Management of fatigue, cognition/dementia Lake of the Isles Charles J. Ryan, M.D. Professor of Medicine B.J. Kennedy Chair in Clinical Medical Oncology Masonic Cancer Center University of Minnesota
Disclosures relevant to this talk Philanthropic Support: • Prostate Cancer Foundation – Th!nk Different Foundation – Consultant (payment to institution) • Bayer – Research Support • Janssen – Sanofi Genzyme – Prostate Cancer Foundation – Movember Foundation – Lake Harriet
Life while Androgen Deprived is not a breeze • Fatigue is common(40% + incidence) • Potent AR Targeting may worsen this • Long term may be assoc with Dementia/cognitive decline. • What is the biological evidence of this link? Bde Mka Ska (formerly Lake Calhoun)
APCCC 2017: Fatigue and Cognition a key driver in mCRPC Therapy Choice EUROPEAN UROLOGY 7 3 ( 2 01 8 ) 1 7 8 – 2 1 1 185
Fatigue: Usually at the top of the AE list! ENZAMET ARAMIS Enza 31% Darolutamide 12.5% Placebo 9.6% control 15% TS + NSAA TS + ENZA N=558 N=563 95% CI: 95% CI: Serious AE rate per yr of Rx exposure 0.33 0.34 0.28-0.39 0.29-0.40 AEs of Interest N % N % Selected adverse events Hypertension: Gde 3 24 4% 43 8% (AE)*: Gde 2 30 5% 60 11% Fatigue: Gde 3 4 1% 31 6% All patients Gde 2 80 14% 142 25% at anytime Falls: Gde 3 2 <1% 6 1% Gde 2 8 1% 28 5% Syncope 7 1% 20 4% Concentration Impairment: Gde 1/2 6 1% 24 4% Any Seizure 0 0% 7 1% *worst grade AE shown Christopher Sweeney,MBBS
Effective Rx Mitigates Fatigue: Fatigue is both a disease and treatment factor Chi et al From Latitude
What is Fatigue, really? Just fatigue or the tip of an iceberg?
Abi, Enza, Daro, Apa – Effect on Depression/ Cognition? “Uptick” in Depressive Symptoms Enza > Abi ( were these at risk patients to begin with?) No significant Cognitive change based on MoCA test (relatively insensitive) But! Most patients take these >24 weeks! Khalaf, Gleave, Chi PROC ASCO 2017
#benchpresstobedside One year randomized controlled trial (RCT) of varying exercise interventions in PCa patients undergoing ADT Exercise improves Fatigue/Vitality in those who need it most Those with the highest baseline levels of fatigue and lowest vitality improved the most with exercise. Here’s the ‘vitality’ Taafe et al. Eur Urol. 2017 Aug;72(2):293-299 . score
Resistance is Utile Resistance exercise > Aerobic Only Taafe et al. Eur Urol. 2017 Aug;72(2):293-299.
#BenchpresstoBedside Cancer Related Fatigue is best managed by exercise and support, not drugs . Meta-Analysis UMN BMT Physician Shernan Holten MD - USPA national squat record and state bench and deadlift records for 82.5 kg masters Mustian et al JAMA Oncology 2017
#BenchpresstoBedside Beyond Fatigue: OS Benefit? Physical Activity, disease aggressiveness and Survival Meir Stampfer Stacy Kenfield Ongoing GAP4 Phase III Study: high intensity aerobic and resistance training plus psychosocial vs psychosocial support alone in MCRPC
How could ADT Affect Cognition? 2. Androgens are Neuro-Protective 1. The normal brain is filled with AR 3. DHT and T decline rapidly in the aging brain 4. Low T In the brains assoc with Beta Amyloid Rosario, Neuroobiol of Aging 2011
Modest Cognitive Decline after 1 year of ADT: Two studies, different instruments Following 1 year of ADT: Immediate Span of Attention: 40% gap vs healthy controls Visuo-spatial Activity 50% gap vs healthy controls Executive Function 40% gap vs healthy controls Controls “learn” and improve ADT Patients do not a challenge Gonzalez JCO 2015 Alibhai JCO 2010
What about ADT And Dementia* ? Limitations of these data 1. Claims based, not clinically validated diagnoses 2. Not corrected for Limited by EMR definition of Don’t be fooled by Alzheimer’s disease (both under- and over-reported). these KM curves! 3. Does not capture the spectrum of cognitive impairment experienced by patients * 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. Nead et al
ADT and Dementia: Hypothesis this that it arises post ADT in an at risk population Applying Polygenic Hazard Score to Cognitive Assesment in ADT Treated patients At Risk Protected Desikan RS, et al. (2017) Genetic assessment of age-associated Alzheimer disease risk: Development and validation of a polygenic hazard score. PLOS Medicine 14(3):
Conceptual Framework: What about directly targeting the AR? Highest Risk Individuals Genetic Effects: PHS AR polymorphisms Drug Effects: CNS Penetration Patient Effects: Potency of AR Age blockade Comorbidity Etc Hypothesis: Cognitive Impairment on ENZA or DARA arises from the interaction of genetic and modifiable risk factors shown here.
Alicia Morgans MD MPH
Summary Treatment with an ADT may be associated with fatigue and cognitive dysfunction. #benchpresstobedside Speak carefully with patients! Dementia and transient reversible cognitive dysfunction are very different processes! Claims based data suggests an association between ADT and Alzheimer’s disease Measurement of cognitive function remains challenging. Include assessments of patient reported Stone Arch Bridge Across the Mississippi outcomes and mediators of cognitive function in River your trials. More Potent AR antagonists, while improving disease outcome, may lead to compounded effects and require detailed study.
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