Study cancelled: Withdrawn before enrollment of any participants

This study is being conducted to characterize the safety and recommended phase 2 dose (RP2D) of combining afuresertib, independently with 2 approved drugs: enzalutamide (Xtandi®, "Xtandi is a trademark of Astellas Pharma, Inc." ) and abiraterone (Zygita®, "Zytiga is a trademark of Janssen Biotech, Inc."). The study will be conducted in two parts. Part 1, a dose escalation phase, will establish RP2D of afuresertib when administered with enzalutamide or abiraterone. Part 2, a dose expansion phase, will further evaluate long-term safety of the combinations at the RP2Ds in additional subjects. Dose-finding cohorts will be studied in parallel and will evaluate safety and pharmacokinetic to guide selection of the dose regimens for further evaluation. Part 2 will begin once the RP2Ds have been established in Part 1. Additional doses and/or schedules may be explored if warranted, based upon the pharmacokinetic (PK) and pharmacodynamic (PD) assessments or emerging preclinical evidence. Overall, approximately 60 chemotherapy-naïve subjects with mCRPC and who are receiving either enzalutamide or abiraterone will be enrolled into the study.

Inclusion Criteria:

• Signed written informed consent provided
• Males >=18 years of age (at the time consent is obtained)
• Histologically or cytologically confirmed diagnosis of metastatic prostate adenocarcinoma, without neuroendocrine or small cell features
• Surgically or medically castrated, with testosterone levels of <=50 nanogram (ng)/deciliter (dL) (<=1.73 nanomolar [nM]). If the subject is being treated with luteinizing hormone releasing hormone analogs (subjects who have not undergone orchiectomy), this therapy must have been initiated at least 4 weeks prior to Cycle 1 Day 1 and must be continued throughout the study.
• Rising Prostate-specific antigen (PSA) after initial response to enzalutamide or abiraterone without radiographic or symptomatic evidence of progression (per Prostate Cancer Working Group 2 criteria): Most recent enzalutamide dose received is 160 milligram (mg) once daily with no change in dose for at least 4 weeks prior to Cycle 1, Day 1. Most recent abiraterone dose received is 1000 mg once daily with prednisone 5 mg twice daily (BID), with no change in dose for at least 2 weeks prior to Cycle 1, Day 1.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Able to swallow and retain orally administered medication.
• Adequate baseline organ function defined as: Absolute neutrophils count>=1.5 x 10^9/Liter (L), hemoglobin>=9 grams (g)/dL, Platelets>=75 x 10^9/L, Prothrombin time/International normalized ratio<=1.3 x Upper limit of normal (ULN), Partial thromboplastin time<=1.3 x ULN, Albumin>=2.5 g/dL, Total bilirubin<=1.5 ULN, Aspartate aminotranseferase and Alanine aminotransferase <=2.5 x ULN, Serum creatinine<=ULN OR Estimated glomerular filtration rate>=30 millilite per Minute (mL/min), Fasting Serum Glucose <126 mg/dL, Hemoglobin A1C<=8%. Note: Subjects with ALT or bilirubin values outside the ranges noted in the table above due to Gilbert's syndrome or asymptomatic gallstones are not excluded.
• Male subject with a female partner of childbearing potential must either have a prior vasectomy or agree to use effective contraception from time of first dose of study treatment until 3 months after last dose of study treatment.

Exclusion Criteria:

• Prior treatment with cytotoxic chemotherapy or inhibitors of the Phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/ mechanistic target of rapamycin (mTOR) pathway.
• Any investigational drug(s) within 30 days or 5 half-lives of enrollment, whichever is longer.
• Prior malignancy other than Castrate-resistant prostate cancer (CRPC). Exception: Subjects who have been disease-free of the prior malignancy for 3 years, or subjects with a history of completely resected non-melanoma skin cancer or successfully treated in situ carcinoma are eligible.
• Any unresolved >=Grade 2 (per Common Toxicity Criteria for Adverse Events 4.0) toxicity from previous anti-cancer therapy at the time of enrollment, except alopecia or Grade 2 anemia (if hemoglobin is >9.0 gram (g)/dL).
• Presence of any clinically significant gastrointestinal (GI) abnormality or other condition(s) that may alter absorption such as malabsorption syndrome or major resection of the stomach or substantial portion of the small intestine. NOTE: If clarification is needed as to whether a GI abnormality, condition or resection will significantly affect the absorption of study treatment, contact the Sponsor's Medical Monitor.
• Major surgery, radiation therapy, or immunotherapy within 28 days prior to enrollment.
• Known active infection requiring intravenous (IV) or oral anti-infective treatment.
• Evidence of severe or uncontrolled systemic diseases (e.g., unstable or uncompensated respiratory, hepatic, renal or cardiac disease).
• For those subjects who will receive afuresertib plus enzalutamide: History of seizures, underlying brain injury with loss of consciousness, transient ischemic attack in the past 12 months, cerebral vascular accident, brain metastases, brain arteriovenous malformation, or use of concomitant medications that may lower the subjects' seizure threshold.
• History or evidence of cardiovascular risk including any of the following:

Clinically significant ECG abnormalities including second degree (Type II) or third degree atrioventricular block.

History of myocardial infarction, acute coronary syndromes (including unstable angina), coronary angioplasty, stenting, or bypass grafting within the past 6 months prior to enrollment.

Class III or IV heart failure as defined by the New York Heart Association functional classification system Left ventricular ejection fraction (LVEF) below 50% Known cardiac metastases Corrected QT interval of >470 millisecond (msec) (or >480 msec with bundle branch block)

• Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to afuresertib, enzalutamide, abiraterone, or excipients.
• Any serious and/or unstable pre-existing medical, psychiatric disorder or other conditions that could interfere with subject's safety, obtaining informed consent or compliance to the study procedures.
• Have a known Human Immunodeficiency Virus (HIV) infection.
• Subjects who are Hepatitis B surface antigen (HbSAg) positive.
• Subjects with a positive test for Hepatitis C virus (HCV) antibody, regardless of viral load. (Note: the subject is eligible if a confirmatory recombinant immunoblot assay [RIBA] test is negative).