Brain Metabolic Correlates of the Off-Target Effects of Enzalutamide on the Central Nervous System of Patients with Advanced Prostate Cancer

The management of prostate cancer increasingly relies on androgen axis–targeted therapies, such as enzalutamide, which is now administered progressively earlier and for longer durations (1). Enzalutamide increases the risk of fatigue, falls, dizziness, headache, and mild cognitive impairment (2,3). These off-target effects seem to be associated with enzalutamide’s pharmacodynamics and ability to penetrate the blood–brain barrier. [¹⁸F]FDG PET can capture synaptic function or dysfunction in neurocognitive disorders.

We compared brain metabolism in a cohort of metastatic castration-resistant prostate cancer patients, some treated with enzalutamide and others not, all undergoing [¹⁸F]FDG PET. The institutional review board approved this retrospective study (Ethics Committee, Liguria, approval 590/2020), and the requirement to obtain informed consent was waived. Patients had preserved daily living activities and no history of neuropsychiatric diseases. Whole-brain voxelwise group analysis (SPM12 software) was used to identify relative hypometabolism compared with 48 age-matched controls (familywise error–corrected P < 0.05; nuisance variables: age, previous androgen deprivation therapy duration, previous abiraterone or taxane-based chemotherapy).

Of 68 patients, 39 had previously received enzalutamide. Aside from the duration of previous androgen deprivation therapy, the clinical characteristics of the 2 subgroups were balanced (Supplemental Table 1; supplemental materials are available at http://jnm.snmjournals.org). Enzalutamide treatment was associated with hypometabolism in the left dorsolateral-prefrontal and front-insular cortex (P < 0.005; Fig. 1), whereas enzalutamide-naïve patients did not show significant regions of hypometabolism. The topography of these findings corresponds to cortical correlates of fatigue and memory/executive dysfunction (2,3). These findings align with the only imaging study with arterial spin-labeling MRI showing reduced blood flow in the prefrontal cortex in patients receiving enzalutamide (4). Our finding linking prefrontal cortex metabolism to enzalutamide suggests further investigation of [¹⁸F]FDG PET for symptom objectification or biomarker validation.

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FIGURE 1.

Hypometabolism in patients treated with enzalutamide compared with controls. Color bar indicates z scores for significant voxels. Left in the image is left in the patient.

• © 2024 by the Society of Nuclear Medicine and Molecular Imaging.

• Received for publication January 26, 2024.
• Revision received March 15, 2024.