JNJ-87189401 Plus Pasritamig Drives Deep PSA Responses With Favorable Safety in Pretreated mCRPC

The combination of the PSMA x CD28 costimulatory T-cell engager JNJ-87189401 (JNJ-9401) and the first-in-class KLK2 x CD3 bispecific T-cell engager pasritamig (JNJ-78278343) generated deep and durable prostate-specific antigen (PSA) responses with a favorable safety profile in patients with heavily pretreated metastatic castration-resistant prostate cancer (mCRPC), according to findings from a first-in-human phase 1 study (NCT06095089) presented at the 2026 SITC Annual Meeting.¹

Findings demonstrated that at the recommended phase 2 regimen (RP2R; n = 15) of intravenous pasritamig at 300 mg every 6 weeks following 2 step-up doses plus subcutaneous JNJ-87189401 at 200 mg every 6 weeks starting on day 15, 73.3% of patients experienced a PSA decline of at least 50% from baseline (PSA50), and 46.7% achieved a PSA decline of at least 90% (PSA90). Four patients (26.7%) reached undetectable PSA levels (<0.2 ng/mL); all 4 were in response for more than 6 months, and their responses were ongoing at the June 15, 2026, data cutoff.

"Historically, prostate cancer has been a very immunologically cold tumor, so we don't see a lot of T-cell activity. We don't see a lot of T-cell infiltration," lead study author Laura S. Graham, MD, said in an exclusive interview with OncLive^®. "What's unique about [these] data is that you are targeting a very prostate-specific antigen with KLK2 and pasritamig, and now you're adding this second complementary costimulatory mechanism, and we are showing that you can do that with promising deep and durable activity, and with excellent tolerability."

Graham is a medical oncologist and an assistant professor of medicine in the Division of Medical Oncology at the University of Colorado Anschutz Medical Campus in Aurora.

How was the study designed?

Early studies of immune checkpoint inhibitors in prostate cancer produced single-digit response rates, Graham explained. Pasritamig engages CD3 on T cells to deliver the first T-cell activation signal, whereas JNJ-87189401 binds PSMA on tumor cells and CD28 on T cells to deliver a costimulatory second signal. In a prior phase 1 study, pasritamig monotherapy at the recommended phase 2 dose produced a median radiographic progression-free survival (rPFS) of 7.85 months (95% CI, 2.89-not estimable) and a PSA50 rate of 42.4% in heavily pretreated mCRPC.²

Because JNJ-87189401 showed no single-agent activity in preclinical models, the trial was initiated as a combination study, Graham noted. Investigators evaluated JNJ-87189401 at doses ranging from 1.5 mg to 800 mg on every-3-week and every-6-week schedules across 144 treated patients.¹

Patients treated at the RP2R had a median age of 77 years (range, 52-94) and had received a median of 4 (range, 2-6) prior lines of systemic therapy; all had received an androgen receptor pathway inhibitor, and 66.7% each had received taxane chemotherapy and radioligand therapy. Visceral disease was present in 26.7% of patients.

What additional efficacy data were reported?

Responses trended deeper in patients with nonvisceral disease (n = 11), with PSA50, PSA90, and undetectable PSA rates of 82%, 54%, and 36%, respectively. Among patients with visceral disease (n = 4), the PSA50 and PSA90 rates were 50% and 25%, respectively, and no patients achieved undetectable PSA levels. At a median follow-up of 7.4 months, the median rPFS was not reached in patients with nonvisceral disease (95% CI, 5.88-not estimable).

Across all dose levels, 23 of 30 patients with a PSA90 response, including all 7 at the RP2R, remained on treatment for more than 6 months without disease progression.

In translational analyses, adding JNJ-87189401 enhanced CD8-positive T-cell proliferation and increased interleukin-2 (IL-2) levels with marginal changes in IL-6, consistent with the observed CRS profile.

What did the safety analysis show?

At the RP2R, treatment-related adverse effects (TRAEs) occurred in 46.7% of patients. No grade 3 or higher TRAEs, serious TRAEs, dose-limiting toxicities, TRAE-related discontinuations, or TRAE-related deaths were reported. Cytokine release syndrome (CRS) occurred in 20.0% of patients, although all events were grade 1 and limited to transient fever, and no patients required tocilizumab (Actemra). No immune effector cell–associated neurotoxicity syndrome (ICANS) was reported, and 2 patients (13%) experienced reversible grade 1 elevated alanine aminotransferase (ALT)/aspartate aminotransferase (AST) levels.

Across all doses (n = 144), any-grade and grade 3 or higher TRAEs occurred in 63.9% and 12.5% of patients, respectively. The rates of any-grade and grade 2 CRS were 20.8% and 4.8%, respectively. Immune-mediated hepatitis occurred only at JNJ-87189401 doses or exposures above the RP2R or with more frequent dosing, arose within the first 2 combination cycles, and was reversible with steroids.

According to Graham, higher doses of JNJ-87189401 did not produce greater activity, which supported selection of the 200-mg dose.

What are the next steps for JNJ-87189401 plus pasritamig?

Pasritamig with or without JNJ-87189401 is being evaluated in late-line mCRPC in the phase 3 KLK2-comPAS trial (NCT07164443), which is comparing pasritamig alone or with JNJ-87189401 vs placebo, each with best supportive care, with overall survival as the primary end point.³

References

1. Graham LS, Massard C, Rasco DW, et al. Combining PSMA×CD28 costimulatory T-cell engager (TCE) JNJ-87189401 with pasritamig (KLK2×CD3): first-in-human phase 1 results of a dual-antigen targeted TCE regimen in prostate cancer. Presented at: 2026 Society for Immunotherapy of Cancer (SITC) Annual Meeting; November 4-8, 2026; Phoenix, AZ. Abstract LBA 1175.
2. Stein MN, Vinceneux A, Robbrecht D, et al. Pasritamig, a first-in-class, bispecific T-cell engager targeting human kallikrein 2, in metastatic castration-resistant prostate cancer: a phase I study. J Clin Oncol. 2025;43(22):2515-2526. doi:10.1200/JCO-25-00678
3. A study of pasritamig versus placebo in late line metastatic castration-resistant prostate cancer (KLK2-comPAS). ClinicalTrials.gov. Accessed November 8, 2026. https://clinicaltrials.gov/study/NCT07164443