Fatigue and cognition appear to be a key driver when physicians choose therapy for metastatic castrate-resistant prostate cancer (mCRPC) patients.1 Fatigue is usually reported at the top of the list of the adverse effects, as can be seen in the ENZAMET (31% of enzalutamide treated patients)2 and ARAMIS (12.5% of darolutamide treated patients)3 trials in metastatic hormone-sensitive prostate cancer (mHSPC) patients. Fatigue is both a disease by itself and a treatment factor. The combination of abiraterone + prednisone + ADT significantly improved fatigue in the LATITUDE trial,4 as can be seen in figure 1.
Figure 1 – The combination of abiraterone + prednisone + ADT significantly improved fatigue:
A randomized trial published in 2017 demonstrated that exercise interventions in prostate cancer patients treated with ADT improve fatigue/vitality in those who need it the most. Those with the highest baseline levels of fatigue and the lowest baseline levels of vitality improved the most with exercise.5 Moreover, it has been shown that resistance exercise is more beneficial than aerobic only exercise.5 In a recent meta-analysis, cancer-related fatigue was shown to be best managed by exercise and support, and not drugs.6
The next topic discussed by Dr. Ryan was the effect of ADT on cognition. Apparently, the normal brain is filled with androgen receptors, and androgens are known to be neuroprotective. With age, testosterone and dihydrotestosterone decline rapidly, and low testosterone levels are associated with Beta Amyloid and cognitive deterioration.7 Two studies using different methods have shown that after one year of ADT there is a modest cognitive decline.8,9
Before concluding his talk, Dr. Ryan spoke about the association between ADT and dementia. Dementia is a chronic or persistent disorder of the mental processes caused by brain disease or injury; and marked by memory disorders, personality changes, and impaired reasoning. In a population-based study published in 2016 and using claims-based data, an association between ADT and dementia development was described.10 This study had many limitations consisting of the fact that the data was claims-based and did not consist of clinically validated diagnoses. Moreover, it did not capture the spectrum of cognitive impairment experienced by patients. There is a hypothesis that dementia in ADT treated patients arises after ADT in an at-risk population and is not caused directly by ADT.
The ARA-COG study (Androgen Receptor And Cognitive function in darolutamide and enzalutamide treated patients) is a randomized trial aiming to compare the percent change in the maximally changed cognitive domain by 24 weeks of treatment with either enzalutamide or darolutamide in mCRPC patients (Figure 2).
Figure 2 – The ARA-COG trial design:
In summary, ADT may be associated with fatigue and cognitive dysfunction, and claims-based data suggest an association between ADT and Alzheimer’s disease. The measurement of cognitive function remains challenging. It is therefore important to include assessments of patients reported outcomes and mediators of cognitive function in future trials. The more potent androgen receptor antagonists may improve disease outcome but may lead to compounded effects and require detailed study.
Presented by: Charles Ryan, MD, The B.J. Kennedy Chair in Clinical Medical Oncology and Director of the Division of Hematology, Oncology, and Transplantation, University of Minnesota, USA
Written by: Hanan Goldberg, MD, Urology Department, SUNY Upstate Medical University, Syracuse, New York, USA @GoldbergHanan at the 2019 Advanced Prostate Cancer Consensus Conference (APCCC) #APCCC19, Aug 29 - 31, 2019 in Basel, Switzerland
- Gillessen S. et al. Management of Patients with Advanced Prostate Cancer: The Report of the Advanced Prostate Cancer Consensus Conference APCCC 2017. European Urology. Urol 2018 Feb;73(2):178-211. doi: 10.1016/j.eururo.2017.06.002.
- Davis IA et al. Enzalutamide with Standard First-Line Therapy in Metastatic Prostate Cancer. New England Journal of Medicine. 2019; 381:121-131
- Fizazi K. et al. Darolutamide in Nonmetastatic, Castration-Resistant Prostate Cancer. New England Journal of Medicine. 2019; 380:1235-1246
- Chi K. et al. Patient-reported outcomes following abiraterone acetate plus prednisone added to androgen deprivation therapy in patients with newly diagnosed metastatic castration-naive prostate cancer (LATITUDE): an international, randomised phase 3 trial. The Lancet Oncology. 2018 DOI:https://doi.org/10.1016/S1470-2045(17)30911-7.
- Taafe et al. Effects of Different Exercise Modalities on Fatigue in Prostate Cancer Patients Undergoing Androgen Deprivation Therapy: A Year-long Randomised Controlled Trial. European Urology. 2017 Aug;72(2):293-299. doi: 10.1016/j.eururo.2017.02.019.
- Mustian et al. Comparison of Pharmaceutical, Psychological, and Exercise Treatments for Cancer-Related Fatigue A Meta-analysis. JAMA Oncology. 2017;3(7):961-968. doi:10.1001/jamaoncol.2016.6914.
- Rosario et al. Brain levels of sex steroid hormones in men and women during normal aging and in Alzheimer’s disease. Neurobiology of Aging 32. 2011 604–613.
- Alibhai SH et al. Neratinib, an irreversible ErbB receptor tyrosine kinase inhibitor, in patients with advanced ErbB2-positive breast cancer. Journal of Clinical Oncology. 2010 Mar 10;28(8):1301-7. doi: 10.1200/JCO.2009.25.8707.
- Gonzalez et al. Course and Predictors of Cognitive Function in Patients With Prostate Cancer Receiving Androgen-Deprivation Therapy: A Controlled Comparison. Journal of Clinical Oncology. 2015 Jun 20;33(18):2021-7. doi: 10.1200/JCO.2014.60.1963.
- Nead KT et al. Association Between Androgen Deprivation Therapy and Risk of Dementia. JAMA Oncology. 2016;3(1):49-55. doi:10.1001/jamaoncol.2016.3662.
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