Background We report Phase 1 trial results for pasritamig, a first-in-class, T-cell engaging bispecific antibody targeting human kallikrein 2 (KLK2) expressed on the surface of prostate cancer (PC) cells. Methods Participants had metastatic castration-resistant PC and ≥1 prior therapy. Pasritamig was escalated from 0.5 mg to 2000 mg for subcutaneous administration and from 150 mg to 900 mg for intravenous (IV) administration at dosing frequencies ranging from every week to every 6 weeks with different step-up dosing schedules. The primary objectives were to determine safety and the recommended Phase 2 dose (RP2D) of pasritamig. Secondary objectives included preliminary assessment of antitumor activity. Results 174 participants received pasritamig, with a median of 4 prior lines of systemic therapy. Treatment-related adverse events (TRAEs) occurred in 144/174 (82.8%) participants, with 17/174 (9.8%) experiencing Grade ≥3 TRAEs. The RP2D was determined to be 3.5 mg (Day 1), 18 mg (Day 8), 300 mg (Day 15), then 300 mg IV every 6 weeks. In the RP2D safety population (N=45), infusion-related reactions (11/45, 24.4%), fatigue (7/45, 15.6%), cytokine release syndrome (CRS; 4/45, 8.9%, all Grade 1), and lipase increase (4/45, 8.9%) were the most frequent TRAEs; all were Grade 1 or 2. In the RP2D efficacy population (N=33), median radiographic progression-free survival was 7.85 (95% CI 2.89, not estimable) months, and 14/33 (42.4%) participants achieved a ≥50% decline in prostate-specific antigen. Conclusions Pasritamig demonstrated a favorable safety profile with very low rates of CRS and could be safely administered in an outpatient setting. Preliminary antitumor activity demonstrated proof of concept for KLK2 as a target in PC, warranting further development of pasritamig.