Background: Six-transmembrane epithelial antigen of prostate 1 (STEAP1) is overexpressed on the surface of prostate cancer cells with low or no expression on normal tissue. AMG 509 is a bispecific XmAb 2+1 T-cell engager that simultaneously binds to STEAP1 on tumor cells and the CD3 complex on T cells resulting in T-cell mediated lysis of STEAP1-expressing cells. AMG 509 demonstrated significant antitumor activity in preclinical prostate cancer models. Methods: This 4-part, first-in-human study will evaluate AMG 509 in pts with mCRPC previously treated with novel hormonal therapy (NHT) and will assess the safety, tolerability, pharmacokinetics (PK), and efficacy of AMG 509 to establish the maximum tolerated dose (MTD) and/or the recommended phase 2 dose (RP2D). Part 1 is currently enrolling pts previously treated with NHT and up to 2 prior taxanes. As of 31 January 2022, 60 of up to 110 pts have been enrolled for treatment with intravenous (IV) AMG 509 with initial inpatient dosing followed by outpatient treatment. Part 2 will evaluate subcutaneous dosing of AMG 509 in the same patient population as in Part 1. Part 3 will explore AMG 509 IV dosing in chemotherapy-naïve pts who have been treated previously with one NHT and will provide additional data on the safety, PK, efficacy, pharmacodynamics, and correlative biomarkers at the MTD or RP2D determined in Part 1. Part 4 will evaluate the combination of AMG 509 with abiraterone (Part 4A) or enzalutamide (Part 4B) in pts previously treated with one NHT and up to 1 prior taxane for castration-sensitive disease. Primary outcome measures include dose-limiting toxicities, treatment-emergent and treatment-related adverse events, and change in clinical and laboratory parameters. Key secondary outcome measures include PK, objective response per RECIST 1.1, prostate-specific antigen response, progression-free survival, and overall survival. Key inclusion criteria are men ≥18 years of age with pathologically confirmed mCRPC, refractoriness to NHT, evidence of progressive disease, and ECOG performance status of 0–1. Key exclusion criteria are pure small cell or neuroendocrine carcinoma of the prostate, untreated CNS metastases or leptomeningeal disease, recent anticancer therapy or immunotherapy within 4 weeks of start of first dose not including luteinizing hormone-releasing hormone/gonadotropin-releasing hormone analogue (agonist/antagonist) therapy, radiation therapy, and a history of or current autoimmune disease or any disease requiring chronic immunosuppressive therapy. The trial is being carried out in investigative sites in North America, Australia, Asia, and Europe. The study opened in January 2020 and is recruiting pts for the dose exploration phase of Part 1; parts 2 and 4 are open for enrollment. Part 3 will be initiated once the MTD and/or RP2D have been determined in Part 1. Clinical trial information: NCT04221542.