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

Inclusion Criteria:

• Parts 1, 2, and 5: Participants with histologically or cytologically confirmedmetastatic castration-resistant prostate cancer (mCRPC) who are refractory to anovel antiandrogen therapy (abiraterone acetate and/or enzalutamide, apalutamide, ordarolutamide) and have failed at least 1 (but not more than 2) taxane regimensincluding for metastatic hormone-sensitive prostate cancer (mHSPC) (or who aredeemed medically unsuitable to be treated with a taxane regimen or have activelyrefused treatment with a taxane regimen). Note: A taxane regimen is defined as aminimum exposure of 2 cycles of a taxane. Any NHT that has been administered and hasbeen stopped for reasons other than progression will not be counted as an additionalline of treatment.

1. Dose exploration phase: Novel antiandrogen therapy must have been given fortreatment of metastatic disease.

2. Dose expansion phase: participants must not have had more than 2 NHTs and 2taxane regimens in any setting, and an additional up to 2 other systemicanti-cancer treatments are allowed (eg, anti-PD1, PARP inhibitors, radioligandtherapies, sipuleucel-T, experimental agents) Note: Combinations are consideredone systemic anti-cancer treatment.

• Part 3: Participants with histologically or cytologically confirmed mCRPC who havereceived no or 1-2 prior NHTs (abiraterone acetate, enzalutamide, apalutamide, ordarolutamide) given in any disease setting and who are deemed medically unsuitableto be treated with a taxane regimen or have actively refused treatment with a taxaneregimen (unless taxane treatment was administered in HSPC setting). 0 1 prior PARPinhibitors or sipuleucel T treatments are acceptable. Subjects who received priorinvestigational therapy for the treatment of metastatic disease are not eligible.

• Parts 4A and 4B:

1. Participants with histologically or cytologically confirmed mCRPC who havereceived no or 1-2 prior NHTs (given in any disease setting depending on thepart), and no or 1 taxane regimen (for HSPC).

2. Dose-expansion phase: at least 1 prior NHT must have been given; 0-1 prior PARPinhibitors 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 ofaction (apalutamide, enzalutamide or darolutamide) in the non-mCRPC and mCRPCsetting.

• Dose expansion phase: up to approximately 10 subjects with prior exposure toabiraterone 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 noteligible).

• All parts:

• Participants must have undergone bilateral orchiectomy or be on continuousandrogen-deprivation therapy with a gonadotropin releasing hormone (GnRH) agonist orantagonist.

• 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 atleast 1 week apart.

2. Nodal or visceral progression as defined by Response Evaluation Criteria inSolid Tumors (RECIST) 1.1 with PCGW3 modifications.

3. Appearance of 2 or more new lesions in bone scan.

• Eastern Cooperative Oncology Group performance status of 0-1.

• Adequate organ function, defined as follows:

1. Hematological function:

2. absolute neutrophil count >= 1 x 10^9/L (without growth factor supportwithin 7 days from screening assessment).

3. platelet count >= 75 x 10^9/L (without platelet transfusion within 7 daysfrom screening assessment).

4. hemoglobin >= 9 g/dL (90 g/L) (without blood transfusion within 7 daysfrom screening assessment).

5. Renal function:

6. estimated glomerular filtration rate based on Modification of Diet inRenal Disease calculation >= 30 ml/min/1.73 m^2.

7. Hepatic function:

8. aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3 xupper limit of normal (ULN) (or < 5 x ULN for participants with liverinvolvement).

9. total bilirubin (TBL) < 1.5 x ULN (or < 2 x ULN for participants withliver metastases).

10. Cardiac function:

11. left ventricular ejection fraction > 50% (2-D transthoracic echocardiogram [ECHO] is the preferred method of evaluation; multi-gated acquisition scanis acceptable if ECHO is not available).

12. Baseline electrocardiogram (ECG) QTcF <= 470 msec (average of triplicatevalues).

Part 3-Retreatment group:

• Deriving benefit from initial treatment with AMG 509 as evidenced by one of thefollowing:

1. confirmed PSA50 response.

2. radiographic stable disease/partial response/complete response during 6 cyclesof initial treatment with AMG 509 and without progression during the first 6cycles.

• No discontinuation for toxicity during the initial treatment with 6 cycles of AMG

• Progressive disease as defined in I106 within 12 months of final dose in theirinitial treatment with 6 cycles (EOT_1).

• Willingness to have a fresh tumor biopsy prior to initiating the additional courseof treatment, depending on safety and feasibility as assessed by investigator.

Exclusion Criteria:

• Pathological finding consistent with pure small cell, neuroendocrine carcinoma ofthe prostate or any other histology different from adenocarcinoma.

• Radiation therapy within 4 weeks of first dose (or local or focal radiotherapywithin 2 weeks of first dose).

• Untreated central nervous system (CNS) metastases or leptomeningeal disease.Participants with a history of treated CNS metastases are eligible if there isradiographic evidence of improvement upon the completion of CNS-directed therapy andno evidence of interim progression between the completion of CNS-directed therapyand the screening radiographic study.

• Participants with symptoms and/or clinical signs and/or radiographic signs thatindicate an acute and/or uncontrolled active systemic infection within 7 days priorto the first dose of investigational product administration.

• Confirmed history or current autoimmune disease or other diseases resulting inpermanent immunosuppression or requiring permanent immunosuppressive therapy.

• History of arterial or venous thrombosis (eg, stroke, transient ischemic attack,pulmonary embolism, or deep vein thrombosis); for arterial thrombosis within 12months of AMG 509 initiation; for venous thrombosis, 6 months and stable onanti-coagulation.

• Myocardial infarction and/or symptomatic congestive heart failure (New York HeartAssociation > class II) within 12 months of first dose of AMG 509 with the exceptionof ischemia or non-ST segment elevation myocardial infarction controlled with stentplacement and confirmed by a cardiologist more than 6 months prior to first dose ofAMG 509.

• Any anti-cancer therapy or immunotherapy within 4 weeks of start of first dose, notincluding luteinizing hormone-releasing hormone (LHRH)/GnRH analogue (agonist/antagonist).

• Prior PSMA radionuclide therapy within 2 months prior to AMG 509 unless participantreceived < 2 cycles (Note: a participant cannot have received PSMA radionuclidetherapy < 35 days prior to enrollment if 1 cycle was given). Parts 3 and 4: priorPSMA radionuclide therapy is prohibited. Participants on a stable bisphosphonate ordenosumab regimen for >= 30 days prior to enrollment are eligible (exception: part 3retreatment).

• Part 3-Retreatment only: Any anticancer therapy or immunotherapy, not includingluteinizing hormone-releasing hormone/gonadotropin releasing hormone (LHRH/GnRH)analogue (agonist/antagonist), and/or bisphosphonate or denosumab regimen after lastdose of AMG 509 initial course of treatment.