Numerous medical and psychological complications are associated with exposure to androgen deprivation therapy (ADT), the most commonly used systemic treatment for prostate cancer. One complication that remains controversial is cognitive function. While multiple studies suggest an association between ADT and cognitive change, others suggest that the risk of cognitive decline does not increase with exposure to ADT. This brief report reviews the association between treatment with ADT and cognitive decline, as well as potential cognitive effects of androgen receptor (AR) signaling inhibitors and ongoing trials.

The idea that ADT is associated with impaired cognitive function is consistent with our understanding of the effects of hypogonadism in noncancer populations. ARs are expressed throughout the central nervous system (CNS), with higher concentrations in the hippocampus and amygdala. These regions of the brain are involved in memory formation and emotional processing, among other activities. Studies of patients with naturally occurring hypogonadism due to aging suggest that low levels of testosterone are associated with reduced processing speed and verbal and visual memory, as well as decreased visuomotor and spatial abilities in aging men, especially among men over 70 years of age.^1–5

Multiple studies have evaluated the effect of ADT on cognitive function of men with prostate cancer, with conflicting results. One population-based study of 16,888 prostate cancer patients in the SEER (Surveillance, Epidemiology, and End Results)-Medicare database evaluated the association between exposure to ADT and claims for Alzheimer’s disease.⁶ A multivariable analysis and propensity score analysis both demonstrated an association between ADT exposure and an increased risk of Alzheimer’s disease, with hazard ratios of 1.66 (95% CI 1.05–2.64) and 1.88 (95% CI 1.10–3.20), respectively. The authors used a similar approach to evaluate the association between ADT and development of all dementias within a SEER-Medicare data set including 9,272 patients with prostate cancer.⁷ At 5 years, there was an absolute increase in risk of 4.4% for patients exposed to ADT (HR 2.17, 95% CI 1.58–2.99). Gonzalez and colleagues performed a prospective clinical trial of 58 men with prostate cancer undergoing treatment with ADT, 84 men with prostate cancer not treated with ADT and 88 control patients who did not have prostate cancer.⁸ At 12 months, a greater proportion of men receiving ADT met criteria for cognitive impairment than control participants without prostate cancer (OR 1.21, 95% CI 0.66–2.22). Finally, McGinty and colleagues performed a systematic review of 14 trials assessing the association between ADT and declining cognitive function in men with prostate cancer.⁹ The authors found that ADT was associated with decreased visuomotor skills without a consistent decline in other cognitive domains.

In contrast, several studies failed to find an association between ADT and cognitive decline. Alibhai and colleagues prospectively evaluated 3 groups of men older than 50 years, including 77 men with nonmetastatic prostate cancer treated with ADT, 82 patients with prostate cancer not receiving ADT and 82 men without prostate cancer.¹⁰ After being assessed 5 times during a 36-month period, there was no significant difference between groups in the proportion of men who met criteria for cognitive decline on 14 cognitive tests. The same research team assessed patient-reported cognitive function by the FACT-Cog (Functional Assessment of Cancer Therapy-Cognitive Function) patient-reported outcome measure and similarly failed to find a difference at 12 months between groups in terms of cognitive complaints.¹¹

There is interest in determining whether intensified suppression of testosterone signaling may be associated with more significant cognitive complaints. There are currently limited head-to-head comparative data demonstrating a difference in cognitive effects between the AR signaling inhibitors. While abiraterone acetate would not directly affect ARs in the CNS, data from preclinical studies suggest that enzalutamide and apalutamide cross the blood-brain barrier to a greater extent than darolutamide and may have direct AR antagonist activity within the CNS.^11–13 Both the AQUARiUS and REAAcT studies compared cognitive outcomes between men with metastatic castration-resistant prostate cancer treated with enzalutamide versus abiraterone acetate and demonstrated greater cognitive change associated with enzalutamide.^14,15 The ODENZA trial is a recently reported phase 2 study in which 249 men with metastatic castration-resistant prostate cancer were randomized to treatment with darolutamide or enzalutamide, with crossover after 12 weeks. Verbal memory performance was superior among patients treated with darolutamide versus enzalutamide (p=0.0075).¹⁶

One hypothesis that seeks to explain the conflicting data is that there are patients who are more vulnerable to the effects of hypogonadism who may experience greater cognitive decline in the setting of ADT. Multiple ongoing studies seek to characterize the relationship between different approaches to ADT and cognitive decline in a way that may identify populations who are most susceptible. One is the COGCaP trial, in which men with prostate cancer who are receiving treatment with abiraterone or enzalutamide per standard indications undergo cognitive testing and a germline genetic assessment to identify single nucleotide polymorphisms that may be associated with greater cognitive decline (NCT03016741). A second study is the ARACOG trial, in which men with castration-resistant prostate cancer are randomized to treatment with enzalutamide or darolutamide to compare cognitive function during treatment with AR antagonist treatments with different blood-brain barrier penetration (NCT04335682).

Ultimately whether ADT or intensification treatments that reduce testosterone signaling are associated with cognitive decline remains undefined. Given this, clinicians and patients must be cognizant of the potential for cognitive change during treatment with ADT and identify cognitive decline early if it occurs. Referral of patients to neurologists who specialize in dementia or neurological rehabilitation can enable patients to be diagnosed with early cognitive impairment if it is occurring, and to receive behavioral or pharmacological interventions to reverse or slow decline. Additionally, urologic oncologists can work with patients to change or stop systemic prostate cancer-directed hormonal treatments if doing so is not expected to compromise disease control or is otherwise in the best interest of the patient. Use of a combination of physician and patient awareness, willingness to adjust the initial treatment plan and proactive engagement of consultative services that can support patient neurological health can mitigate these complications for a majority of patients with prostate cancer.