Background: Most patients (pts) who die of prostate cancer (pca) had potentially curable localized disease when first diagnosed, but their cancer subsequently relapsed to an incurable state. Neoadjuvant intense androgen deprivation therapy (ADT) has led to exceptional pathologic responses in up to 30% of pts with intermediate or high risk localized disease, with evidence of longer term clinical benefit. Prostate cancers with loss of the tumor suppressor gene PTEN, however, are resistant to neoadjuvant therapy that only targets the Androgen Receptor. Ipatasertib has shown efficacy in metastatic castration resistant prostate cancer (mCRPC), especially in pts with tumors that lack PTEN. Methods: This is a single arm study of darolutamide 600 mg BID, ipatasertib, and ADT. The initial phase I portion includes pts with nonmetastatic or mCRPC. Pts start with a lead-in of ipatasertib for 7 days, followed by ipatasertib combined with darolutamide 600 mg BID. The dose limiting toxicity period is the first 4 weeks of combination therapy. The phase I portion will enroll 6-18 pts. The phase II portion is given neoadjuvantly and includes pts with high risk localized pca. Pts receive up to 24 weeks of darolutamide 600 mg BID and ipatasertib at the recommended phase II dose (RP2D), followed by prostatectomy 14-42 days after cycle 6. The phase II portion will enroll up to 20 pts (17 evaluable pts) with high risk pca, with an early evaluation for efficacy after 9 pts are enrolled and with an additional stopping rule for safety. Key eligibility criteria for the phase II portion include 2 or more cores of grade group 4 or higher cancer on prostate needle biopsy or grade group 3 or higher with T3 or T4 disease, no distant metastatic disease, and PTEN loss (defined as 50% or more of tumor tissue being negative for PTEN expression). Exclusion criteria for both portions include small cell carcinoma, bowel inflammation, lung disease, diabetes mellitus requiring insulin, and conditions requiring strong CYP3A inducers or inhibitors. The primary endpoint for the phase I lead-in is to identify the RP2D of ipatasertib. The primary endpoint for the phase II portion is the combined rate of pathologic complete response (defined as absence of pathologic disease on hematoxylin and eosin (H&E) stain (ypT0)), or with presence of minimal residual disease ( < 5 mm linearly). We employ a Simon MiniMax two-stage design with 90.5% power to detect the difference between the null hypothesis (5% or less response rate) and the alternative hypothesis (30% response rate) with one-sided type I error of 0.05. Key secondary endpoints are safety, 2 year biochemical recurrence free survival, and rate of PSA₀ (undetectable PSA with testosterone recovery and no additional therapy). Enrollment to the phase 1 portion began in September 2021, and the study is available at select Big Ten institutions. Clinical trial information: NCT04737109.