More evidence supports enzalutamide’s link with poorer mood and cognitive outcomes in mCRPC

Patients with metastatic castration-resistant prostate cancer (mCRPC) treated with enzalutamide reported more fatigue, depression and deterioration in perceived cognitive ability, and slower reaction time than those receiving abiraterone acetate, according to results of the ACE study.

“Abiraterone acetate and enzalutamide are both approved for treatment of mCRPC,” said Professor Amit Bahl of the Bristol Haematology and Oncology Centre, University Hospitals Bristol, UK, at the 2024 American Society of Clinical Oncology Genitourinary Cancers Symposium (ASCO GU 2024). “Understanding the early impact of these treatments on various domains of cognitive function, depression and fatigue would lead to optimization of treatment selection and promote supportive care planning in this patient group.” [J Clin Oncol 2024;doi:10.1200/JCO.2024.42.4_suppl.20]

In the multicentre, prospective ACE study, the researchers analyzed data from 253 men with mCRPC (median age, 74 years) receiving enzalutamide (n=112) or abiraterone acetate (n=141) at 12 UK centres. Half of the patients (49 percent) received prior treatment with docetaxel.

Cognition was measured by the Cambridge Neuropsychological Test Automated Battery (CANTAB) assessment. Patient-reported outcomes were evaluated using the Functional Assessment of Chronic Illness Therapy (FACIT)–Fatigue Scale, FACIT-Cognitive Function Scale, and Patient Health Questionnaire-9 (for depression).

Although the mean composite cognitive outcome was comparable between the two groups at 3 months (p=0.553) and 6 months (p=0.198), the researchers reported differences in individual components of patient-reported outcomes.

The enzalutamide group showed significantly higher levels of depression (3 months, p=0.022; 6 months, p=0.020) and fatigue (p<0.001 for both 3 and 6 months), worse perceived cognitive ability (p<0.001 for both 3 and 6 months) and longer reaction time (3 months, p=0.009; 6 months, p=0.037) vs the abiraterone acetate group.

The real-world AQUARiUS study (n=211; mean age, 76 years) suggested an advantage of abiraterone acetate plus prednisone over enzalutamide on fatigue and cognitive functions such as memory and thinking abilities (p<0.05) over 12 months. A phase II open-label randomized trial (n=202) revealed that patients with mCRPC treated with abiraterone acetate had fewer depression symptoms at weeks 4, 8 and 12 vs enzalutamide recipients (all p<0.05). [Eur Urol 2020;77:380-387]

A meta-analysis of randomized clinical trials with real-world reporting patterns from EUDRA indicated that patients treated with enzalutamide had significantly higher risks of anxiety, headache and insomnia vs controls, but increased risks were not found in those treated with abiraterone acetate plus prednisone. [Eur Urol 2019;75:940-947]

Results of ACE are generally consistent with these real-world and clinical trial data, suggesting differential effects on cognitive function and central nervous system (CNS)–related adverse events within the drug class of second-generation androgen receptor inhibitors. [J Clin Oncol 2024;doi:10.1200/JCO.2024.42.4_suppl.20; Prostate Cancer Prostatic Dis 2020;23:207-219]

Enzalutamide, but not abiraterone acetate, is known to penetrate the blood-brain barrier, which may at least partially explain its effect on the CNS. [JAMA Netw Open 2021;4:e2114694]

“Mood and cognitive outcomes are important considerations for optimizing treatment and ensuring supportive strategies for mCRPC patients,” pointed out Bahl. Particular consideration should be given to patients with mCRPC, many of whom require long-term androgen deprivation therapy and second-generation androgen receptor inhibitors, which could lead to worsening in cognitive function, subsequently affecting functional independence and quality of life. [Clin Genitourin Cancer 2021;19:467.e1-467.e11]