Summary Background Interleukin-23 (IL23) has been reported to drive androgen receptor (AR) and JAK2-STAT3 signaling, promoting treatment resistance and disease progression in advanced prostate cancer (PC). We evaluated the safety, tolerability, and antitumor activity of the anti-IL23 monoclonal antibody tildrakizumab in combination with the AR pathway inhibitor (ARPI) abiraterone acetate (AA) in men with ARPI-resistant metastatic castration-resistant PC (mCRPC). Methods mCRPC patients of ECOG performance status (PS) ≤ 2, who had previously progressed on first-line ARPI therapy, were treated with tildrakizumab (100 mg, 300 mg, 600 mg; 4-weekly) in combination with AA (YonsaTM, 500 mg daily). The primary objective was to determine the recommended phase 2 dose. Secondary endpoints were elucidation of pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity. Results No dose limiting toxicities (DLTs) were observed, nor any grade ≥ 3 adverse effects (AEs). The most common treatment-related AEs attributable to tildrakizumab were grade 1—2 fatigue (n = 3/12; 25.0%) and grade 1 nausea (n = 2/12; 16.7%). PK analyses showed no obvious drug-drug interactions. Overall, no objective responses were observed. Median progression free survival (PFS) was 3.7 months (n = 10; 95% CI 1.6-not reached) with median overall survival (OS) of 9.7 months (n = 10; 95% CI 6.9-not reached). Conclusions Tildrakizumab and abiraterone acetate combination therapy is well tolerated but did not show clinical efficacy in this small, unselected, cohort of ARPI-resistant mCRPC patients. Further study into the causes of primary resistance to IL23 targeting in mCRPC, and development of biomarkers of downstream IL23-IL23R activity, are now needed to translate IL23 blockade into the clinic.
Chandran et al. (2026) studied this question.