Second-Generation Antiandrogens Up Risk for Cognitive, Functional Toxic Effects

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The increasing number of indications for second-generation antiandrogens may result in a large group of men at risk for toxic effects.

Second-generation antiandrogens have cognitive and functional toxic effects, a new study confirms.

Investigators conducted a systematic review and meta-analysis of 12 randomized clinical trials published 2011 to 2020 involving 13,524 men with metastatic or nonmetastatic prostate cancer who were treated or not with abiraterone, apalutamide, darolutamide, or enzalutamide.

Second-generation antiandrogen users had a significant 2.1-fold increased risk of cognitive toxic effects compared with nonusers, Kevin T. Nead, MD, MPhil, MD Anderson Cancer Center, University of Texas in Houston, and colleagues reported in JAMA Oncology. They also had a significant 1.3- and 1.9-fold increased risk of fatigue and falls, respectively, including falls requiring hospitalization or invasive intervention. Older men had greater risk for fatigue. Baseline cognitive function was unknown.

The findings were consistent in studies that included concomitant use of traditional androgen deprivation therapy (ADT), which also have been linked with adverse effects.

The increasing number of indications for second-generation antiandrogens may result in a large group of men at risk for toxic effects, according to Dr Nead’s team.

“Our findings have practical implications for patient care,” the team wrote. “There is strong evidence that poor cognitive function and mental health are linked to worse outcomes and increased mortality among patients with cancer. Cognitive dysfunction might also decrease adherence to cancer treatment.”

Regarding plausible biological mechanisms, the investigators noted that androgen receptors are common in the central nervous system and play a role in mood, attention, and memory. It’s also plausible that depression linked to androgen deprivation contributes to cognitive impairment and cancer-related fatigue.

The investigators pointed out that many interventions are being studied, such as donepezil, methylphenidate, low-fat diet, acupuncture, martial arts, and high-intensity exercise.

“Our work supports the need for further research to determine how to identify, prevent, and treat cognitive and functional toxic effects in patients treated with second-generation [antiandrogens].”


Nowakowska MK, Ortega RM, Wehner MR, Nead KT. Association of second-generation antiandrogens with cognitive and functional toxic effects in randomized clinical trials: a systematic review and meta-analysis. JAMA Oncol. Published online May 25, 2023. doi:10.1001/jamaoncol.2023.0998

This article originally appeared on Renal and Urology News