Purpose <p>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.</p> Methods <p>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&#xa0;mg. The primary endpoint was safety. Secondary endpoints included pharmacokinetics (PK), immunogenicity, and prostate-specific antigen (PSA).</p> Results <p>At final analysis, 39 participants received 0.1–180&#xa0;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.</p> Conclusions <p>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.</p> Clinicaltrial.Gov information <p>NCT05441501, Registered July 1, 2022.</p>