Summary

The overall aim of the trial is to evaluate the safety, tolerability, and
pharmacokinetics (PK) of AMG 509 (monotherapy and in combination with abiraterone acetate
and enzalutamide) and to evaluate preliminary efficacy. As of Protocol Amendment 10 (09
July 2025), only Parts 4A expansion, 6, and 7 are open to accrual.

Eligibility

1. Parts 1, 2, 5 and 7: Participants with histologically or cytologically confirmed metastatic castration-resistant prostate cancer (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.
2. Dose exploration phase: Novel antiandrogen therapy must have been given for treatment of metastatic disease.
3. 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.
4. 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. Participants who received prior investigational therapy for the treatment of metastatic disease are not eligible.
5. Parts 4A, 4B and 7:
6. 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).
7. Dose-expansion phase: at least 1 prior NHT must have been given; 0-1 prior PARP inhibitors are acceptable.
8. 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.
9. Dose-expansion phase: up to approximately 10 participants 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).
10. Part 6:
11. Prior disease progression on 1, and only 1, NHT (either enzalutamide, apalutamide, or darolutamide) is required. NOTE: Prior progression on or intolerance to abiraterone is not allowed.
12. No prior treatment with any chemotherapy regimen in the mCRPC setting; = 6 cycles of docetaxel treatment in the mHSPC setting is allowed.
13. mCRPC with = 1 RECIST v1.1 measurable lesion that is present on baseline computed tomography (CT) or magnetic resonance imaging (MRI).
14. All parts:
15. Participants must have undergone bilateral orchiectomy or be on continuous androgen-deprivation therapy with a gonadotropin releasing hormone (GnRH) agonist or antagonist.
16. Total serum testosterone = 50 ng/dL or 1.7 nmol/L.
17. Evidence of progressive disease, defined as 1 or more Prostate Cancer Working Group 3 (PCWG3) criteria:
18. PSA level = 1 ng/mL that has increased on at least 2 successive occasions at least 1 week apart.
19. Nodal or visceral progression as defined by RECIST v1.1 with PCGW3 modifications.
20. Appearance of 2 or more new lesions in bone scan.
21. Eastern Cooperative Oncology Group performance status of 0-1.
22. Life expectancy = 3 months.
23. Adequate organ function, defined as follows:
24. Hematological function:
25. absolute neutrophil count = 1 x 10^9/L (without growth factor support within 7 days from screening assessment).
26. platelet count = 75 x 10^9/L (without platelet transfusion within 7 days from screening assessment).
27. hemoglobin = 9 g/dL (90 g/L) (without blood transfusion within 7 days from screening assessment).
28. Renal function:
29. estimated glomerular filtration rate based on Modification of Diet in Renal Disease calculation = 30 ml/min/1.73 m^2.
30. Hepatic function:
31. aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3 x upper limit of normal (ULN) (or < 5 x ULN for participants with liver involvement).
32. total bilirubin (TBL) < 1.5 x ULN (or < 2 x ULN for participants with liver metastases).
33. Cardiac function:
34. left ventricular ejection fraction > 50% (2-D transthoracic echocardiogram [ECHO] is the preferred method of evaluation; multi-gated acquisition scan is acceptable if ECHO is not available).
35. Baseline electrocardiogram (ECG) QTcF = 470 msec (average of triplicate values).
36. Pulmonary function:
37. baseline oxygen saturation > 92% on room air at rest and no oxygen supplementation. Part 3-Retreatment group:
38. Deriving benefit from initial treatment with AMG 509 as evidenced by one of the following:
39. confirmed PSA50 response.
40. radiographic stable disease/partial response/complete response during 6 cycles of initial treatment with AMG 509 and without progression during the first 6 cycles.
41. No discontinuation for toxicity during the initial treatment with 6 cycles of AMG
42. - Progressive disease as defined in I106 within 12 months of final dose in their initial treatment with 6 cycles (EOT_1).
43. Willingness to have a fresh tumor biopsy prior to initiating the additional course of treatment, depending on safety and feasibility as assessed by investigator. Key

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