "Seems like my cancer decided to become less aggressive at the moment I stopped the pills"

If I was the type of patient who blindly does what the doctor tells me, I probably would no longer be around today.

[Justfor_ in reply to Mascouche]

You are dead right ! (playing with words face here).

[PELHA in reply to Graham49]

Husband was put on bicalutimude for a year but after a few months PSA started to rise so was switched to doublet and now numbers declining.

[velobard]

I've been on Nubeqa since Feb 2020 and I can vouch for the fact that my fatigue went through the roof for the first several days. It settled down some eventually, but never back to the baseline of Lupron alone. Ever since then my fatigue has steadily crept upwards.

[Sagewiz]

I feel it. The fatigue has been my major issue. Thank yuou for posting this!!

[GFFF]

really interesting post thank you.

My OH has had a significant decline in both cognitive ability and mobility since starting these meds.

[Graham49]

This statement might be useful to those on ARSIs:

"There is a growing interest in interventions aimed at improving cognitive and functional outcomes among patients with cancer. Interventions currently under investigation include donepezil, methylphenidate, low-fat diet, acupuncture, martial arts, and high-intensity exercise, among many others.48-53"

Here are refs 48 to 53.

48.

Lawrence JA, Griffin L, Balcueva EP, et al. A study of donepezil in female breast cancer survivors with self-reported cognitive dysfunction 1 to 5 years following adjuvant chemotherapy.  J Cancer Surviv. 2016;10(1):176-184. doi:10.1007/s11764-015-0463-x

49.

Chapman EJ, Martino ED, Edwards Z, Black K, Maddocks M, Bennett MI. Practice review: evidence-based and effective management of fatigue in patients with advanced cancer.  Palliat Med. 2022;36(1):7-14. doi:10.1177/02692163211046754

50.

Mijwel S, Backman M, Bolam KA, et al. Adding high-intensity interval training to conventional training modalities: optimizing health-related outcomes during chemotherapy for breast cancer: the OptiTrain randomized controlled trial.  Breast Cancer Res Treat. 2018;168(1):79-93. doi:10.1007/s10549-017-4571-3

51.

Li F, Harmer P, Fitzgerald K, Winters-Stone K. A cognitively enhanced online Tai Ji Quan training intervention for community-dwelling older adults with mild cognitive impairment: a feasibility trial.  BMC Geriatr. 2022;22(1):76. doi:10.1186/s12877-021-02747-0

52.

Assaf AR, Beresford SAA, Risica PM, et al. Low-fat dietary pattern intervention and health-related quality of life: the Women’s Health Initiative Randomized Controlled Dietary Modification Trial.  J Acad Nutr Diet. 2016;116(2):259-271. doi:10.1016/j.jand.2015.07.016

53.

Arring NM, Barton DL, Brooks T, Zick SM. Integrative therapies for cancer-related fatigue.  Cancer J. 2019;25(5):349-356. doi:10.1097/PPO.0000000000000396

[Tall_Allen]

Someone posts such stuff all the time - I suppose they imagine they are being helpful, like chicken little. Before anyone takes the leap to concluding that ADT causes dementia from yet another retrospective observational study or review of such (1,000 x 0 = 0), one should ask oneself if there is obvious "selection bias" that accounts for the association. There is. Men who don't take ADT for their diagnosed prostate cancer generally don't need it. Men who take ADT, generally do. So the increased observation of dementia in men who take ADT has a lot to do with the debilitating effects of advanced cancer. In studies where the degree of cancer is corrected for, no such association is found.

For example:

"A multivariate analysis for dementia incidence showed no significance of ADT type or use duration among patients with PC (p > 0.05), whereas old age, obesity, regional SEER stage, a history of cerebrovascular disease, and a high Charlson Comorbidity Index were significant factors for dementia (p < 0.05). Insignificant correlation was observed between ADT and the incidence of dementia based on the extension survival model with PSM among patients with PC.

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

"In this population-based study, the use of ADT was not associated with an increased risk of dementia. "

ascopubs.org/doi/full/10.12...

"These data suggest that ADT treatment has no hazard for AD and no meaningful hazard for dementia among men age 67 years or older who are enrolled in Medicare."

ascopubs.org/doi/full/10.12...

"We concluded that there was no difference in the risk of subsequent dementia between PC patients who did and those who did not receive ADT."

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

"Our analysis of FDA MedWatch adverse event data reports does not support the idea that androgen deprivation therapy per se is associated with Alzheimer’s disease or cognitive dysfunction. Perhaps the prostate cancer itself, or the stress it imposes on the man who has it, may be detrimental to mood and intellect, increasing susceptibility to Alzheimer’s disease and cognitive disorder."

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

[Graham49 in reply to Tall_Allen]

The main concern is fatigue and cognitive ability. I don’t know why are you going on about dementia and Alzheimer’s. Nobody mentioned dementia or Alzheimer’s. Perhaps you think you are being helpful, like Chicken Little.

[Tall_Allen in reply to Graham49]

Because that's what you posted.

"second generation anti-androgens associated with cognitive and functional toxic effects: This study of 12 randomized clinical trials comprising 13 524 participants observed an increased risk of cognitive toxic effects, fatigue, and falls among individuals treated with second-generation AAs (abiraterone, apalutamide, darolutamide, or enzalutamide)."

[Justfor_ in reply to Graham49]

Plus, all the papers referenced above by TA are related to ADT while present thread is about ANTI-ANDROGENS. Both starting with A and lowering PSA confuses some to think they are one and the same thing.

[j-o-h-n]

I just switched from Casodex (Bicalutamide) to Darolutamide (Nubeqa) in April 2023. Is that my fucking luck or is it my fucking luck.....(Tired, out of breath and falling).

Good Luck, Good Health and Good Humor.

j-o-h-n

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

could be the company you keep.....

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

Could be the company that remarks about the company I keep....

Good Luck, Good Health and Good Humor.

j-o-h-n

[mababa]

What a great thread for someone about to jump into the ARSI/ARPI drug world with my MO’s intention to add abiraterone to my ADT. Yikes! At 72, and since getting my BP under control (can’t stress that enough), I’m feeling pretty damn good mentally. My frequency of brain farts may have krept up just a hair, but not to a concerning level. I’m still in on adding the ARPI but I am going to talk to my MO about bringing me up gradually on the drug to avoid overloading—something that is frequently mentioned. Appreciate the input offered in this thread.

[Bacana]

My husband’s quality of life took a nose dive when he started Xtandi. Zytiga was a breeze comparatively.