Background: Studies have shown that localized PCs may resist neoadjuvant androgen receptor (AR)-targeted therapies as a result of persistent intraprostatic androgens, likely arising through upregulation of steroidogenic enzymes. Therefore, we sought to evaluate clinical effects of combinatorial AR-targeted therapy, including indomethacin (Indo) to inhibit the steroidogenic enzyme AKR1C3, 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 localized high to very-high risk PC, as defined by NCCN criteria. Patients received 12 weeks of neoadjuvant apalutamide (Apa), abiraterone (Abi) plus prednisone, degarelix, and Indo at their respective FDA-approved doses followed by RP. The primary objective was to determine the pathologic complete response (pCR) rate. Secondary objectives included assessing for minimal residual disease (MRD) (i.e. ≤0.25 cm³ tumor volume corrected for cellularity), measuring intraprostatic androgens and assessing molecular features associated with drug resistance. Twenty evaluable patients provided 91% power (one-sided alpha = 7.5%) to detect a difference in pCR rate of 5% (H0) vs. 25% (H1). Results: Twenty-two patients enrolled and 20 were evaluable for the primary endpoint (1 patient came off to pursue stereotactic radiosurgery; 1 was removed after developing grade 2 transaminitis). At baseline, the median PSA was 10.1 ng/mL (4.4-159.4), 4 (20%) patients had Gleason grade group (GG) 4 disease and 16 had GG 5 disease. At RP, 1 (5%) patient had a pCR, 6 (30%) had MRD, 18 (90%) had ypT3 disease and 7 (35%) had lymph node (LN) metastases. Treatment was generally well tolerated and adverse events were consistent with each individual drug’s known safety profile. Additional follow up data and correlative work will be presented at the meeting. Conclusions: In our cohort of men with high-risk PC, pCR rates remained low even with combinatorial AR-directed therapy. Ongoing pharmacodynamic studies aimed at determining if Indo effectively inhibited AKR1C3 will provide important insights regarding the utility of targeting this steroidogenic enzyme. Clinical trial information: NCT02849990