Targeted Androgen Pathway Suppression in Localized Prostate Cancer: A Pilot Study

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 cm3 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.

Impact of Therapy on Genomics and Transcriptomics in High-Risk Prostate Cancer Treated with Neoadjuvant Docetaxel and Androgen Deprivation Therapy

“…Although AR-V7 expression increased along with wild type AR gene expression, the AR-V7/AR-WT ratio remained unchanged in treated specimens. Despite no obvious changes in AR itself, the degree of AR signalling activity and the depth of AR target suppression did vary between patients and were dynamic in patient-matched specimens before and after neoadjuvant therapy, consistent with that observed in prior early phase neoadjuvant ADT trials (16,17,19). Overall these data suggest that AR signalling is relevant at early time-points and potentially driving response and resistance to therapy, yet is not likely driven through the common mechanisms associated with later AR reactivation in CRPC.…”

External Beam Radiation Therapy and Abiraterone in Men With Localized Prostate Cancer: Safety and Effect on Tissue Androgens

“…Median serum hormone levels prior to therapy and following 12 weeks of treatment with LHRHa and abiraterone are shown in Table 3. Serum hormone levels from a prior trial of LHRHa and bicalutamide (given for 12 weeks prior to prostatectomy in men with localized prostate cancer) are included for comparison [21]. In that study, the percent difference in mean serum testosterone, DHT, DHEA, and androstenedione levels in patients who received 12 weeks of LHRHa and bicalutamide compared to those who received no treatment were −92% (p<0.001), −68% (p<0.001), +16% (p not significant), and +16% (p not significant), respectively.…”

“…Compared to 12 weeks of treatment with LHRHa plus bicalutamide [21], treatment with LHRHa plus abiraterone resulted in significantly greater suppression of all downstream steroids. Our results in serum and tissue are similar in range and magnitude to those recently reported in a neoadjuvant study of LHRHa plus abiraterone for 12 or 24 weeks prior to prostatectomy [21], but our study is the first to report measurements of intraprostatic DHEA-S and tissue abiraterone.…”

Beyond T and DHT - Novel Steroid Derivatives Capable of Wild Type Androgen Receptor Activation

“…The addition of dutasteride and ketoconazole to combined androgen blockade (CAB) prior to prostatectomy lowered prostate 5α-DHT from 0.92 ng/g (in the CAB arm) to 0.03ng/g 15, while the addition of the potent CYP17A1 inhibitor abiraterone decreased prostate tissue 5α-DHT from 1.3 ng/g (in men treated with LHRH agonist therapy alone) to 0.18 ng/g and also decreased prostate levels of AED and DHEA 16.…”

“…While absolute tissue levels of 11OH-AED have not been reported, extrapolation from available data on AED suggests that serum and tissue levels of 11OH-AED are likely to be unchanged after castration. In particular, although serum and tissue levels of 5α-DHT decrease markedly following castration (to 0.18 nM in serum; 15 to 5.3 nM in tissue), serum and tissue levels of the adrenal androgens AED do not (AED: 1.2 nM in serum, 0.9 to 0.9 nM in tissue) 15, 16. These observations suggest that serum and tissue levels of adrenally-derived 11OH-AED may also be preserved following castration.…”