Background: Tumor-infiltrating inflammatory myeloid cells promote prostate cancer (PC) growth and therapeutic resistance. Myeloid inflammatory cells release interleukin-23 (IL-23) to fuel tumor growth via JAK2-STAT3 signalling and facilitate tumor-promoting T helper 17 (T_H17) differentiation in PC models in vivo. IL-23 blockade reverses resistance to AR-targeting in vivo; we hypothesise that targeting IL-23 can be an effective therapeutic strategy for CRPC. Tildrakizumab, an anti-IL-23 (p19) monoclonal antibody, is FDA/EMA approved for treating moderate-severe psoriasis. In progress is the first clinical trial to combining IL-23 and AR signalling blockade in humans. Methods: This is an open-label, single-arm, Ph 1/2, dose-escalation and expansion study evaluating safety and tolerability of tildrakizumab and abiraterone acetate combination therapy in patients with mCRPC. Eligible patients must have progressed on androgen deprivation therapy, plus abiraterone and/or enzalutamide. The Ph 1 trial will adopt a one-stage Bayesian Continual Reassessment Method design exploring escalating doses of 4-weekly, IV tildrakizumab (100 mg, 300 mg, and 600 mg), in combination with standard fixed doses of abiraterone acetate and methylprednisolone, with the aim of determining the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). Depending on the number of responses observed, tolerable dose levels may be expanded up to 10 patients after review by the Safety Review Committee (SRC). The RP2D and MTD determination will be based on the rate of toxicity and efficacy, reviewed by the SRC. Once RP2D is determined, the Ph 2 study will enrol up to 25 response-evaluable patients using a Simon’s two-stage design. Primary endpoint of the Ph 2 trial is overall response rate. Adverse events are assessed according to CTCAE v5. Tumor response is determined according to RECIST v1.1, confirmed PSA decline of at least 50%, and/or CTC conversion. PK analyses is being performed for both drugs to identify potential drug-drug interactions. PD analyses is being performed on archival and serial tumour biopsies and blood samples to investigate putative predictive biomarkers and confirm on-target and downstream effector modulation. The trial began enrolling in January 2021 in the United Kingdom and Switzerland. As of January 22th 2023, 12 patients were included in the study. Clinical trial information: NCT04458311.