Neoadjuvant Androgen Pathway Suppression Prior To Prostatectomy.
Background: Optimizing tissue androgen suppression may provide better local and systemic control of prostate cancer (PCa). Standard androgen deprivation therapy (ADT) has limited effect on tissue androgens which remain in a range which supports tumor survival. We determined whether targeting androgen metabolism using CYP17 and 5a-reductase (SRD5A) inhibitors would more effectively suppress tissue androgens and tumor volume. Methods: Open label, multicenter neoadjuvant study in men with localized PCa treated for 3 months prior to prostatectomy with zoladex and 1) avodart 3.5 mg QD; 2) avodart and casodex 50 mg QD; or 3) casodex, avodart and ketoconazole 200 mg TID. Serum and tissue androgens were measured by LC/MS/MS. Data were compared to men treated with standard ADT (LHRH agonist plus Casodex), and untreated prostatectomy tissue. The primary outcome measure was suppression of tissue dihydrotestosterone (DHT). Results: 35 men with intermediate/high risk PCa were enrolled. Tissue DHT was suppressed 30 fold (> 95%) in all groups vs. LHRH agonist/Casodex (0.92 ± 0.20 pg/mg vs. 0.03± 0.03 for all groups combined, p<0.0001). Tissue testosterone was 3-4 fold higher (consistent with SRD5A inhibition) in all treatment groups vs. LHRH agonist/Casodex (0.33 vs. 0.07 pg/mg, p < 0.05). Differences in DHT/T between groups 1 through 3 were not statistically significant. There was no correlation between tissue and serum androgens, or tissue androgen and tumor volume (p> 0.05). In subset analysis, total serum DHEA declined significantly in group 3, with free DHEA unchanged, suggesting differential effect on free and total DHEA. Pathologic complete response (CR) was seen in 2 men, and an additional 8 men had <0.2 cc of tumor, with the largest number of CR or near CR in the cohort treated with ADT, CYP17 and SRD5A inhibitor, 4 of 12 men (33%). Due to small cohort size, differences were not statistically significant. Conclusions: Addition of high dose SRD5A inhibition (with and without CYP17 inhibition) achieves prostate DHT levels 30 fold below standard ADT. In this relatively high risk population, CR or near CR was seen in 10 of 35 men receiving protocol therapy. Further suppressing the androgen receptor signaling axis may provide better local and systemic control of PCa.