Cognitive outcomes in prostate cancer treatment: insights from the ODENZA trial and future considerations

Hormone therapy is an important component of treatment for advanced prostate cancer (1-3). Second-generation androgen receptor (AR) antagonists have been developed that have increased affinity and potency compared to prior therapies (3,4). Second-generation AR antagonists, such as enzalutamide, apalutamide, darolutamide, improve survival in patients with prostate cancer, and obtained Food and Drug Administration (FDA) approval in 2012, 2018, and 2019, respectively (1,5-8). Despite better survival outcomes, second-generation AR antagonists may have unintended effects that impact function and quality of life (9-11). Among the most common side effects of these agents are cognitive dysfunction, fatigue, and falls (10). The recently published ODENZA trial provides valuable comparative data regarding common side effects and quality of life between two commonly used second-generation AR antagonists (12).

Cognitive effects of AR inhibition

Testosterone is believed to play an important role in adult cognition due to various mechanisms including support of neuronal survival and neurogenesis, synaptic plasticity, regulation of neurotransmitter function, reduced oxidative stress, and improved mitochondrial function (13,14). ARs are found throughout the brain, with the highest concentration within the hippocampus, amygdala, and prefrontal cortex, supporting the role of androgen signaling in cognitive function (14,15). Second-generation AR antagonists inhibit the physiologic effects of androgens thereby limiting the growth and progression of prostate cancer (4). However, there may be unintended action with inhibition of AR function leading to side effects (10). While there remains debate (16), AR inhibition (and androgen deprivation) has been associated with cognitive dysfunction in numerous studies (10,17-19).

Note that while AR antagonists inhibit the effect of androgens, another commonly used therapy in prostate cancer—androgen deprivation therapy (ADT) including gonadotropin-releasing hormone (GnRH) agonists and antagonists—also has been associated with cognitive dysfunction in patients with prostate cancer (20). These therapies work by depletion of circulating testosterone through decreasing levels of luteinizing hormone and follicle-stimulating hormone. Lower testosterone can have deleterious effects on cognition through limiting normal androgen effect on the brain, but is also complicated by other common side effects of ADT therapy including fatigue, mood changes, and metabolic/cardiovascular dysfunction (21). See Nead et al. (20) for a systematic review and meta-analysis on the risk for dementia in patients with a history ADT use.

ODENZA trial: key findings

The ODENZA trial is a randomized (1:1), phase 2, crossover trial designed to assess patient preference between darolutamide and enzalutamide in men with metastatic castrate resistant prostate cancer (12). Specifically, patients were randomly assigned to either darolutamide (half-life approximately 20 hours) during the first period followed by enzalutamide (half-life approximately 6 days) during the second period, or vice versa. Each period was 3 months without intervening washout. The primary endpoint was to determine patient preference between these two second-generation AR antagonists. Key secondary outcomes included measures of quality of life, including fatigue, and cognition. A total of 249 patients were randomized and 200 patients were included in the final analysis. The most common reason participants were excluded from the primary analysis was secondary to intervening disease progression, which was a pre-specified exclusion criterion.

Regarding the primary endpoint of patient preference at week 12, there was no significant difference observed between darolutamide and enzalutamide with 49% (n=97), 40% (n=80), and 12% (n=23) choosing darolutamide, enzalutamide, or no preference, respectively. Interestingly, both treatment arms numerically favored the medication they were randomized to in period 1, suggesting that the cumulative toxicity of both treatment periods, or recall bias, may have impacted the results. Of note are also the differences in half-life between darolutamide and enzalutamide, which may impact the study findings.

Analysis of factors influencing patient preference indicated that fatigue was a primary driver of participant decision making. Based on the Brief Fatigue Inventory (0, no fatigue; 10, extreme fatigue) fatigue was low in both groups, but numerically greater with enzalutamide (mean score 3.3) compared to darolutamide (mean score 2.7). The authors also reported a moderate benefit in episodic memory favoring darolutamide in verbal learning (P<0.001) and verbal memory (P<0.01). Other cognitive measures, including tasks of attention and executive function, were not different between darolutamide and enzalutamide. Notably, cognitive function was not cited as a primary driver of patient preference. There were no reported differences in magnitude of depressive symptoms (12).

Context and clinical implications

The cognitive function results of the ODENZA trial have implications for both the clinical management of prostate cancer and future study design (12). When there is clinical need for hormone therapy in prostate cancer, physicians have multiple therapeutic options (1,3). Three FDA approved second-generation AR inhibitors all provide survival benefit, however, they have varying side effect profiles for consideration by both clinician and patient (4,10,11). The ODENZA trial data highlights that darolutamide may confer fewer cognitive side effects and less fatigue. However, these results should be interpreted with caution, as the trials primary aim was to determine therapeutic preference and there was no statistically significant difference in patient preference between groups. Importantly, this result may simply be due to insufficient power to show smaller than anticipated differences in preference between groups, complicating the interpretation of the study results.

The finding that darolutamide has less adverse impact on learning and memory function than enzalutamide is supported by several factors. Darolutamide is distinct from enzalutamide in that it has minimal blood brain barrier penetration, which may reduce the risk for central nervous system (CNS) side effects via AR inhibition within regions important for cognition, including the hippocampus (22). Previous studies have shown that enzalutamide also increases the risk for other CNS side effects, including seizures and headaches, which are rarely reported in patients receiving darolutamide (23). The ODENZA trial supports results from the ARAMIS trial, which showed that darolutamide is safe and effective in non-metastatic castration-resistant prostate cancer, with minimal CNS-related toxicity when combined with ADT (5,12). While the ODENZA trial offers important insight comparing adverse effect profiles of two second-generation AR antagonists (12), there are limitations including small sample size, crossover design, lack of washout between treatments, limited follow-up (6 months for last cognitive evaluation), and cognitive function as a secondary end point.

Gaps and future directions

While the relationship between hormone therapy and cognitive impairment has been reported in patients with prostate cancer, most of this evidence comes from secondary analyses of clinical trials and/or observational studies with limited longitudinal follow-up or control for relevant comorbidities (9-11,18-20,24). Additionally, with the advent of newer classes of agents with increased potency, continued active investigation is needed. Ultimately, we have a relatively limited understanding of cognitive impairment from hormone therapy or the unique patient specific factors that may impact individual risk, including genetic. Additionally, there are no established pharmacologic interventions to improve cognitive impairment in patients with cancer being treated with hormone therapy, although engagement in physical and cognitive activity can provide a supportive role (25). Future research should focus on the longitudinal assessment of subjective cognitive concerns and objective cognitive function in patients with prostate cancer to assess clinically relevant changes, as the ODENZA trial ultimately sought to achieve through examination of patient preference. Moreover, paring longitudinal cognitive assessment with patient reported outcome and experience measures (PROMs and PREMs) is important given the discordance between objective and subjective cognitive performance and impact on function and quality of life. The ODENZA trial has shown that it is feasible to perform longitudinal cognitive assessment leveraging digital cognitive tests to obtain objective measures of cognitive function. Ultimately, the results of the ODENZA trial, and prior studies, support continued investigation regarding the cognitive effects of hormone therapy in prostate cancer and the advancement of mitigation strategies. Lastly, it will be important to follow the results of several ongoing clinical studies assessing cognitive dysfunction in patients with prostate cancer (NCT04335682, NCT05820932).

Acknowledgments

This work has been supported by the generous philanthropic contributions to The University of Texas MD Anderson Cancer Center Cancer Neuroscience Program.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Andrology and Urology. The article has undergone external peer review.

Peer Review File: Available at https://tau.amegroups.com/article/view/10.21037/tau-2024-747/prf

Funding: This work was supported by the Cancer Prevention and Research Institute of Texas (CPRIT) (No. RR190077 to K.T.N.).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-2024-747/coif). J.S.W. reports grants from Bayer, GT Medical Technologies, and Novocure; consulting fees from Intra-Cellular Therapies; and participation on a Data Safety Monitoring Board or Advisory Board for Bayer. K.T.N. is a CPRIT Scholar in Cancer Research. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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