Phase 1 Study Evaluating JNJ-80038114 in Metastatic CRPC Discontinues Early

A phase 1 study (NCT05441501) evaluating JNJ-80038114, a PSMA/CD3-binding bispecific antibody, among patients with metastatic castration-resistant prostate cancer (CRPC) has been discontinued early, according to results published in Cancer, Chemotherapy and Pharmacology.¹ Specifically, the investigators made the decision due to a lack of preliminary clinical activity, presence of neurologic toxicities, a high rate of cytokine release syndrome (CRS), and the development of anti-drug antibodies (ADA) affecting pharmacokinetics (PK).

Among 39 patients treated with the investigational therapy, all experienced treatment-emergent adverse effects (TEAEs). The most frequent higher treatment-related AEs (TRAEs) included CRS (51.3%), fatigue (48.7%), injection-site reactions (ISRs, 46.2%), lymphopenia (43.6%), and diarrhea (35.9%). Additionally, grade 3 or higher TRAEs occurred in 51.3% of patients, the most common of which was lymphopenia (33.3%).

Dose-limiting toxicities (DLTs) were reported in 3 patients (7.7%), with events including grade 2 reversible multiple cranial nerve polyneuropathy, grade 3 peripheral sensory neuropathy, and 1 patient experiencing grade 2 hepatitis and grade 3 pancreatitis. Additionally, 2 patients developed peripheral neuropathies after receiving 180 mg of the agent following a grade 1 and a grade 2 CRS event, respectively.

Furthermore, serious TEAEs were observed in 51.3% of patients, with 12.8% of patients experiencing CRS. TRAEs leading to dose discontinuation were observed in 3 patients. Five fatalities due to disease progression were observed on study, with 1 additional death occurring following database lock possibly due to disease progression and/or drug toxicity.

“Although this first-in-human study demonstrated a manageable safety profile of JNJ-80038114, the lack of antitumor activity and the immunogenicity results do not support further development for [metastatic] CRPC,” Andre Hudson, MBChB, BSc (Hons), MRCP, FRCR, PhD, consultant clinical oncologist at the Christie NHS Foundation Trust, wrote in the publication with coauthors.¹ “These data contribute to the emerging clinical experience with T-cell engagers and bispecific antibodies in prostate cancer. Additional exploration of PSMA/CD3 bispecific antibodies, including optimal dosage, half-life, and delivery is warranted.”

Preliminary anti-tumor activity findings showed that 10.9% of patients experienced a decrease in prostate-specific antigen (PSA) of at least 50% at any time during treatment. Moreover, 1 patient had a confirmed PSA decrease of at least 50% at the 10 mg dose at week 6. Three patients experienced a partial response per PCWG3 criteria, but with rapidly increasing PSA.

Additional data revealed that, following the first dose of JNJ-80038114 ranging from 1.0 to 180 mg, the maximum observed concentration and area under the concentration vs time curve from day 0 to 21 increased with each increasing dose given every 3 weeks. Additionally, the median time to reach maximum observed concentration was between 71 hours and 154 hours, with steady state achieved after the fourth dose. A total of 56.8% of patients experienced treatment-emergent ADAs, of whom 33.3% showed non-detectable pre-dose serum concentration at the time of peak ADA titer.

The first-in-human trial enrolled patients 18 years and older with pretreated metastatic CRPC and assigned them to receive escalating doses of JNJ-80038114 subcutaneously every 3 weeks starting at 0.1 mg up to 180 mg. Subsequent dose levels and step-up dosing were determined by a study evaluation team based on emerging safety and PK data.

Patients enrolled on trial (n = 39) had a median age of 67.0 years (range, 50-84); 33 had an ECOG performance status of 1; and 9 had metastatic disease to the lungs, liver, adrenal glands, or central nervous system. The median baseline PSA level was 189 ug/L (range, 5-3074). All patients received prior cancer-related therapy, with 37 (94.9%) receiving prior androgen receptor pathway inhibitors, 34 (87.2%) receiving prior taxanes, and 12 (30.8%) receiving prior radioligand therapy.

The primary end points of the trial included AEs in the dose-escalation and dose-expansion portions and DLTs in the dose-escalation portion of the trial. Secondary end points included PK parameters, PSA concentration and response, objective response rate, and duration of response.²

References

1. Hudson A, Jayaram A, Garmezy B, et al. A phase 1, first-in-human, dose escalation study of JNJ-80038114, a PSMAxCD3 bispecific antibody, in participants with metastatic castration-resistant prostate cancer. Cancer Chemother Pharmacol. 2026;96:5. doi:10.1007/s00280-025-04846-w
2. A study of JNJ-80038114 in participants with advanced stage prostate cancer. ClinicalTrials.gov. Updated March 4, 2025. Accessed January 15, 2026. https://tinyurl.com/2ja28692