Neurotoxicities of Novel Non-Steroidal Anti-Androgens for Prostate Cancer: A Systematic Review and Meta-Analysis - Beyond the Abstract

Non-steroidal anti-androgens (NSAAs) have started a new era in the treatment of prostate cancer (PCa). They differ from the first-generation AAs with their more potent effect on inhibition of androgen-signaling. Up to now, four NSAAs (i.e., enzalutamide, apalutamide, darolutamide, abiraterone acetate) have been approved for the treatment of PCa. In addition to the common adverse event (AE) profile, they have dissimilar AEs because of their different chemical structures.

The effect of all NSAAs on gamma-aminobutyric acid-A (GABA-A) receptors may cause central nervous system toxicity (CNS). In this context, the seizure is one of the most well-known adverse events (AEs) of NSAAs, especially enzalutamide. Despite its rarity, patients with a history of seizure, epilepsy, and antiepileptic drug use were excluded from the clinical trials. However, no study was compared the CNS toxicities of NSAAs.

In our meta-analysis, we evaluated and compared the CNS toxicities of NSAAs, such as seizure, dizziness, fall, headache, and fatigue. Eight phase-III trials (five of them included enzalutamide, two of them included apalutamide, and one of them included darolutamide) were included in this meta-analysis.

Patients with metastatic castration-resistance PCa (mCRPC), non-metastatic CRPC, and metastatic castration-sensitive PCa (mCSPC) were evaluated. Our findings showed that seizure risk was not higher in the NSAAs arm than in the control arm. Surprisingly, fall risk was higher in the NSAAs arm than in the control arm (odds ratio [OR]:1.76; 95% confidence interval [CI]:1.25-2.49). Additionally, headache (OR:1.74; 95% CI:1.42-2.14), dizziness (OR:1.70; 95% CI:1.33-2.19), and fatigue (OR:1.66; 95% CI:1.32-2.08) were more common in the NSAAs arm than in the control arm. Indeed, our results were consistent with the UPWARD study, which evaluated the seizure risk of enzalutamide. The UPWARD study concluded that the seizure rate was not higher than the general population of patients with metastatic CRPC.2

Our study showed that focusing only on seizure risk is not reasonable because fall risk was higher in the NSAAs arm. Most patients with PCa are diagnosed in old age. Thus, they are more prone to falling because of decreased muscle mass, multiple comorbidities, and polypharmacy. On the other hand, dizziness, headache, and fatigue are the risk factors for falls and our meta-analysis showed that these risk factors were more common in patients treated with NSAAs. Taken together, increased fall risk with the use of NSAAs should be evaluated carefully in each patient. Patients should be warned against falls, and preventive measures should be discussed.

Written by: Emre Yekedüz, MD and Yüksel Ürün, MD. Ankara University Faculty of Medicine Department of Medical Oncology, Ankara, Turkey


  1. Bakouny Z, Yekedüz E, Braun DA, et al. Neurotoxicities of novel non-steroidal anti-androgens for prostate cancer: A systematic review and meta-analysis. Critical Reviews in Oncology/Hematology. 2021;166:103463. doi:10.1016/j.critrevonc.2021.103463
  2. Slovin S, Clark W, Carles J, et al. Seizure Rates in Enzalutamide-Treated Men With Metastatic Castration-Resistant Prostate Cancer and Risk of Seizure: The UPWARD Study. JAMA Oncology. 2018;4(5):702-706. doi:10.1001/jamaoncol.2017.3361

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