Background: Understanding the lethal nature of high risk prostate cancer, there is a need for the development of multimodal therapies. Prior studies have confirmed a survival benefit with the addition of docetaxel to androgen deprivation therapy (ADT) in men with metastatic hormone-sensitive prostate cancer (HSPC). We conducted a Phase II trial enrolling men with very high risk localized, locally advanced or oligometastatic prostate cancer (PC) to examine resistance and response to neoadjuvant chemohormonal therapy. This analysis aims to identify the preoperative predictors of biochemical recurrence (BCR). Methods: UW17009 is an IRB-approved open-label, single-arm trial that recruited 26 men with newly diagnosed advanced PC. Patients received ADT and docetaxel for 3 months followed by prostatectomy. The primary endpoint was pathologic complete response rate. A secondary clinical objective was the rate of PSA recurrence 12 months after surgery. The pre-trial PSAs, age, cancer grade, stage, percent tumor involvement of the initial biopsy, metastatic disease on conventional and ¹⁸F-DCFPyL PSMA (DCFPyL) PET/CT and MRI imaging, completion of chemohormonal therapy and PSA nadirs following chemohormonal therapy were assessed in relationship to biochemical recurrence. One way ANOVA was used to evaluate differences among continuous values: age, PSA at diagnosis, percent tumor involvement, and PSA nadir after chemo ADT. Fisher’s exact tests were used to evaluate the differences among categorical variables: stage at diagnosis, positive bone scan, and positive PSMA PET. Results: 26 patients were enrolled and underwent neoadjuvant treatment, radical prostatectomy (RP) and lymph node dissection. The median age was 62 (IQR 58-66), mean PSA at diagnosis was 32.8 ng/dl and 88.4% had Gleason 9 cancer. At study initiation, 12/26 patients had metastatic disease detected by DCFPyL-based PSMA PET. Final pathology demonstrated 81%(21/26) had ≥ pT3 and 73%(19/26) patients had negative margins. Positive lymph nodes were found in 10/26(38.5%) patients on final pathology. At week 6 after surgery, 91%(24/26) had undetectable PSA. At a mean follow up of 12.1 months(5.2-21.4), the biochemical recurrence rate is 58%(15/26). Features associated with BCR include stage, % tumor involvement, and positive PSMA PET scan. All patients with positive margins and 9/10 patients with positive nodes at final pathology developed BCR at a mean follow up of 12 months. Conclusions: In this neoadjuvant cohort, stage T2c, elevated PSA, positive pre-operative PSMA PET/CT, and PSA nadir > 1 following chemohormonal therapy predict biochemical recurrence. Clinically, and in the short term, neoadjuvant chemohormonal therapy prior to definitive surgery for very high risk localized and/or oligometastatic PC generates local tumor control with a high rate of negative surgical margins.