Men treated with androgen deprivation therapy (ADT) for prostate cancer had a significantly higher risk of dementia and other neurocognitive disorders, according to a meta-analysis of more than 2.5 million patients.

The magnitude of excess risk ranged from 20% for dementia to 66% for depression. The risk of Alzheimer’s disease, vascular dementia, and Parkinson’s disease were all significantly increased among men exposed to ADT versus those who did not receive the hormonal therapy, including those with and without prostate cancer.

“The increased risk of dementia is observed regardless of the treatment modality and duration; however, quantitative analysis is needed to assess the differences between treatment modalities and durations accurately,” concluded David E. Hinojosa-Gonzalez, MD, of Massachusetts General Hospital in Boston, and colleagues in Prostate Cancer and Prostatic Diseases. “It is important to note that some studies may have used similar databases and overlapping patient cohorts, which could introduce potential bias or duplicate data in this analysis.”

“Clinicians should be vigilant in monitoring prostate cancer patients undergoing ADT for symptoms of cognitive decline and other neurodegenerative disorders,” they added.

The findings add to a large volume of data on the relationship between ADT and neurocognitive functioning. Dozens of studies and reviews have examined the relationship without producing definitive answers. For example, another recent systematic review and meta-analysis included 31 studies, 16 of which showed no association between ADT and cognitive function; 11 of which showed a negative effect on one or more outcomes; and four that yielded inconclusive results.

Another systematic review showed no consistency among studies, many of which were retrospective. Authors of yet another review published just last year concluded that “studies continue to illustrate the varied outcomes in terms of the association of ADT and other systemic treatments for [prostate cancer] with cognitive decline, despite similar methodologies and design. Patient selection, varied neuropsychological testing, and varied duration of ADT probably account for the differences seen.”

Numerous individual studies have yielded suggestive evidence of negative impact of ADT on cognitive function. A review of a national drug-safety database showed that men treated with ADT had a 47% higher likelihood of cognitive impairment versus men who did not receive hormonal therapy. The risk was even higher in men treated with newer androgen receptor signaling inhibitors (ARSIs), but the association was not consistent across the ARSI class: increased risk with enzalutamide (Xtandi) and apalutamide (Erleada) but decreased risk with abiraterone (Zytiga).

Prostate cancer specialists note that consideration of the potential adverse effects of ARSIs on cognition should be balanced by consideration of potentially significant clinical benefits. In the landmark ENZAMET trial, enzalutamide was associated with a significant decline in cognitive function but also with a significant improvement in survival for men with metastatic hormone-sensitive prostate cancer, which “outweighed early deterioration in [health-related quality of life].”

Noting the inconsistent and sometimes conflicting evidence reported to date, Hinojosa-Gonzalez and colleagues performed a systematic review of contemporary studies examining the relationship between ADT and neurocognitive function, including dementia, Alzheimer’s disease, vascular dementia, and Parkinson’s disease.

The analysis included studies published through April 2023. Beginning with an initial list of 305 studies, the authors trimmed the number to 27. The studies involved a total of 2,543,483 patients, including 900,994 with prostate cancer treated with ADT, 1,262,905 with prostate cancer not treated with ADT, and 334,682 men without prostate cancer or exposure to ADT.

The data showed that treatment with ADT was associated with significantly increased hazard ratios (HRs) for:

• Dementia: HR 1.20 (95% CI 1.11-1.29, P<0.00001)
• Alzheimer’s disease: HR 1.26 (95% CI 1.10-1.43, P=0.0007)
• Depression: HR 1.66 (95% CI 1.40-1.97, P<0.00001)
• Parkinson’s disease: HR 1.57 (95% CI 1.31-1.88, P<0.00001)

Additionally, ADT conferred an increased risk of vascular dementia (HR 1.30, 95% CI 0.97-1.73, P<0.00001).

“All analyzed treatment modalities showed an increased risk of dementia,” the authors noted in their discussion. “Orchiectomy had the highest estimated risk; however, it is important to note that this treatment modality also had the least evidence. Furthermore, the employed methodology does not differentiate whether there are statistical differences between types of ADT. Future studies should incorporate comparisons of treatment modalities into the results using network analysis or similar approaches.”

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