Andrew Hudson, Anuradha Jayaram, Benjamin Garmezy, Nicholas A. Zorko, Kevin Zarrabi, Ligi Mathews, Brent Rupnow, Mengjie Li, D. Ghosh, Karen Urtishak, Peter Francis, Sherry Wang, Edward F. Attiyeh, Johann S. de Bono
Abstract Purpose Prostate-specific membrane antigen (PSMA) has been identified as a therapeutic target for metastatic castration-resistant prostate cancer (mCRPC). The recent success of radioligands targeting PSMA spurred development of new PSMA-targeting agents including immunotherapy. JNJ-80038114 is a bispecific antibody that binds PSMA on tumor cells and CD3 on T cells to induce anti-tumor activity. Methods This was a phase 1, open-label, multicenter study of JNJ-80038114 in participants with mCRPC and ≥ 1 prior systemic therapy. JNJ-80038114 was administered subcutaneously every 3 weeks (Q3W), starting at 0.1 mg. The primary endpoint was safety. Secondary endpoints included pharmacokinetics (PK), immunogenicity, and prostate-specific antigen (PSA). Results At final analysis, 39 participants received 0.1–180 mg JNJ-80038114 across 11 dose-escalation cohorts for a median of 9.3 weeks (range, 0.1–31.1). The most common treatment-related adverse events (TRAEs; ≥20%) included cytokine release syndrome (CRS, 51.3%, all Grade 1–2), injection-site reactions (46.2%), and fatigue (30.8%). Related Grade ≥ 3 TRAEs occurred in 51.3% of participants; dose-limiting toxicities occurred in 3 (7.7%). Four participants (10.3%) developed clinically significant neuropathies. In 37 PK-evaluable participants, mean exposure (C max , AUC) increased with increasing doses. Anti-drug antibodies (ADA) were reported in 56.8% (21/37) participants. One participant had confirmed PSA decrease ≥ 50%. Three participants had radiological responses in the context of rapidly rising PSA. Following a review of data, the study was terminated. Conclusions This first-in-human study of JNJ-80038114 was discontinued early due to its lack of preliminary clinical activity, neurologic toxicities, high rates of CRS, and the development of ADAs impacting PK. Clinicaltrial.Gov information NCT05441501, Registered July 1, 2022.