General Inclusion Criteria:

• Signed Informed Consent Form(s).
• Age ≥ 18 years old.
• Eastern Collaborative Oncology Group (ECOG) performance status of 0 or 1 at screening.
• Adequate hematologic and organ function within 28 days before the first study.
• treatment, defined using the following (hematologic parameters must be assessed ≥ 14 days after a prior transfusion, if any):
  • Neutrophils: ANC ≥ 1500 cells/L (1.5 x 109/L);
  • Hemoglobin ≥ 10 g/dL;
  • Platelet count ≥ 100,000 cells/L;
  • Total bilirubin ≤ 1.5 x the upper limit of normal (ULN) with the following exception:
    • Patients with known Gilbert disease who have serum bilirubin ≤ 3 x ULN may be enrolled;
    • AST and ALT ≤ 1.5 x ULN, with the exception that patients with liver metastasis may have AST and/or ALT ≤ 2.5 x ULN, and total bilirubin ≤ 1.5 x ULN;
  • Serum creatinine < 1.5 x ULN and creatinine clearance ≥ 50 mL/min based on Cockroft-Gault glomerular filtration rate estimation:
    • (140 - age in years) x (weight in kg);
       72 x (serum creatinine in mg/dL);
  • Serum albumin ≥ 3.5 g/dL;
  • Serum potassium ≥ 3.5 mmol/L;
  • Fasting glucose ≤ 150 mg/dL (8.3 mmol/L) and hemoglobin A1c ≤ 7.5% (58 mmol/mol).
• Ability to comply with the study protocol, in the investigator’s judgment.
• Willingness and ability of patients to use the electronic device to report selected study outcomes (e.g., symptom severity). Caregivers and site staff can assist with patient diary input but patient must be able to independently comprehend and answer the questionnaires.
• Life expectancy of at least 6 months.
• Agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm, as defined below:
  • With female partners of childbearing potential or pregnant female partners, men must remain abstinent or use a condom along with another effective contraceptive method during the treatment period and for at least 28 days after the last dose of study treatment to avoid exposing the embryo. Men must refrain from donating sperm during this same period.
  • The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post-ovulation methods) and withdrawal are not acceptable methods of contraception.

Disease-Specific Inclusion Criteria:

• Histologically confirmed prostate adenocarcinoma without neuroendocrine differentiation or small-cell features.
• Consent to provide a formalin-fixed paraffin-embedded (FFPE) tissue block (preferred) or a minimum of 15 (20 preferred) freshly cut unstained tumor slides from the most recently collected, available tumor tissue accompanied by an associated pathology report (with tumor content information, Gleason score, and disease staging) for PTEN IHC and NGS testing and for other protocol-mandated secondary and exploratory assessments. If only 12-14 slides are available, the patient may still be eligible for the study, after discussion with and approval by the Medical Monitor. Cytologic or fine-needle aspiration samples are not acceptable. Tumor tissue from bone metastases is not acceptable.
• A valid PTEN IHC result (central laboratory tested with results directly sent to IxRS), patients with an “invalid” or “failed” PTEN IHC result are not permitted to enroll.
• Metastatic disease documented prior to randomization by clear evidence of bone lesions on bone scan and/or measurable soft tissue disease by CT and/or MRI (at least one target lesion) according to RECIST v1.1
  • Patients whose spread of disease is limited only to regional pelvic lymph nodes are not eligible.
• Asymptomatic or mildly symptomatic form of prostate cancer:
  • A score of 0 or 1 on the pain at its worst (24-hour recall) 10-point NRS will be considered asymptomatic, and a score of 2 or 3 will be considered mildly symptomatic.
  • Progressive disease before initiating study treatment, defined using at least one of the following criteria:
  • Two rising PSA levels measured ≥ 1 week apart, with second result ≥ 1 ng/mL according to PCWG3 criteria:
    • Patients who have received an anti-androgen therapy must have PSA progression after withdrawal (≥ 4 weeks since last flutamide or ≥  6 weeks since last treatment of bicalutamide or nilutamide).
    • Radiographic evidence of disease progression in soft tissue according to RECIST v1.1 and/or bone scan according to PCWG3 criteria.
• Ongoing androgen deprivation with gonadotropin-releasing hormone (GnRH) analog or bilateral orchiectomy, with serum testosterone ≤ 50 ng/dL (≤ 1.7 nmol/L) within 28 days before randomization.
• Patients on GnRH analog must have therapy initiated at least 4 weeks before Cycle 1, Day 1, and treatment must be continued throughout the study.

General Exclusion Criteria:

• Inability or unwillingness to swallow whole pills.
• History of malabsorption syndrome or other condition that would interfere with enteral absorption.
• Clinically significant history of liver disease consistent with Child-Pugh Class B or C, including cirrhosis, current alcohol abuse, or current known active infection with hepatitis B virus (HBV) or hepatitis C virus (HCV).
• Active infection is defined as requiring treatment with antiviral therapy or presence of positive test results for hepatitis B (hepatitis B surface antigen [HBsAg] and/or total hepatitis B core antibody [anti-HBc]) or HCV antibody.
• Unless required by local regulations, patients are not required to have HIV, HBV, or HCV assessments at screening if these assessments have not been previously performed.
• Patients who are positive for anti-HBc are eligible only if test results are also negative for HBsAg and polymerase chain reaction is negative for HBV DNA.
• Patients who are positive for HCV serology are eligible only if testing for HCV RNA is negative.
• Need of more than 10 mg/day of prednisone or an equivalent dose of other anti-inflammatory corticosteroids as a current systemic corticosteroid therapy to treat a chronic disease (e.g., rheumatic disorder)
• Concurrent use of inhaled corticosteroids is allowed.
• Active infection requiring IV antibiotics within 14 days before Cycle 1, Day 1.
• Immunocompromised status because of current known active infection with HIV or because of the use of immunosuppressive therapies for other conditions.
• Major surgical procedure or significant traumatic injury within 28 days prior to Cycle 1, Day 1, or anticipation of the need for major surgery during study treatment.
• History of ventricular dysrhythmias or risk factors for ventricular dysrhythmias, such as structural heart disease (e.g., severe left ventricular systolic dysfunction, left ventricular hypertrophy), untreated coronary heart disease (symptomatic or with ischemia demonstrated by diagnostic testing), myocardial infarction or atrial thrombotic events within the past 6 months, severe or unstable angina, New York Heart Association Class III and IV heart disease or depressed left ventricular ejection fraction (LVEF; previously documented LVEF< 50% without documentation of recovery), clinically significant electrolyte abnormalities (e.g., hypokalemia, hypomagnesemia, hypocalcemia), or family history of sudden unexplained death or long QT syndrome.
• History of another malignancy within 5 years prior to randomization, except for either adequately treated non-melanomatous carcinoma of the skin, adequately treated melanoma in situ, adequately treated non-muscle-invasive urothelial carcinoma of the bladder (Tis, Ta, and low grade T1 tumors), or other malignancies where the patient has undergone potentially curative therapy with no evidence of disease and are deemed by the treating physician to have a recurrence rate of < 5% at 5 years.
• Any other diseases, cardiovascular, pulmonary, or metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or renders the patients at high risk from treatment complications.

Disease-Specific Exclusion Criteria:

• Pathologic findings consistent with small-cell or neuroendocrine carcinoma of the prostate.
• Use of opioid medication for cancer-related pain, including codeine and dextropropoxyphene, currently or any time within 4 weeks of Cycle 1, Day 1.
• Any therapy including chemotherapy (e.g., docetaxel) or biological therapy (e.g., vaccine, immunotherapy) for the treatment of castration-resistant prostate cancer. Previous treatment with flutamide, steroidal anti-androgens, androgens, estrogens, bicalutamide, nilutamide, or 5-α reductase inhibitor is permitted.
• In the setting of hormone-sensitive prostate cancer, chemotherapy (e.g., docetaxel) is permitted provided that it is initiated within 6 months from the time of first castration (i.e., concurrent initiation of chemotherapy and ADT for HSPC). Patient should not have progressed during or within 3 months after the completion of chemotherapy-based treatment (i.e., rapid progression on chemotherapy for HSPC).
• Prior treatment with abiraterone or other known potent CYP17 inhibitors (e.g., ketoconazole, orteronel) or investigational agents that block androgen synthesis. Previous treatment with itraconazole and fluconazole is permitted.
• Prior treatment with enzalutamide or other potent androgen-receptor blockers, approved or experimental (e.g., ARN-509, ODM-201, or galeterone).
• Prior treatment with flutamide (Eulexin®), steroidal anti-androgens (e.g., cyproterone acetate, chlormadinone acetate), androgens, or estrogens treatment within 4 weeks of Cycle 1, Day 1.
• Prior treatment with bicalutamide (Casodex®) or nilutamide (Nilandron®) within 6 weeks of Cycle 1, Day 1.
• Prior treatment with 5-α reductase inhibitors within 4 weeks of Cycle 1, Day 1.
• Prior treatment with systemic radiopharmaceuticals (e.g., radium-223 and strontium-89). Radiopharmaceuticals for the purpose of imaging are permitted.
• Focal palliative radiation to treat cancer-related pain is permitted provided that the last treatment with radiation is at least 14 days prior to Cycle 1, Day 1.
• Prior treatment with approved or experimental therapeutic agents with known inhibition of the PI3K pathway, including PI3K inhibitors, AKT inhibitors, and mTOR inhibitors.
• Administration of an investigational therapeutic agent within 28 days of Cycle 1, Day 1.
• Known untreated or active CNS metastases (progressing or requiring anticonvulsant medications or corticosteroids for symptomatic control); a CT or MRI scan of the brain will be performed at screening if required by the local health authority:
  • Patients with a history of treated CNS metastases are eligible, provided they meet all of the following criteria:
    • Evaluable or measurable disease according to the inclusion criteria outside the CNS is present.
    • Radiographic demonstration of improvement upon the completion of CNS-directed therapy and no evidence of interim progression between the completion of CNS-directed therapy and the screening radiographic study.
    • No history of intracranial hemorrhage or spinal cord hemorrhage.
• Minimum of 2 weeks between completion of radiotherapy and Cycle 1, Day 1, and recovery from significant (Grade ≥ 3) acute toxicity, with no ongoing requirement for ≥ 10 mg/day of prednisone or an equivalent dose of another corticosteroid.
• Any chronic therapy or use of food supplements that are strong CYP3A4/5 inducers or inhibitors or sensitive substrates of CYP3A or CYP2D6 with a narrow therapeutic window

Abiraterone-Specific Exclusion Criteria:

• Uncontrolled hypertension (systolic blood pressure ≥ 60 mmHg or diastolic blood pressure ≥ 95 mmHg).
• Patients with a history of hypertension are eligible provided blood pressure is controlled by anti-hypertensive treatment prior to or within the 28 days of screening period.
• History of pituitary or adrenal dysfunction.
• Any ongoing cardiac arrhythmias (including atrial fibrillation) that require medical therapy.

Ipatasertib-Specific Exclusion Criteria:

• Type 1 or Type 2 diabetes mellitus requiring insulin at study entry:
  • Patients who are on a stable dose of oral diabetes medication ≥ 4 weeks prior to initiation of study treatment may be eligible for enrollment. Patients must meet the laboratory eligibility criteria for fasting blood glucose and hemoglobin A1c as outlined in Section 4.1.1.
• History of inflammatory bowel disease (e.g., Crohn disease and ulcerative colitis), active bowel inflammation (e.g., diverticulitis).