Biological and Pharmacodynamic Determinants of AR Therapy Associated Cognitive Effects (ARTACE)

Approximately 40-50% of the nearly 161,360 American men diagnosed with prostate cancer each year will receive treatment with androgen deprivation therapy (ADT) at some time during the course of their disease.[1,2] After castration-resistance has developed, further suppression of androgen receptor (AR) signaling can provide renewed disease control and prolong life[3-6]. The novel AR directed therapies (enzalutamide (ENZ) and darolutamide (DARO) accomplish this by directly antagonizing the AR. ENZ is a Food and Drug Administration (FDA) approved for treatment across the disease spectrum of mCRPC (metastatic castration resistant prostate cancer), while DARO is currently in phase III testing. The cognitive effects of exposure to cancer treatments have been evaluated for decades.[7-10] The constellation of effects, typically attributed to exposure to chemotherapy, includes poor short-term memory, impaired multi-tasking, poor concentration and attention, and word-finding difficulties, among others. These changes can negatively impact interactions with family and loved ones, work performance, and continued access to health services.[7, 11, 12] Although there is a robust literature on these complications among patients with some solid tumors, such as breast cancer, there is a relative paucity of literature describing the cognitive effects of cancer treatment among men with prostate cancer.[10, 13-19, 20-22]. Novel AR targeted therapies may be associated with cognitive effects specific to the direct antagonism of the AR in the brain, a syndrome we have termed AR Therapy Associated Cognitive Effects (ARTACE). This syndrome is likely distinct from dementia, as well as the effects of ADT alone, which only lowers testosterone levels and does not directly antagonize the AR in the brain. Further, ARTACE may be reversible with conversion to an alternate therapy or treatment discontinuation. These effects are being studied in a clinical trial called ARACOG: A Randomized Phase II Study of Androgen Receptor Directed Therapy on COGnitive Function in Patients Treated with Darolutamide or Enzalutamide (Also known as Alliance Foundation Trial 47, or AFT47). This trial offers a unique opportunity to interrogate the interface of hormonally directed therapies for prostate cancer with the neuroscience of cognitive function. The purpose of the current Challenge Award application is to support the ARACOG clinical trial through a series of correlative studies that will further our understanding of AR signaling and its relationship to cognition, deepen our understanding of the overlap of risk factors for dementia with the risk of AR targeted associated cognitive dysfunction, and the relative contribution of two pharmacological agents to this process. We hypothesize that men with PCa receiving AR directed therapy may develop ARTACE, and that affected men possess identifiable pre-treatment risk factors that increase the risk of cognitive impairment in the setting of direct AR antagonist activity in the CNS. To address these, we propose the following specific aims, which are distinct from the primary endpoint of the ARACOG clinical study, randomizing men with CRPC to treatment with DARO or ENZ, and will be assessed as correlative outcomes: Aim 1: To evaluate genetic polymorphisms associated with ARTACE. Aim 1a Evaluate the association between development of ARTACE and a dementia-associated polygenic hazard score (PHS) in CRPC patients receiving treatment with AR antagonist therapy. Aim 1b To determine the relative contribution of germline AR genotype to the devel