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
”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.”
Written by
Graham49
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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?
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.
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
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."
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_
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.
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.
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.
"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
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.
"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."
"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."
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.
"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)."
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.
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).
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.
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