Document Type
Article
Publication Date
1-6-2026
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 (Cmax, AUC) increased with increas- ing 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.
GOV INFORMATION: NCT05441501, Registered July 1, 2022.
Recommended Citation
Hudson, Andrew; Jayaram, Anuradha; Garmezy, Benjamin; Zorko, Nicholas; Zarrabi, Kevin; Mathews, Ligi; Rupnow, Brent; Li, Mengjie; Ghosh, Debopriya; Urtishak, Karen; Francis, Peter; Wang, Sherry; Attiyeh, Edward; and de Bono, Johann, "A Phase 1, First-In-Human, Dose Escalation Study of JNJ-80038114, a PSMAxCD3 Bispecific Antibody, in Participants With Metastatic Castration-Resistant Prostate Cancer" (2026). Department of Medical Oncology Faculty Papers. Paper 324.
https://jdc.jefferson.edu/medoncfp/324
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
PubMed ID
41493473
Language
English
Included in
Chemicals and Drugs Commons, Clinical Trials Commons, Male Urogenital Diseases Commons, Oncology Commons
Comments
This article is the author’s final published version in Cancer chemotherapy and pharmacology, Volume 96, Issue 1, 2026, Article number 5.
The published version is available at https://doi.org/10.1007/s00280-025-04846-w. Copyright © The Author(s) 2025.