This is a first-in-human, Phase 1/2, multicenter, open-label study to evaluate the safety, PK, PDy, and preliminary anti-tumor activity of ARX517 in subjects with mCRPC who are resistant or refractory to standard therapies. Phase 1a and 1b dose-escalation and dose expansion stages will identify the MTD and/or RP2D(s). Phase 2 will randomize subjects to receive ARX517 at the RP2D(s) or ICT as comparator. The ICT to be used in Phase 2 will be determined after reviewing all available clinical data in Phase 1
Key Inclusion Criteria:
* Male subjects ≥ 18 years at the first time of providing written informed consent.
* Histologically confirmed prostate adenocarcinoma.
* Documented metastatic disease.
* Castration-resistant prostate cancer per the Prostate Cancer Working Group 3 (PCWG3).
* Ongoing therapy with (and willing to continue with) a gonadotropin-releasing hormone agonist or antagonist (unless prior orchiectomy) AND serum testosterone level \< 50 ng/dL at Screening.
* Prior treatment with at least two FDA-approved therapies for metastatic prostate cancer with at least one being an androgen receptor signaling inhibitor
* Adequate blood counts
Key Exclusion Criteria:
* Have central nervous system (CNS) metastasis, unless the CNS metastasis was treated with local therapy and has proven to be stable over the last 2 months prior to the enrollment date, and not currently requiring ongoing systemic steroid treatment
* History of any invasive malignancy (other than primary) within previous 2 years prior to the enrollment date that requires active therapy
* Marked baseline prolongation of QT/QT interval corrected for heart rate (QTc), e.g., a triplicate average QTc interval \> 480 milliseconds (CTCAE Grade 1) using Fridericia's QT correction formula.
* Prior history of interstitial lung disease, pneumonitis, or other clinically significant lung disease within 12 months prior to enrollment date
* Clinically significant ocular findings by a qualified ophthalmologist or optometrist including active ocular infections or chronic corneal disorders
