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

Inclusion Criteria:

• Parts 1, 2, 5 and 7: 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. Participants who receivedprior investigational therapy for the treatment of metastatic disease are noteligible.

• Parts 4A, 4B and 7:

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 participants 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).

• Part 6:

1. Prior disease progression on 1, and only 1, NHT (either enzalutamide,apalutamide, or darolutamide) is required. NOTE: Prior progression on orintolerance to abiraterone is not allowed.

2. No prior treatment with any chemotherapy regimen in the mCRPC setting; ≤ 6cycles of docetaxel treatment in the mHSPC setting is allowed.

3. mCRPC with ≥ 1 RECIST v1.1 measurable lesion that is present on baselinecomputed tomography (CT) or magnetic resonance imaging (MRI).

• 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 RECIST v1.1 with PCGW3modifications.

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

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

• Life expectancy ≥ 3 months.

• 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 days fromscreening assessment).

5. Renal function:

6. estimated glomerular filtration rate based on Modification of Diet in RenalDisease 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).

13. Pulmonary function:

14. baseline oxygen saturation > 92% on room air at rest and no oxygensupplementation.

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.

Key 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.

• Prior major surgery within 4 weeks of first dose.

• 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. Simple urinary tractinfections and uncomplicated bacterial pharyngitis are permitted if responding toactive treatment and after consultation with sponsor. Screening for chronicinfectious conditions is not required.

• 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. Participants with a recent history of venous thrombosis must bemaintained on the same anti-coagulation therapy for a minimum of 28 days prior tofirst dose of study treatment.

• 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 prostate specific membrane antigen (PSMA) radionuclide therapy within 2 monthsprior to AMG 509 unless participant received < 2 cycles (Note: a participant cannothave received PSMA radionuclide therapy < 35 days prior to enrollment if 1 cycle wasgiven). Parts 3 and 4: prior PSMA radionuclide therapy is prohibited. Participantson a stable bisphosphonate or denosumab regimen for ≥ 30 days prior to enrollmentare eligible (exception: part 3 retreatment).

• Part 3-Retreatment only: Any anti-cancer 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.