Study of AMG 509 in Participants With Metastatic Castration-Resistant Prostate Cancer

• Drug: AMG 509
• Drug: Abiraterone
• Drug: Enzalutamide

Inclusion Criteria:

• Parts 1, 2, and 5: Participants with histologically or cytologically confirmed metastatic castration-resistant prostatea walnut-shaped gland in the male reproductive system that is responsible for producing semen - a bodily fluid that acts as a vessel for sperm transport during ejaculation cancera disease where abnormal cells split without control and spread to other nearby body tissue and/or organs (mCRPC) who are refractory to a novel antiandrogen therapy (abiraterone acetate and/or enzalutamide, apalutamide, or darolutamide) and have failed at least 1 (but not more than 2) taxane regimens including for metastatic hormone-sensitive prostate cancer (mHSPC) (or who are deemed medically unsuitable to be treated with a taxane regimen or have actively refused treatment with a taxane regimen). Note: A taxane regimen is defined as a minimum exposure of 2 cycles of a taxane. Any NHT that has been administered and has been stopped for reasons other than progression will not be counted as an additional line of treatment.
  1. Dose exploration phase: Novel antiandrogen therapy must have been given for treatment of metastatic disease.
  2. Dose expansion phase: participants must not have had more than 2 NHTs and 2 taxane regimens in any setting, and an additional up to 2 other systemic anti-cancer treatments are allowed (eg, anti-PD1, PARP inhibitors, radioligand therapies, sipuleucel-T, experimental agents) Note: Combinations are considered one systemic anti-cancer treatment.
• Part 3: Participants with histologically or cytologically confirmed mCRPC who have received no or 1-2 prior NHTs (abiraterone acetate, enzalutamide, apalutamide, or darolutamide) given in any disease setting and who are deemed medically unsuitable to be treated with a taxane regimen or have actively refused treatment with a taxane regimen (unless taxane treatment was administered in HSPC setting). 0 1 prior PARP inhibitors or sipuleucel T treatments are acceptable. Subjects who received prior investigational therapy for the treatment of metastatic disease are not eligible.
• Parts 4A and 4B:
  1. Participants with histologically or cytologically confirmed mCRPC who have received no or 1-2 prior NHTs (given in any disease setting depending on the part), and no or 1 taxane regimen (for HSPC).
  2. Dose-expansion phase: at least 1 prior NHT must have been given; 0-1 prior PARP inhibitors are acceptable.
  3. 4A: Participants planning to receive abiraterone acetate for the first time (participants who received prior abiraterone acetate are not eligible). Participants may have had exposure to up to 2 NHTs with a similar mechanism of action (apalutamide, enzalutamide or darolutamide) in the non-mCRPC and mCRPC setting.
• Dose expansion phase: up to approximately 10 subjects with prior exposure to abiraterone acetate may be enrolled into Part 4A expansion cohort.d. 4B: Participants planning to receive enzalutamide for the first time (participants who received prior enzalutamide/apalutamide or daralutamide are not eligible).
• All parts:
• Participants must have undergone bilateralaffecting both sides orchiectomyremoval of one or both testicles, also known as orchidectomy or be on continuous androgen-deprivation therapy with a gonadotropin releasing hormonea chemical substance produced by glands in the endocrine system that regulates various functions in the body (GnRH) agonist or antagonist.
• Total serum testosterone <= 50 ng/dL or 1.7 nmol/L.
• Evidence of progressive disease, defined as 1 or more Prostate Cancer Working Group 3 (PCWG3) criteria:
  1. PSA level >= 1 ng/mL that has increased on at least 2 successive occasions at least 1 week apart.
  2. Nodal or visceral progression as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 with PCGW3 modifications.
  3. Appearance of 2 or more new lesions in bone scana type of medical imaging that uses a radioactive tracer to detect bone conditions or abnormalities.
• Eastern Cooperative Oncologythe study, diagnosis and treatment of cancer Group performance status of 0-1.
• Adequate organ function, defined as follows:
  1. Hematological function:
     1. absolute neutrophil count >= 1 x 10^9/L (without growth factor support within 7 days from screeningtesting for cancer or conditions that can lead to cancer before symptoms appear, also known as cancer screening assessment).
     2. platelet count >= 75 x 10^9/L (without platelet transfusion within 7 days from screening assessment).
     3. hemoglobin >= 9 g/dL (90 g/L) (without bloodthe red bodily fluid that transports oxygen and other nutrients around the body transfusion within 7 days from screening assessment).
  2. Renal function:1. estimated glomerular filtration rate based on Modification of Diet in Renal Disease calculation >= 30 ml/min/1.73 m^2.
  3. Hepatic function:
     1. aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3 x upper limit of normal (ULN) (or < 5 x ULN for participants with liver involvement).
     2. total bilirubin (TBL) < 1.5 x ULN (or < 2 x ULN for participants with liver metastases).
  4. Cardiac function:
     1. left ventricular ejection fraction > 50% (2-D transthoracic echocardiograma type of ultrasound that uses sound waves to create detailed images of the heart to assess heart structure, function and blood flow [ECHO] is the preferred method of evaluation; multi-gated acquisition scan is acceptable if ECHO is not available).
     2. Baseline electrocardiogram (ECG) QTcF <= 470 msec (average of triplicate values).

Part 3-Retreatment group:

• Deriving benefit from initial treatment with AMG 509 as evidenced by one of the following:
  1. confirmed PSA50 response.
  2. radiographic stable disease/partial response/complete response during 6 cycles of initial treatment with AMG 509 and without progression during the first 6 cycles.
• No discontinuation for toxicity during the initial treatment with 6 cycles of AMG 509.
• Progressive disease as defined in I106 within 12 months of final dose in their initial treatment with 6 cycles (EOT_1).
• Willingness to have a fresh tumor biopsyremoval of a section of tissue to analyse for cancer cells prior to initiating the additional course of treatment, depending on safety and feasibility as assessed by investigator.