A phase 3 randomized, double-blind, placebo-controlled study of a pasritamig plus best supportive care in metastatic castration-resistant prostate cancer.

Abstract

TPS5136 Background: Metastatic castration-resistant prostate cancer (mCRPC) remains an incurable disease with high morbidity and a median overall survival of 2 years. Human kallikrein 2 (KLK2) is highly and specifically expressed in normal and malignant prostate tissue, including late stage mCRPC. Pasritamig is a humanized, IgG1-based bispecific antibody that targets KLK2-expressing cells via CD3 engagement, inducing T cell-mediated targeted cytotoxicity. In a first-in-human study in participants with mCRPC refractory to standard therapies, pasritamig demonstrated a favorable safety profile (< 5% grade 3 or higher treatment-related adverse events and < 10% cytokine release syndrome, all grade 1) and encouraging efficacy at the recommended phase 2 dose with every 6-week (Q6W) outpatient dosing. Methods: KLK2-comPAS is a double-blind, randomized, global phase 3 study to evaluate the safety and efficacy of pasritamig in participants with mCRPC who have previously received all available and suitable life-prolonging therapies including androgen receptor pathway inhibitor, taxane chemotherapy, radioligand therapy (RLT), and poly(ADP-ribose) polymerase inhibitors (for patients with BRCA mutations). Other key inclusion criteria include ECOG performance status 0–2, PSA ≥2 ng/mL, adequate organ function, and ongoing androgen deprivation therapy or prior orchiectomy. Key exclusion criteria include visceral metastases, prior KLK2- or CD3-directed therapies, and active autoimmune disease requiring systemic immunosuppression. Approximately 663 patients will be randomized in a 2:1 ratio to receive pasritamig plus best supportive care (BSC) or placebo plus BSC, stratified by prior PSMA-targeted RLT, number of prior taxanes, and ECOG performance status. BSC may include palliative external beam radiation, low dose steroids, pain medications, bone protective agents, and needed palliative procedures. Pasritamig is administered outpatient at a target dose of 300 mg IV Q6W with two step-up doses of 3.5 mg IV on cycle 1 day 1 and 18 mg IV on cycle 1 day 8. Pre-medications (dexamethasone, diphenhydramine, acetaminophen) will be administered for step-up and first target dose. Participants will receive treatment until confirmed radiographic progression or unequivocal clinical progression, intolerable toxicity, withdrawal, or death. The primary endpoint is overall survival. Key secondary endpoints include radiographic progression-free survival (rPFS), PFS (including clinical progression and unconfirmed bone progression), time to symptomatic progression, and time to skeletal-related events. Enrollment commenced in September 2025 and remains ongoing. Clinical trial information: NCT07164443 .