Study of GDC-0068 Or GDC-0980 With Abiraterone Acetate Versus Abiraterone Acetate in Patients With Castration-Resistant Prostate Cancer Previously Treated With Docetaxel Chemotherapy

• Incidence of dose-limiting toxicity (DLTs) for Phase Ib [ Time Frame: up to 28 days ] [ Designated as safety issue: No ]
• Nature of dose-limiting toxicity (DLTs) for Phase Ib [ Time Frame: up to 28 days ] [ Designated as safety issue: No ]
• Progression-free survival in all patients and in patients with PTEN loss in Phase II [ Time Frame: up to approximately 9 months ] [ Designated as safety issue: No ]
• Incidence of adverse events (AEs), graded according to the NCI CTCAE v4.0 [ Time Frame: up to approximately 9 months ] [ Designated as safety issue: No ]
• Nature of adverse events (AEs), graded according to the NCI CTCAE v4.0 [ Time Frame: up to approximately 9 months ] [ Designated as safety issue: No ]
• Severity of adverse events (AEs), graded according to the NCI CTCAE v4.0 [ Time Frame: up to approximately 9 months ] [ Designated as safety issue: No ]
• Radiographic progression-free survival for Phase II [ Time Frame: up to approximately 9 months ] [ Designated as safety issue: No ]

• Pharmacokinetics: total exposure (AUC) from Time 0 to the last measurable concentration (AUC0-last) [ Time Frame: Days 1 and 15 of Cycle 1, and on Day 1 of subsequent cycles ] [ Designated as safety issue: No ]
• Overall survival for Phase II [ Time Frame: up to approximately 24 months ] [ Designated as safety issue: No ]
• PSA response, defined as a > 50% decrease in PSA from baseline, which is confirmed after >/= 4 weeks by a confirmatory PSA measurement for Phase II [ Time Frame: up to approximately 9 months ] [ Designated as safety issue: No ]
• Confirmed objective tumor response in patients with measurable soft tissue disease at baseline, as assessed by the investigator per modified RECIST v1.1 for Phase II [ Time Frame: up to approximately 9 months ] [ Designated as safety issue: No ]
• Duration of objective response in Phase II, defined as the time from first observation of an objective confirmed tumor response until first observation of disease progression, as assessed by the investigator per modified RECIST v1.1 for Phase II [ Time Frame: up to approximately 9 months ] [ Designated as safety issue: No ]
• Decrease in number of circulating tumor cells for Phase II [ Time Frame: from baseline to up to approximately 9 months ] [ Designated as safety issue: No ]
• Change in pain symptom score as measured by the modified Brief Pain Inventory-Short Form for Phase II [ Time Frame: from baseline to up to approximately 9 months ] [ Designated as safety issue: No ]

• Pharmacokinetics: total exposure (AUC) from Time 0 to the last measurable concentration (AUC0 last) [ Time Frame: Days 1 and 15 of Cycle 1, and on Day 1 of subsequent cycles ] [ Designated as safety issue: No ]
• Overall survival defined as the time from randomization until death from any cause [ Time Frame: up to approximately 24 months ] [ Designated as safety issue: No ]
• PSA response, defined as a > 50% decrease in PSA from baseline, which is confirmed after >/= 4 weeks by a confirmatory PSA measurement [ Time Frame: up to approximately 9 months ] [ Designated as safety issue: No ]
• Confirmed objective tumor response in patients with measurable soft tissue disease at baseline,\nas assessed by the investigator per modified RECIST v1.1 [ Time Frame: up to approximately 9 months ] [ Designated as safety issue: No ]
• Duration of objective response in Phase II, defined as the time from first observation of an objective confirmed tumor response until first observation of disease progression, as assessed by the investigator per modified RECIST v1.1 [ Time Frame: up to approximately 9 months ] [ Designated as safety issue: No ]

This multicenter, international, Phase Ib/II trial consists of two stages: a Phase Ib, open-label stage in which the recommended Phase II dose will be determined for GDC-0068 and GDC-0980 in combination with abiraterone and prednisone/prednisolone and a Phase II, 3-arm, double-blind, randomized comparison of GDC-0068 with abiraterone and prednisone/prednisolone versus placebo with abiraterone and prednisone/prednisolone.

• Drug: GDC-0068
  Repeating oral dose
• Drug: GDC-0980
  Repeating oral dose
• Drug: placebo
  Repeating oral dose
• Drug: abiraterone
  Repeating oral dose
• Drug: prednisone
  Repeating oral dose
• Drug: GDC-0068
  400 mg once daily
• Drug: GDC-0068
  200 mg once daily

• Experimental: Phase I: Arm A
  Interventions:

  • Drug: GDC-0068
  • Drug: abiraterone
  • Drug: prednisone
• Experimental: Phase I: Arm B
  Interventions:

  • Drug: GDC-0980
  • Drug: abiraterone
  • Drug: prednisone
• Placebo Comparator: Phase I: Arm C
  Interventions:

  • Drug: placebo
  • Drug: abiraterone
  • Drug: prednisone
• Experimental: Phase II: Arm A
  Interventions:

  • Drug: abiraterone
  • Drug: prednisone
  • Drug: GDC-0068
• Experimental: Phase II: Arm B
  Interventions:

  • Drug: abiraterone
  • Drug: prednisone
  • Drug: GDC-0068
• Placebo Comparator: Phase II: Arm C
  Interventions:

  • Drug: placebo
  • Drug: abiraterone
  • Drug: prednisone

Inclusion Criteria:

• Histologically confirmed metastatic or advanced prostate adenocarcinoma that has been previously treated with docetaxel and has progressed during treatment of at least one hormonal therapy
• Two rising PSA levels >/= 2 ng/mL measured >/= 1 week apart or radiographic evidence of disease progression in soft tissue or bone
• ECOG performance status of 0, 1, or 2
• Adequate hematologic and organ function
• Documented willingness to use an effective means of contraception

Exclusion Criteria:

• History of Type I or Type II diabetes mellitus requiring insulin
• NYHA Class III or IV heart failure or LVEF < 50% or ventricular arrhythmia requiring medication
• Significant atherosclerotic disease, as evidenced by: unstable angina, history of myocardial infarction within 6 months prior to Day 1, or cerebrovascular accident within 6 months prior to Day 1 - Active autoimmune disease that is not controlled by nonsteroidal anti inflammatory drugs or active inflammatory disease which requires immunosuppressive therapy
• Clinically significant history of liver disease
• History of adrenal insufficiency or hyperaldosteronism
• Phase II only: Previous therapy for prostate cancer with CYP17 inhibitors, including abiraterone
• Phase II only: Previous treatment for prostate cancer with Akt, PI3K, and/or mTOR inhibitors
• Need for chronic corticosteroid therapy of >/= 20 mg of prednisone per day or an equivalent dose of other anti inflammatory corticosteroids or immunosuppressant