Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Clinical Trial
. 2025 Sep;28(3):802-808.
doi: 10.1038/s41391-024-00870-8. Epub 2024 Jul 17.

Body composition as a determinant of the therapeutic index with androgen signaling inhibition

Andrew W Hahn  1 , Rebecca S Tidwell  2 , Patrick G Pilie  3 , Yao Yu  4 , Jingjing Liu  5 , Devaki Shilpa Surasi  6 , Mark Titus  3 , Jianhua Zhang  5 , Neha Venkatesh  7 , Theocharis Panaretakis  3 , Justin R Gregg  8 , Amado J Zurita  3 , Bilal A Siddiqui  3 , Paul G Corn  3 , Sumit K Subudhi  3 , Pavlos Msaouel  3   9   10 , Efstratios Koutroumpakis  11 , Chad D Huff  4 , Ana Aparicio  3 , Jennifer L McQuade  12 , Daniel E Frigo  3   13 , Christopher J Logothetis  3   10
Affiliations
Clinical Trial

Body composition as a determinant of the therapeutic index with androgen signaling inhibition

Andrew W Hahn et al. Prostate Cancer Prostatic Dis. 2025 Sep.

Abstract

Background: Androgen signaling is central to prostate cancer and men's health. Prior data indicates that increasing body fat is unfavorable in the localized setting yet associated with favorable outcomes in men with metastatic disease. Understanding the biological links between adiposity and prostate cancer may optimize the therapeutic index with ASI. We hypothesized that host adiposity and androgen synthesis are linked to the efficacy and toxicity of ASI for men with metastatic castration-resistant prostate cancer (mCRPC).

Methods: A post-hoc analysis was done of NCT02703623 where men with mCRPC (n = 186) were treated for 8 weeks with abiraterone acetate, prednisone, and apalutamide (AAPA), and a satisfactory response was defined as a PSA decline >50%. Body composition was measured on baseline CT scans. Germline DNA WES was performed with a focus on variants in steroidogenic genes. Adipokine levels were measured in pre-treatment plasma.

Results: Germline polymorphisms in 3 genes involved in androgen synthesis (AKR1C3 rs12529, CYP17A1 rs6162, SRD5A2 rs523349) were associated with differences in body composition at baseline on ADT alone (prior to receipt of AAPA). Elevated subcutaneous adipose tissue index (SATi, p = 0.02), visceral adipose tissue index (VATi, p = 0.03), and BMI (p = 0.04) were associated with satisfactory response to AAPA. Leptin had positive correlation with VATi (r = 0.47) and SATi (r = 0.48).

Conclusion: Inherited polymorphisms in androgen synthesis correlated with differences in body composition after exposure to ADT and warrant further investigation as candidate markers for body composition toxicity. Elevated subcutaneous and visceral adiposity were associated with improved response to ASI.

PubMed Disclaimer

Conflict of interest statement

Competing interests: AWH reports advisory board consulting for Johnson & Johnson Innovative Medicine, Intellisphere, Exelixis, and Eisai; honoraria from Medscape and Binaytara Foundation; travel support from DAVA Oncology, and institutional research funding from Bayer and Eisai. PGP has received honoraria for service on scientific advisory board for Janssen and AstraZeneca. JRG is a consultant and advisory board member for Bayer. BAS reports advisory board consulting to Merck, travel support from Merck, and institutional research funding from Regeneron. PM has received honoraria for service on a Scientific Advisory Board for Mirati Therapeutics, Bristol Myers Squibb, and Exelixis; consulting for Axiom Healthcare Strategies; non-branded educational programs supported by DAVA Oncology, Exelixis and Pfizer; and research funding for clinical trials from Takeda, Bristol Myers Squibb, Mirati Therapeutics, Gateway for Cancer Research, and the University of Texas MD Anderson Cancer Center. JLM reports honorari from Merck, Bristol-Myers Squibb, and Novartis. CJL reports honoraria from Bayer, Amgen, Novartis, Boehringer Ingelheim, Merck Sharp & Dohme, and Exelixis; and institutional research funding from Janssen, ORIC Pharmaceuticals, Novartis, and Aragon Pharmaceuticals. DEF has received research funding from GTx, Inc, and has a familial relationship with Biocity Biopharmaceuticals, Hummingbird Bioscience, Bellicum Pharmaceuticals, Maia Biotechnology, Alms Therapeutics, Hinova Pharmaceuticals, and Barricade Therapeutics. Ethics approval and consent to participate: This research involving human subjects, human material, and human data is in accordance with the Declaration of Helsinki. Informed consent was obtained from subjects. The research reported here was approved by The University of Texas MDACC Institutional Review Board (PA16-0736 2014-0386, LAB02-152).

References

    1. Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin. 2010;60:277–300. - PubMed
    1. Siegel RL, Miller KD, Wagle NS, Jemal A. Cancer statistics, 2023. CA Cancer J Clin. 2023;73:17–48. - PubMed
    1. Helgstrand JT, Røder MA, Klemann N, Toft BG, Lichtensztajn DY, Brooks JD, et al. Trends in incidence and 5-year mortality in men with newly diagnosed, metastatic prostate cancer—A population-based analysis of 2 national cohorts. Cancer. 2018;124:2931–8. - PubMed - DOI
    1. Hussain M, Tangen CM, Berry DL, Higano CS, Crawford ED, Liu G, et al. Intermittent versus continuous androgen deprivation in prostate cancer. N. Engl J Med. 2013;368:1314–25. - PubMed - PMC - DOI
    1. Fizazi K, Tran N, Fein L, Matsubara N, Rodriguez-Antolin A, Alekseev BY, et al. Abiraterone acetate plus prednisone in patients with newly diagnosed high-risk metastatic castration-sensitive prostate cancer (LATITUDE): final overall survival analysis of a randomised, double-blind, phase 3 trial. Lancet Oncol. 2019;20:686–700. - PubMed - DOI

Publication types

MeSH terms

LinkOut - more resources