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

Authors: Mostaghel, Elahe A; Nelson, Peter S; Lange, Paul; Lin, Daniel W; Taplin, Mary Ellen; Balk, Steven; Ellis, William; Kantoff, Philip; Marck, Brett; Tamae, Daniel; Matsumoto, Alvin M; True, Lawrence D; Vessella, Robert; Penning, Trevor; Hunter Merrill, Rachel; Gulati, Roman; Montgomery, Bruce

Published In J Clin Oncol, (2014 Jan 20)

Abstract: 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.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.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.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.

PubMed ID: 24323034

MeSH Terms: 5-alpha Reductase Inhibitors/administration & dosage; Aged; Aged, 80 and over; Androgen Antagonists/therapeutic use*; Androgen Receptor Antagonists/therapeutic use*; Androsterone/blood; Anilides/administration & dosage; Antineoplastic Agents, Hormonal/therapeutic use*; Antineoplastic Combined Chemotherapy Protocols/therapeutic use*; Azasteroids/administration & dosage; Biomarkers, Tumor/metabolism*; Chemotherapy, Adjuvant; Dihydrotestosterone/blood; Dihydrotestosterone/metabolism; Dutasteride; Goserelin/administration & dosage; Humans; Ketoconazole/administration & dosage; Male; Middle Aged; Molecular Targeted Therapy/methods*; Neoadjuvant Therapy/methods; Neoplasm Staging; Nitriles/administration & dosage; Pilot Projects; Prostate-Specific Antigen/blood; Prostate/metabolism; Prostatic Neoplasms/blood; Prostatic Neoplasms/drug therapy*; Prostatic Neoplasms/metabolism*; Prostatic Neoplasms/pathology; Receptors, Androgen/genetics; Receptors, Androgen/metabolism; Signal Transduction/drug effects; Steroid 17-alpha-Hydroxylase/antagonists & inhibitors; Testosterone/blood; Tosyl Compounds/administration & dosage; Treatment Outcome