Related Experiment Video
Updated: May 5, 2026
A New Technique for Treating Low-risk Prostate Cancer—Super Active Surveillance
Published on: November 7, 2025
Targeted androgen pathway suppression in localized prostate cancer: a pilot study
Elahe A Mostaghel1, Peter S Nelson, Paul Lange
1Elahe 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.
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.
Insights
Combining androgen synthesis inhibitors with standard therapy significantly reduces prostate androgens and AR signaling in prostate cancer (PCa) patients. Further research is needed for optimal PCa control.
Area of Science:
- Oncology
- Endocrinology
- Urology
Background:
- Androgen receptor (AR) signaling is crucial for prostate cancer (PCa) progression.
- Incomplete ablation of androgens limits the effectiveness of current PCa therapies.
- Novel therapeutic strategies are needed to enhance AR signaling suppression.
Purpose of the Study:
- To evaluate the efficacy of combined CYP17A and 5-α-reductase inhibitors in reducing prostate androgen levels.
- To assess the impact of these combinations on AR signaling and PCa volumes.
- To compare different combination therapies for their effects on androgen suppression.
Main Methods:
- Thirty-five men with intermediate/high-risk localized PCa received goserelin plus dutasteride (ZD), bicalutamide plus dutasteride (ZBD), or bicalutamide, dutasteride, and ketoconazole (ZBDK) for 3 months pre-prostatectomy.
- Control patients received standard combined androgen blockade.
- Primary outcome was tissue dihydrotestosterone (DHT) concentration.
Main Results:
- All experimental arms achieved significantly lower prostate DHT levels compared to controls (P < .001).
- The ZBDK group showed the most significant reduction in serum testosterone and other androgens (P < .05).
- AR signaling and androgen-regulated genes were suppressed in both benign and malignant glands (P < .05), with notable complete or near-complete responses in the ZBDK group.
Conclusions:
- Androgen synthesis inhibitors effectively lower prostate androgen levels beyond standard therapy.
- Despite significant reduction, substantial AR signaling persists, indicating a need for further optimization.
- Tissue-level analysis of steroids and AR signaling is essential for developing improved high-risk PCa treatments.
