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Background <p>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).</p> Methods <p>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.</p> Results <p>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).</p> Conclusions <p>Tildrakizumab and abiraterone acetate&#xa0;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.</p>

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A Phase I trial of the anti-IL23 monoclonal antibody tildrakizumab, in combination with abiraterone acetate, for the treatment of metastatic castration-resistant prostate cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月16日

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  • Khobe Chandran,
  • Christina Guo,
  • Simon Pacey,
  • Guillermo Villacampa,
  • Ruth Matthews,
  • Toby Prout,
  • Joan Fernandes,
  • Alison Turner,
  • Mona Parmar,
  • Ruth Riisnaes,
  • Ana Ferreira,
  • Suzanne Carreira,
  • Claudia Bertan,
  • Mateus Crespo,
  • Ines Figueiredo,
  • Wei Yuan,
  • Denisa Bogdan,
  • Florence Raynaud,
  • Ruth Ruddle,
  • Bianca Calì,
  • Martino Maddalena,
  • Arianna Calcinotto,
  • Christina Yap,
  • Adam Sharp,
  • Andrea Alimonti,
  • Johann De Bono,
  • Alec Paschalis

摘要

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.