Neoadjuvant Androgen Deprivation, Darolutamide, and Ipatasertib in Men With Localized, High Risk Prostate Cancer

Eligibility Criteria Approximately 26-38 patients with prostate cancer will be enrolled in this study. This includes 6-18 patients in the Phase I de-escalation cohort with metastatic or nonmetastatic castration resistant prostate cancer, and 20 patients in the Phase II neoadjuvant cohort with high risk localized or locally advanced prostate cancer that has PI3K pathway activation. * For the Phase I de-escalation cohort, the patient must have castration resistant prostate cancer (metastatic or non-metastatic), as defined by PCWG3. * For the Phase II neoadjuvant cohort, the patient must be a candidate for radical prostatectomy at the time of enrollment and be planning to undergo this procedure. The patient must have a histologically-confirmed diagnosis of localized, untreated prostate cancer with high risk features and must have sufficient archival tissue (at least 2 cores) available for targeted sequencing and immunohistochemistry (IHC). The tumor must have PI3K pathway activation. This can be determined by IHC, in which case at least 50% of the tumor tissue evaluated must be negative for PTEN expression by immunohistochemistry on local review. Alternatively, qualifying alteration in PTEN, PIK3CA, or AKT1 on next generation sequencing (NGS) is also acceptable to be eligible, regardless of PTEN expression. If the patient qualifies based on NGS results, IHC must still be performed. * Qualifying mutations include changes in AKT1 at residues E17, L52, or Q79; in PIK3CA at residues R88, G106, K111, G118, N345, E542, E545, Q546, M1043, H1047, or G1049; in PTEN a R130Q/C/H substitution or a deletion, frameshift, or introduction of early stop codon. The assay must be a CLIA-certified assay, and a copy of the report must be provided. Phase I Inclusion Criteria: * Histologically confirmed prostate cancer * Male and \>= 18 years of age * ECOG performance status of \<= 2 * Castration resistant prostate cancer, defined as biochemical, radiographic, and/or clinical progression despite castrate level of testosterone (\<50 ng/dL). There is no restriction on prior therapies for CRPC. * Evaluable disease, with PSA \>= 1.0 ng/ml (nmCRPC) or visible prostate cancer on imaging (mCRPC). * Serum testosterone \< 50 ng/dL * Willing to undergo blood draws to measure PK levels * Able to swallow pills * Must have ability to understand and the willingness to sign a written informed consent prior to receiving a subject ID number. * Unless surgically sterile, sexually active patients must agree to use effective barrier method and refrain from sperm donation during the study treatment and for 3 months after the end of study treatment. * As determined by the enrolling physician or protocol designee, ability of the subject to understand and comply with study procedures for the entire length of the study * Demonstrate adequate organ function as defined in the protocol; all screening labs to be obtained within 14 days prior to registration. * Hematological --Hemoglobin (Hgb): \>/= 9 g/dL * Absolute Neutrophil Count (ANC): \>/= 1,500/uL * Platelet count: \>/= 100,000/uL * Renal --Creatinine: \</= 2 x upper limit of normal (ULN) * Hepatic --Bilirubin: \</= 1.5 ULN or Gilbert's syndrome with normal direct bilirubin * Aspartate aminotransferase (AST) \</= 2.5 x ULN * Alanine aminotransferase (ALT): \</= 2.5 x ULN * Blood sugar * HbA1C: \</= 7.5% * Fasting glucose\</= 150 mg/dL Phase I Exclusion Criteria: * Patients receiving systemic therapy for prostate cancer \<= 21 days or 5 half-lives (whichever is shorter) prior to starting study drug are not eligible. --NOTE: Patients must continue Androgen Deprivation Therapy, and patients can receive bone supportive therapy. * Histology of small cell carcinoma prostate cancer. Adenocarcinoma with neuroendocrine features is allowed. * Any active infection requiring IV antibiotics * Known additional malignancy that has a life-expectancy \< 2 years. * Clinically significant acute infection requiring systemic antibacterial, antifungal, or antiviral therapy including: * hepatitis B (known positive HBV surface antigen (HBsAg) result), * hepatitis C, or * human immunodeficiency virus (positive HIV 1/2 antibodies). ---NOTES: Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody \[anti-HBc\] and absence of HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA. Subjects with HIV/AIDS with adequate antiviral therapy to control viral load would be allowed if they are stable and have been on treatment for \>= 4 weeks prior to first dose of study drug(s). Subjects with viral hepatitis with controlled viral load would be allowed while on suppressive antiviral therapy. * History of type I or type II diabetes mellitus requiring insulin. * Any of the following within 6 months before registration: stroke, myocardial infarction, severe/unstable anginal pectoris, coronary/peripheral artery bypass graft, congestive heart failure New York Heart Association (NYHA) class III or IV. * Congenital long QT syndrome or QTcF \> 480 milliseconds * Grade \>= 2 uncontrolled or untreated hypercholesterolemia (\>300 mg/dL) or hypertriglyceridemia (\>300 mg/dL) * History of or active inflammatory bowel disease (IBD) or active bowel inflammation (diverticulitis) * Lung disease: pneumonitis, interstitial lung disease, idiopathic pulmonary fibrosis, cystic fibrosis, Aspergillosis, active tuberculosis, or history of opportunistic infections (pneumocystis pneumonia or cytomegalovirus pneumonia) * Treatment with strong CYP3A inhibitors or strong CYP3A inducers within 2 weeks or 5 drug-elimination half-lives, whichever is longer, prior to initiation of study drug * History of allergic reaction to darolutamide or ipatasertib. * Any condition that in the opinion of the investigator would impair the patients' ability to comply with study procedures. Phase II Inclusion Criteria: -Histologically-confirmed diagnosis of localized, untreated prostate cancer with high-risk features. High-risk features is defined as: * Two or more cores from prostate biopsy that are grade group 4 (Gleason score 4+4=8) or higher, OR * Stage T3-4 (by clinical exam or MRI), M0, and at least 2 cores from prostate biopsy that are grade group 3 (Gleason score 4+3=7) or higher. NOTE: Pathology confirmation of malignancy must be performed by the participating site (i.e. reports should be issued by the participating site; if a subject's pathology report was not issued by the participating site, archival tissue should be requested by the participating site for internal pathology review.) * Sufficient archival tissue (at least 2 cores) available for targeted sequencing and immunohistochemistry to evaluate for PTEN loss using the Ventana SP218 immunohistochemistry assay at the local institution. Next generation sequencing is also acceptable to be eligible regardless of IHC result, but there must also be sufficient tissue to evaluate for PTEN by IHC. --The tumor evaluated for PTEN expression should be selected based on containing both high grade and high volume of tumor content. The slide evaluated for PTEN expression should be saved for confirmatory central review. Eligibility is based on local review. * Measurable PSA * Must have evidence of PI3K pathway activation. This can be by demonstrating PTEN loss per local institution evaluation, defined as 50% or more of tumor tissue being negative for PTEN expression on Ventana SP218 immunohistochemistry assay. Alternatively, qualifying alteration in PTEN, PIK3CA, or AKT1 on next generation sequencing is also acceptable to be eligible, regardless of PTEN expression. --Qualifying mutations include changes in AKT1 at residues E17, L52, or Q79; in PIK3CA at residues R88, G106, K111, G118, N345, E542, E545, Q546, M1043, H1047, or G1049; or in PTEN a R130Q/C/H substitution, or a deletion, frameshift, or introduction of early stop codon. The assay must be a CLIA-certified assay, and a copy of the report must be provided. * Disease must be untreated and subject must be eligible for (per PI discretion) and planning to undergo radical prostatectomy. * Male and ≥18 years of age. * ECOG performance status of ≤ 1 within 14 days prior to signing consent. * CT or MRI of abdomen and pelvis and bone scan within ≤90 days prior to starting study drug. * Able to swallow pills * Must have ability to understand and the willingness to sign a written informed consent prior to starting study drug. * Sexually active patients, unless surgically sterile, must agree to use effective barrier method and refrain from sperm donation during the study treatment and for 3 months after the end of study treatment. * As determined by the enrolling physician or protocol designee, ability of the subject to understand and comply with study procedures for the entire length of the study * Demonstrate adequate organ function as defined in the protocol; all screening labs to be obtained within 14 days prior to registration. Phase II Exclusion Criteria: * Histology of small cell carcinoma prostate cancer. Adenocarcinoma with neuroendocrine features is allowed. * Active infection requiring IV antibiotics * Distant metastatic disease beyond N1 (regional) lymph nodes on conventional baseline imaging studies within 90 days prior to signing consent. * Known additional malignancy that has a life-expectancy \< 5 years. * Clinically significant acute infection requiring systemic antibacterial, antifungal, or antiviral therapy including: * tuberculosis (clinical evaluation that includes clinical history, physical examination, and radiographic findings, and TB testing in line with local practice), * hepatitis B (known positive HBV surface antigen (HBsAg) result), * hepatitis C, or * human immunodeficiency virus (positive HIV 1/2 antibodies). NOTES: Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody \[anti-HBc\] and absence of HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA. Subjects with HIV/AIDS with adequate antiviral therapy to control viral load would be allowed if they are stable and have been on treatment for ≥ 4 weeks prior to first dose of study drug(s). Subjects with viral hepatitis with controlled viral load would be allowed while on suppressive antiviral therapy. Testing not required. * Prior treatment of prostate cancer with: second generation androgen receptor (AR) inhibitors, other investigational AR inhibitors or CYP17 enzyme inhibitor, radiation therapy, surgery, or chemotherapy. First generation antiandrogen (e.g. bicalutamide) for 28 days or fewer is allowed. * Receipt of an investigational agent within \<= 28 days prior to registration; or herbal medications and marijuana products within \<= 1 day prior to registration. * Receipt of medications (e.g. finasteride, dutasteride) or agents that are likely to alter serum PSA levels within \<= 42 days or 5 half-lives prior to registration, whichever is shorter. * History of type I or type II diabetes mellitus requiring insulin. * Any of the following within 6 months before registration: stroke, myocardial infarction, severe/unstable anginal pectoris, coronary/peripheral artery bypass graft, congestive heart failure New York Heart Association (NYHA) class III or IV. * Congenital long QT syndrome or QTcF \> 480 milliseconds * Grade \>= 2 uncontrolled or untreated hypercholesterolemia (\>300 mg/dL) or hypertriglyceridemia (\>300 mg/dL) * History of or active IBD or active bowel inflammation (diverticulitis) * Lung disease: pneumonitis, interstitial lung disease, idiopathic pulmonary fibrosis, cystic fibrosis, Aspergillosis, active tuberculosis, or history of opportunistic infections (pneumocystis pneumonia or cytomegalovirus pneumonia) * Treatment with strong CYP3A inhibitors or strong CYP3A inducers within 2 weeks or 5 drug-elimination half-lives, whichever is longer, prior to initiation of study drug * History of allergic reaction to darolutamide or ipatasertib. * Any condition that in the opinion of the investigator would impair the patients' ability to comply with study procedures.