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Updated: Nov 11, 2025
A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
Published on: March 6, 2018
Targeting backdoor androgen synthesis through AKR1C3 inhibition: A presurgical hormonal ablative neoadjuvant trial in
Laura S Graham1,2, Lawrence D True3, Roman Gulati2
1Division of Oncology, Department of Medicine, University of Washington, Seattle, Washington, USA.
Background:
Localized prostate cancers (PCs) may resist neoadjuvant androgen receptor (AR)-targeted therapies as a result of persistent intraprostatic androgens arising through upregulation of steroidogenic enzymes. Therefore, we sought to evaluate clinical effects of neoadjuvant indomethacin (Indo), which inhibits the steroidogenic enzyme AKR1C3, in addition to combinatorial anti-androgen blockade, in men with high-risk PC undergoing radical prostatectomy (RP).
Methods:
This was an open label, single-site, Phase II neoadjuvant trial in men with high to very-high-risk PC, as defined by NCCN criteria. Patients received 12 weeks of apalutamide (Apa), abiraterone acetate plus prednisone (AAP), degarelix, and Indo followed by RP. Primary objective was to determine the pathologic complete response (pCR) rate. Secondary objectives included minimal residual disease (MRD) rate, defined as residual cancer burden (RCB) ≤ 0.25cm3 (tumor volume multiplied by tumor cellularity) and elucidation of molecular features of resistance.
Results:
Twenty patients were evaluable for the primary endpoint. Baseline median prostate-specific antigen (PSA) was 10.1 ng/ml, 4 (20%) patients had Gleason grade group (GG) 4 disease and 16 had GG 5 disease. At RP, 1 (5%) patient had pCR and 6 (30%) had MRD. Therapy was well tolerated. Over a median follow-up of 23.8 months, 1 of 7 (14%) men with pathologic response and 6 of 13 (46%) men without pathologic response had a PSA relapse. There was no association between prostate hormone levels or HSD3B1 genotype with pathologic response.
Conclusions:
In men with high-risk PC, pCR rates remained low even with combinatorial AR-directed therapy, although rates of MRD were higher. Ongoing follow-up is needed to validate clinical outcomes of men who achieve MRD.
Insights
Neoadjuvant indomethacin combined with anti-androgen therapy showed low complete response rates but increased minimal residual disease in high-risk prostate cancer patients. Further follow-up is needed to confirm clinical outcomes for those achieving minimal residual disease.
Area of Science:
- Oncology
- Urology
- Pharmacology
Background:
- Localized prostate cancer (PC) can resist neoadjuvant androgen receptor (AR)-targeted therapies due to persistent intraprostatic androgens.
- Upregulation of steroidogenic enzymes contributes to androgen persistence, necessitating novel therapeutic strategies.
Purpose of the Study:
- To evaluate the clinical effects of neoadjuvant indomethacin (Indo), an AKR1C3 inhibitor, combined with anti-androgen blockade in high-risk PC patients.
- To determine the pathologic complete response (pCR) rate and minimal residual disease (MRD) rate after neoadjuvant therapy before radical prostatectomy (RP).
Main Methods:
- An open-label, single-site, Phase II neoadjuvant trial.
- Patients received 12 weeks of apalutamide (Apa), abiraterone acetate plus prednisone (AAP), degarelix, and Indo.
- Primary endpoint was pCR rate; secondary endpoints included MRD rate (RCB ≤ 0.25cm³).
Main Results:
- Twenty evaluable patients with high to very-high-risk PC (Gleason Grade Group 4 or 5) were included.
- One patient (5%) achieved pCR, while 6 patients (30%) achieved MRD.
- Therapy was well-tolerated; PSA relapse occurred in 14% with pathologic response vs. 46% without.
Conclusions:
- Combinatorial AR-directed therapy with Indo resulted in low pCR rates but higher MRD rates in high-risk PC.
- Ongoing follow-up is required to validate the clinical outcomes for patients achieving MRD.
