• Phase 1b - Incidence of adverse events defined by dose-limiting toxicities [ Time Frame: 21 days after the 6th subjects has recieved 1st cycle of AMG 102 in combination with MP ] [ Designated as safety issue: Yes ]
• Phase 2 - Overall survival [ Time Frame: Entire Study ] [ Designated as safety issue: Yes ]

• Phase 1b - Incidence of adverse events, abnormal laboratory values not defined as dose limiting toxicities [ Time Frame: Treatment Period ] [ Designated as safety issue: Yes ]
• Phase 1b - Incidence of anti-AMG 102 antibody formation [ Time Frame: Entire Study ] [ Designated as safety issue: Yes ]
• Phase 1b - Cmax and Cmin of AMG 102 concentration [ Time Frame: Treatment Period ] [ Designated as safety issue: Yes ]
• Phase 2 - Progression-free survival [ Time Frame: Entire Study ] [ Designated as safety issue: No ]
• Phase 2 - Maximum percentage reduction in PSA level [ Time Frame: Entire Study ] [ Designated as safety issue: No ]
• Phase 2 - Percentage change in PSA levels from baseline to 12 weeks (or earlier for those who discontinue therapy) [ Time Frame: Treatment Period ] [ Designated as safety issue: No ]
• Phase 2 - PSA response rate (≥50% reduction in PSA values from baseline) [ Time Frame: Entire Study ] [ Designated as safety issue: No ]
• Phase 2 - Objective response rate (CR and PR per RECIST with modifications) [ Time Frame: Entire Study ] [ Designated as safety issue: No ]
• Phase 2 - Patient Report Outcome including pain-specific measures [ Time Frame: Treatment Period ] [ Designated as safety issue: No ]
• Phase 2 - Incidence of adverse events and significant laboratory value changes from baseline [ Time Frame: Treatment Period ] [ Designated as safety issue: Yes ]
• Phase 2 - Incidence of anti-AMG 102 antibody formation [ Time Frame: Entire Study ] [ Designated as safety issue: Yes ]
• Phase 2 - Cmax and Cmin of AMG 102; Cmax and AUC for Mitoxantrone [ Time Frame: Treatment Period ] [ Designated as safety issue: Yes ]

The primary objectives of this study are the following:

Phase 1b: To identify a safe dose level of AMG 102, up to 15 mg/kg Q3W, to combine with mitoxantrone and prednisone (MP) Phase 2: To estimate with adequate precision the effect of the addition of AMG 102 to MP, compared with placebo plus MP, as assessed by the hazard ratio (HR) for overall survival (OS) of previously treated subjects with castrate-resistant prostate cancer (CRPC)

• Cancer
• Castrate-Resistant Prostate Cancer
• Mestastatic Prostate Cancer
• Prostate Cancer

• Other: Phase 1b is an open-label study with AMG 102 at 15mg/kg de-escalating to 7.5mg/kg and 5mg/kg if needed, will be administered by IV Q3W in combination with MP.
• Experimental: AMG 102 safe dose level in phase 1b in combination with MP, will be administered by IV Q3W.
• Placebo Comparator: Placebo in combination with MP, will be administered by IV Q3W.

Inclusion Criteria:

• Pathologically confirmed adenocarcinoma of the prostate
• Radiographic evidence of metastatic disease

• Progressive disease meeting at least one of the following criteria:

  1. a sequence of at least 2 rising PSA values measured at a minimum of 1 week apart with a 2 ng/mL minimum starting value, or
  2. progression according to RECIST criteria for measurable lesions, or
  3. appearance of 2 or more new lesions on bone scan.
• History of prior taxane-based chemotherapy for metastatic prostate cancer
• For patients without a history of surgical castration, continued GnRH analog administration is required
• ECOG Performance status of 0 or 1
• Life expectancy ≥ 3 months

Exclusion Criteria:

• Treatment with external beam radiotherapy ≤ 14 days before enrollment or radiopharmaceutical ≤8 weeks
• ≤ 4 weeks since receipt of most recent prior chemotherapy, non-GnRH analog hormonal therapy (except for continuing corticosteroids) or other systemic therapy to treat prostate cancer and <6 weeks since receipt of prior bevacizumab.
• Known CNS metastases (epidural disease is allowed if it has been treated and there is no progression in the treated area).
• Significant cardiovascular disease
• LVEF < 50% by MUGA or ECHO
• Treatment of infection with systemic anti-infectives within 7 days before enrollment (with the exception of uncomplicated urinary tract infection)
• Concurrent or prior (within 7 days of enrollment) anticoagulation therapy, except that use of low dose coumarin-type anticoagulants or heparins for prophylaxis against central venous catheter thrombosis is allowed
• Major surgical procedure ≤30 days before enrollment or not yet recovered from prior major surgery
• Presence of peripheral edema > Grade 2
• Known positive test for HIV, hepatitis C, chronic or active hepatitis B
• Serious or non-healing wound
• Unable to begin protocol specified treatment within 7 days after enrollment
• Other investigational procedures are excluded.