Ipatasertib Plus Abiraterone Plus Prednisone/Prednisolone, Relative to Placebo Plus Abiraterone Plus Prednisone/Prednisolone in Adult Male Patients With Metastatic Castrate-Resistant Prostate Cancer

Inclusion Criteria:

   - 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

   - Ability to comply with the study protocol, in the investigator's judgment

   - Willingness and ability of participants to use the electronic device to report
   selected study outcomes; 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

   - For enrollment into the China extension cohort, residence in the People's Republic of
   China

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 (testingcentral laboratory tested with results directly sent
   to IxRS) (e.g., participants 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 computed tomography (CT) and/or
   magnetic resonance imaging (MRI) (at least one target lesion) according to RECIST v1.1

   - Asymptomatic or mildly symptomatic form of prostate cancer

   - Progressive disease before initiating study treatment

   - 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

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)

   - 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)

   - Active infection requiring intravenous (IV) antibiotics within 14 days before Day 1,
   Cycle 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 Day
   1, Cycle 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 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 participants at high risk
   from treatment complications.

Disease-Specific Exclusion Criteria:

   - Pathologic findings consistent with small-cell or neuroendocrine carcinoma of the
   prostate

   - 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.

   - Use of opioid medications for cancer-related pain, including codeine and
   dextropropoxyphene, currently or any time within 4 weeks of Day 1, Cycle 1

   - 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-alpha 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 central nervous system (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

   - 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 ≥ 160 mmHg or diastolic blood
   pressure ≥ 95 mmHg)

   - 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

   - History of inflammatory bowel disease (e.g., Crohn disease and ulcerative colitis),
   active bowel inflammation (e.g., diverticulitis)