Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Targeted Oncology
Published in: Targeted Oncology 3/2023

Open Access 27-04-2023 | Magnetic Resonance Imaging | Original Research Article

Comparison of Cerebral Blood Flow in Regions Relevant to Cognition After Enzalutamide, Darolutamide, and Placebo in Healthy Volunteers: A Randomized Crossover Trial

Authors: Steven C. R. Williams, Ndaba Mazibuko, Owen O’Daly, Christian Zurth, Fiona Patrick, Christian Kappeler, Iris Kuss, Patricia E. Cole

Published in: Targeted Oncology | Issue 3/2023

Login to get access

Abstract

Background

Off-target central nervous system (CNS) effects are associated with androgen receptor (AR)-targeting treatments for prostate cancer. Darolutamide is a structurally distinct AR inhibitor with low blood–brain barrier penetration.

Objective

We compared cerebral blood flow (CBF) in grey matter and specific regions related to cognition after darolutamide, enzalutamide, or placebo administration, using arterial spin-label magnetic resonance imaging (ASL-MRI).

Methods

This phase I, randomized, placebo-controlled, three-period crossover study administered single doses of darolutamide, enzalutamide, or placebo to 23 healthy males (aged 18–45 years) at 6-week intervals. ASL-MRI mapped CBF 4 h post-treatment. Treatments were compared using paired t-tests.

Results

Drug concentrations during scans confirmed similar unbound exposure of darolutamide and enzalutamide, with complete washout between treatments. A significant localized 5.2% (p = 0.01) and 5.9% (p < 0.001) CBF reduction in the temporo-occipital cortices was observed for enzalutamide versus placebo and versus darolutamide, respectively, with no significant differences for darolutamide versus placebo. Enzalutamide reduced CBF in all prespecified regions, with significant reductions versus placebo (3.9%, p = 0.045) and versus darolutamide (4.4%, p = 0.037) in the left and right dorsolateral prefrontal cortices, respectively. Darolutamide showed minimal changes in CBF versus placebo in cognition-relevant regions.

Conclusions

Darolutamide did not significantly alter CBF, consistent with its low blood–brain barrier penetration and low risk of CNS-related adverse events. A significant reduction in CBF was observed with enzalutamide. These results may be relevant to cognitive function with early and extended use of second-generation AR inhibitors, and warrant further investigation in patients with prostate cancer.

Trial Registration Number

NCT03704519; date of registration: October 2018.
Literature
1.
Ryan C, Wefel JS, Morgans AK. A review of prostate cancer treatment impact on the CNS and cognitive function. Prostate Cancer Prostatic Dis. 2020;23:207–19.CrossRefPubMed
2.
Tae BS, Jeon BJ, Shin SH, Choi H, Bae JH, Park JY. Correlation of androgen deprivation therapy with cognitive dysfunction in patients with prostate cancer: a nationwide population-based study using the national health insurance service database. Cancer Res Treat. 2019;51:593–602.CrossRefPubMed
3.
Wefel JS, Ryan CJ, Van J, Jackson JC, Morgans AK. Assessment and management of cognitive function in patients with prostate cancer treated with second-generation androgen receptor pathway inhibitors. CNS Drugs. 2022;36:419–49.CrossRefPubMedPubMedCentral
4.
Low KL, Ma C, Soma KK. Tyramide signal amplification permits immunohistochemical analyses of androgen receptors in the rat prefrontal cortex. J Histochem Cytochem. 2017;65:295–308.CrossRefPubMedPubMedCentral
5.
Tobiansky DJ, Wallin-Miller KG, Floresco SB, Wood RI, Soma KK. Androgen regulation of the mesocorticolimbic system and executive function. Front Endocrinol (Lausanne). 2018;9:279.CrossRefPubMed
6.
Wu LM, Diefenbach MA, Gordon WA, Cantor JB, Cherrier MM. Cognitive problems in patients on androgen deprivation therapy: a qualitative pilot study. Urol Oncol. 2013;31:1533–8.CrossRefPubMed
7.
8.
Moilanen AM, Riikonen R, Oksala R, et al. Discovery of odm-201, a new-generation androgen receptor inhibitor targeting resistance mechanisms to androgen signaling-directed prostate cancer therapies. Sci Rep. 2015;5: 12007.CrossRefPubMedPubMedCentral
9.
Shore ND, Bono P, Massard C, Snapir A, Sarapohja T, Fizazi K. Odm-201 and the CNS: a clinical perspective [abstract]. J Clin Oncol. 2014;32(4 Suppl):275.CrossRef
10.
Merriman JD, Von Ah D, Miaskowski C, Aouizerat BE. Proposed mechanisms for cancer- and treatment-related cognitive changes. Semin Oncol Nurs. 2013;29:260–9.CrossRefPubMed
11.
12.
Sanchez Iznaola M, Parra R, Angela G, Casariego J, MuÑoz Del Toro J, Robinson P. Neuropsychiatric adverse events of enzalutamide and abiraterone acetate plus prednisone treatment: contrasting a meta-analysis of randomized clinical trials with real world reporting patterns from eudra [abstract 831p]. Ann Oncol. 2017;28(Suppl 5):289.CrossRef
13.
Smith MR, Saad F, Chowdhury S, et al. Apalutamide treatment and metastasis-free survival in prostate cancer. N Engl J Med. 2018;378:1408–18.CrossRefPubMed
14.
Sandmann S, Trummel D, Seidel D, Nubbemeyer R, Gieschen H, Zurth C. Higher blood–brain barrier penetration of [14C]apalutamide and [14C]enzalutamide compared to [14C]darolutamide in rats using whole-body autoradiography [poster]. Presented at the Annual Genitourinary Cancers Symposium, 14–16 February 2019, San Francisco.
15.
Zurth C, Sandmann S, Trummel D, Seidel D, Gieschen H. Blood–brain barrier penetration of [14C]darolutamide compared with [14C]enzalutamide in rats using whole body autoradiography [abstract]. J Clin Oncol. 2018;36(6 Suppl):345.CrossRef
16.
Zurth C, Sandman S, Trummel D, Seidel D, Nubbemeyer R, Gieschen H. Higher blood–brain barrier penetration of [14C]apalutamide and [14C]enzalutamide compared to [14C]darolutamide in rats using whole-body autoradiography [abstract]. J Clin Oncol. 2019;37(7 Suppl):156.CrossRef
17.
Fizazi K, Shore N, Tammela TL, et al. Darolutamide in nonmetastatic, castration-resistant prostate cancer. N Engl J Med. 2019;380:1235–46.CrossRefPubMed
18.
Fizazi K, Shore N, Tammela TL, et al. Nonmetastatic, castration-resistant prostate cancer and survival with darolutamide. N Engl J Med. 2020;383:1040–9.CrossRefPubMed
19.
Li Z, Vidorreta M, Katchmar N, Alsop DC, Wolf DH, Detre JA. Effects of resting state condition on reliability, trait specificity, and network connectivity of brain function measured with arterial spin labeled perfusion MRI. Neuroimage. 2018;173:165–75.CrossRefPubMed
20.
Handley R, Zelaya FO, Reinders AA, et al. Acute effects of single-dose aripiprazole and haloperidol on resting cerebral blood flow (RCBF) in the human brain. Hum Brain Mapp. 2013;34:272–82.CrossRefPubMed
21.
Marquand AF, O’Daly OG, De Simoni S, et al. Dissociable effects of methylphenidate, atomoxetine and placebo on regional cerebral blood flow in healthy volunteers at rest: a multi-class pattern recognition approach. Neuroimage. 2012;60:1015–24.CrossRefPubMed
22.
Hawkins PCT, Wood TC, Vernon AC, et al. An investigation of regional cerebral blood flow and tissue structure changes after acute administration of antipsychotics in healthy male volunteers. Hum Brain Mapp. 2018;39:319–31.CrossRefPubMed
23.
Xie L, Dolui S, Das SR, et al. A brain stress test: cerebral perfusion during memory encoding in mild cognitive impairment. Neuroimage Clin. 2016;11:388–97.CrossRefPubMedPubMedCentral
24.
Mato Abad V, García-Polo P, O’Daly O, Hernández-Tamames JA, Zelaya F. Asap (automatic software for asl processing): a toolbox for processing arterial spin labeling images. Magn Reson Imaging. 2016;34:334–44.CrossRefPubMed
25.
26.
27.
Alsop DC, Detre JA, Golay X, et al. Recommended implementation of arterial spin-labeled perfusion MRI for clinical applications: a consensus of the ISMRM perfusion study group and the European Consortium for ASL in Dementia. Magn Reson Med. 2015;73:102–16.CrossRefPubMed
28.
Murphy K, Harris AD, Diukova A, et al. Pulsed arterial spin labeling perfusion imaging at 3 T: estimating the number of subjects required in common designs of clinical trials. Magn Reson Imaging. 2011;29:1382–9.CrossRefPubMed
29.
Brett M, Anton J-L, Valabregue R, Poline J-B. Region of interest analysis using an spm toolbox [abstract 497]. Presented at the International Conferance on Functional Mapping of the Human Brain, 2–6 June 2002, Sendai.
30.
Nubeqa [package insert]. Whippany: Bayer HealthCare Pharmaceuticals; 2021.
31.
32.
33.
Bigler ED, Mortensen S, Neeley ES, et al. Superior temporal gyrus, language function, and autism. Dev Neuropsychol. 2007;31:217–38.CrossRefPubMed
34.
Krall SC, Rottschy C, Oberwelland E, et al. The role of the right temporoparietal junction in attention and social interaction as revealed by ale meta-analysis. Brain Struct Funct. 2015;220:587–604.CrossRefPubMed
35.
36.
Plata-Bello J, Plata-Bello A, Pérez-Martín Y, et al. Changes in resting-state measures of prostate cancer patients exposed to androgen deprivation therapy. Sci Rep. 2021;11: 23350.CrossRefPubMedPubMedCentral
37.
Stuss DT. Functions of the frontal lobes: relation to executive functions. J Int Neuropsychol Soc. 2011;17:759–65.CrossRefPubMed
38.
Fassbender C, Murphy K, Foxe JJ, et al. A topography of executive functions and their interactions revealed by functional magnetic resonance imaging. Brain Res Cogn Brain Res. 2004;20:132–43.CrossRefPubMed
39.
Koechlin E, Ody C, Kouneiher F. The architecture of cognitive control in the human prefrontal cortex. Science. 2003;302:1181–5.CrossRefPubMed
40.
Bench CJ, Friston KJ, Brown RG, Scott LC, Frackowiak RS, Dolan RJ. The anatomy of melancholia—focal abnormalities of cerebral blood flow in major depression. Psychol Med. 1992;22:607–15.CrossRefPubMed
41.
Khalaf DJ, Sunderland K, Eigl BJ, et al. Health-related quality of life for abiraterone plus prednisone versus enzalutamide in patients with metastatic castration-resistant prostate cancer: results from a phase II randomized trial. Eur Urol. 2019;75:940–7.CrossRefPubMed
42.
Farrall AJ, Wardlaw JM. Blood-brain barrier: ageing and microvascular disease—systematic review and meta-analysis. Neurobiol Aging. 2009;30:337–52.CrossRefPubMed
Metadata
Title
Comparison of Cerebral Blood Flow in Regions Relevant to Cognition After Enzalutamide, Darolutamide, and Placebo in Healthy Volunteers: A Randomized Crossover Trial
Authors
Steven C. R. Williams
Ndaba Mazibuko
Owen O’Daly
Christian Zurth
Fiona Patrick
Christian Kappeler
Iris Kuss
Patricia E. Cole
Publication date
27-04-2023
Publisher
Springer International Publishing
Published in
Targeted Oncology / Issue 3/2023
Print ISSN: 1776-2596
Electronic ISSN: 1776-260X
DOI
https://doi.org/10.1007/s11523-023-00959-5

Other articles of this Issue 3/2023

Targeted Oncology 3/2023 Go to the issue

Commentary

P-REALITY X: A Real-World Analysis of Palbociclib Plus an Aromatase Inhibitor in HR+/HER2− Metastatic Breast Cancer—A Podcast

Review Article

Place in Therapy of Cyclin-Dependent Kinase 4/6 Inhibitors in Breast Cancer: A Targeted Literature Review

Adis Drug Evaluation

Trastuzumab Deruxtecan: A Review in Unresectable or Metastatic HER2-Positive Breast Cancer

Original Research Article

Uncovering the Burden of Immune-Related Adverse Events in Immunotherapy: Insights from a Nationally Representative Sample

Original Research Article

A Phase II Trial of Trifluridine/Tipiracil in Combination with Cetuximab Rechallenge in Patients with RAS Wild-Type mCRC Refractory to Prior Anti-EGFR Antibodies: WJOG8916G Trial

Original Research Article

Genomic Landscape of Primary Resistance to Osimertinib Among Hispanic Patients with EGFR-Mutant Non-Small Cell Lung Cancer (NSCLC): Results of an Observational Longitudinal Cohort Study
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits