The impact of androgen receptor (AR)-directed therapies on cognitive function and the central nervous system needs to be rigorously investigated to ensure that patient quality of life (QoL) is maintained in men with prostate cancer, according to a recently published review in Prostate Cancer and Prostatic Diseases.

“Novel AR-targeted drugs may be an issue,” said first author Charles Ryan, MD, of the Division of Hematology, Oncology and Transplantation at the University of Minnesota in Minneapolis. “We think only a fraction of the men who experience cognitive impairment report it.”

Dr Ryan and his coauthors conducted a MEDLINE search for appropriate papers published from January 2000 to December 2018. The team found that enzalutamide and apalutamide were associated with some central nervous system (CNS)-related adverse events (AEs). Abiraterone was associated with a safer CNS profile than enzalutamide. In clinical trials, darolutamide had an incidence rate of cognitive disorders comparable to ADT alone. Falls were reported as a CNS-related event in men with metastatic disease treated with abiraterone and enzalutamide. The authors noted, however, that there have been no head-to-head randomized studies of these agents, and a full investigation into their CNS effects is warranted.

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Men with PCa are living longer on hormonal therapy, potentially increasing the consequences of the novel antiandrogens, which are more potent than the previous class of medications. “The challenge is that urologists and oncologists don’t have a simple test they can do,” Dr Ryan told Renal & Urology News. “Detailed cognitive testing takes hours and must be done by a cognitive professional, and there is no standard of care when get it comes to getting cognitive testing.”

Research in this area has been severely hampered by a lack of guidelines and use of different methodologies. “Acute cognitive impairment is getting mixed up with dementia,” Dr Ryan said. Studies suggest some men may be at higher risk for cognitive impairment.

Genetic, societal, and comorbid conditions influence cognitive function, so trials can be difficult to design and execute. Amar U. Kishan, MD, Assistant Professor and Chief of Genitourinary Oncology Service at the University of California in Los Angeles, said there is an urgent need to examine cognitive changes associated with the newer antiandrogens. “I think there are important adverse effects to consider,” Dr Kishan said. “As the authors eloquently point out, neurologic and/or psychiatric adverse effects from any of these therapies can certainly affect quality of life in a negative way. Patients and providers should be aware of these risks in order to make an informed choice about therapy.”

Leonard J. Appleman, MD, PhD, Associate Professor of Medicine at the University of Pittsburgh, said this current review comes at an important time. “We are still looking at developing the tools that we need to look at the problem,” he said. “We have to separate long-term effects from short-term effects.”

Cognitive issues in this patient population are commonly discussed among clinicians, but not in the medical literature, said Megan Caram, MD, Clinical Assistant Professor at the University of Michigan in Ann Arbor. “Anecdotally, most of us who treat patients chronically with androgen deprivation will hear patients report problems with their memory or tell us that they just feel like their thinking has slowed,” Dr Caram said.

It is challenging to tease apart true cognitive decline from such side effects as depression and anxiety, which can occur in patients on ADT as well as those coping with a chronic and terminal cancer diagnosis. “I am not surprised by the authors’ conclusion that there may be a difference between the different secondary androgen inhibitors,” Dr Caram said. “In my practice, I have had to recommend stopping enzalutamide to several patients due to severe quality-of-life adverse events such as fatigue, depression or cognitive decline.”

Many men with recurrent or metastatic prostate cancer are older than 65 years and have other comorbid conditions, Dr Caram said. “It’s not uncommon to see a patient in clinic with recurrent prostate cancer, who may have some early signs of dementia or cognitive decline before starting these treatments,” she said.

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Ryan, C, Wefel, JS, Morgans, AK et al. A review of prostate cancer treatment impact on the CNS and cognitive function [published online December 16, 2019]. Prostate Cancer Prostatic Dis. doi: 10.1038/s41391-019-0195-5