Format

Send to

Choose Destination
J Clin Oncol. 2014 Jan 20;32(3):229-37. doi: 10.1200/JCO.2012.48.6431. Epub 2013 Dec 9.

Targeted androgen pathway suppression in localized prostate cancer: a pilot study.

Author information

1
Elahe A. Mostaghel, Rachel Hunter Merrill, and Roman Gulati, Fred Hutchinson Cancer Research Center; Elahe A. Mostaghel, Peter S. Nelson, Paul Lange, Daniel W. Lin, William Ellis, Robert Vessella, and Bruce Montgomery, University of Washington; Brett Marck, Alvin M. Matsumoto, and Lawrence D. True, Veterans Affairs Puget Sound Health Care System, Seattle, WA; Mary Ellen Taplin and Philip Kantoff, Dana-Farber Cancer Institute, Harvard Medical School; Steven Balk, Beth Israel Deaconess Medical Center, Boston, MA; and Daniel Tamae and Trevor Penning, University of Pennsylvania, Philadelphia, PA.

Abstract

PURPOSE:

Ligand-mediated activation of the androgen receptor (AR) is critical for prostate cancer (PCa) survival and proliferation. The failure to completely ablate tissue androgens may limit suppression of PCa growth. We evaluated combinations of CYP17A and 5-α-reductase inhibitors for reducing prostate androgen levels, AR signaling, and PCa volumes.

PATIENTS AND METHODS:

Thirty-five men with intermediate/high-risk clinically localized PCa were randomly assigned to goserelin combined with dutasteride (ZD), bicalutamide and dutasteride (ZBD), or bicalutamide, dutasteride, and ketoconazole (ZBDK) for 3 months before prostatectomy. Controls included patients receiving combined androgen blockade with luteinizing hormone-releasing hormone agonist and bicalutamide. The primary outcome measure was tissue dihydrotestosterone (DHT) concentration.

RESULTS:

Prostate DHT levels were substantially lower in all experimental arms (0.02 to 0.04 ng/g v 0.92 ng/g in controls; P < .001). The ZBDK group demonstrated the greatest percentage decline in serum testosterone, androsterone, and dehydroepiandrosterone sulfate (P < .05 for all). Staining for AR and the androgen-regulated genes prostate-specific antigen and TMPRSS2 was strongly suppressed in benign glands and moderately in malignant glands (P < .05 for all). Two patients had pathologic complete response, and nine had ≤ 0.2 cm(3) of residual tumor (defined as a near-complete response), with the largest numbers of complete and near-complete responses in the ZBDK group.

CONCLUSION:

Addition of androgen synthesis inhibitors lowers prostate androgens below that achieved with standard therapy, but significant AR signaling remains. Tissue-based analysis of steroids and AR signaling is critical to informing the search for optimal local and systemic control of high-risk prostate cancer.

TRIAL REGISTRATION:

ClinicalTrials.gov NCT00298155.

PMID:
24323034
PMCID:
PMC3887479
DOI:
10.1200/JCO.2012.48.6431
[Indexed for MEDLINE]
Free PMC Article

Publication types, MeSH terms, Substances, Secondary source ID, Grant support

Publication types

MeSH terms

Substances

Secondary source ID

Grant support

Supplemental Content

Full text links

Icon for Atypon Icon for PubMed Central
Loading ...
Support Center