Prostate cancer is the second leading cause of
cancer death in the United States. Treatment of localized high-risk disease and de novo metastatic disease frequently leads to relapse. These metastatic
castration resistant
prostate cancers (mCRPC) claim a high mortality rate, despite the extended survival afforded by the growing armamentarium of
androgen deprivation, radiation and
immunotherapies. Here, we review two studies of
neoadjuvant treatment of high-risk localized
prostate cancer prior to
prostatectomy, the total
androgen pathway suppression (TAPS) trial and the neoadjuvant
abiraterone acetate (AA) trial. These two trials assessed the efficacy of the non-specific P450c17 inhibitor,
ketoconazole and the specific P450c17 inhibitor, AA, to inhibit tissue and serum
androgen levels. Furthermore, a novel and validated stable
isotope dilution liquid chromatography electrospray ionization selected reaction monitoring mass spectrometry assay was used to accurately quantify adrenal and gonadal
androgens in circulation during the course of these trials. The adrenal
androgens, Δ(4)-androstene-3,17-dione,
dehydroepiandrosterone and
dehydroepiandrosterone sulfate were significantly reduced in the patients receiving
ketoconazole or AA compared to those who did not. However, in both trials, a significant amount of
DHEA-S (∼20 μg/dL) persists and thus may serve as a depot for intratumoral conversion to the potent
androgen receptor ligands,
testosterone (T) and 5α-dihydrotestosterone (DHT). The final step in conversion of Δ(4)-androstene-3,17-dione and 5α-androstanedione to T and DHT, respectively, is catalyzed by AKR1C3. We therefore present the case that in the context of the
DHEA-S depot, P450c17 and AKR1C3 inhibition may be an effective combinatorial treatment strategy.