JNJ-6143 Elicits PSA Responses in Heavily Pretreated mCRPC

Treatment with the investigational oral therapy JNJ-6143 (formerly HLD-0915) resulted in deep prostate-specific antigen (PSA) declines and radiographic responses in heavily pretreated patients with metastatic castration-resistant prostate cancer (mCRPC), also called metastatic androgen pathway modulation-resistant prostate cancer (mAPMR), according to phase 1 study (NCT06800313) results presented at the European Society for Medical Oncology (ESMO) Congress 2026.^1,2

Among 38 patients treated at the recommended phase 2 dose (RP2D) of 50 mg once daily, 77% had a confirmed PSA decline of at least 50% (PSA50) and 48% had a confirmed decline of at least 90% (PSA90) as of a September 21, 2026, data cutoff. Among 16 patients with measurable disease at that dose, the confirmed objective response rate (ORR) was 69% (11 of 16), including complete responses in 13% and partial responses in 56%; the median duration of response (DOR) was 11.0 months (95% CI, 5.9-not evaluable). One additional patient with stable disease had a confirmed partial response after the cutoff, bringing the ORR to the 75%, according to a subsequent update from Johnson & Johnson.

“This is a completely novel mechanism of action for patients. JNJ-6143 was highly active with an encouraging safety profile in this phase 1 study of patients with heavily pretreated mCRPC,” said Benjamin Garmezy, MD, associate director of Genitourinary Cancer Research at Sarah Cannon Research Institute, in his presentation of the data.

Drug Background

JNJ-6143 is a first-in-class RIPTAC (Regulated Induced Proximity Targeting Chimeras) molecule, a heterobifunctional small molecule that simultaneously binds the androgen receptor (AR) and BRD4 in prostate cancer cells to trigger cell death. The resulting complex sequesters BRD4, a protein essential for cell survival, and prevents it from engaging chromatin to drive transcription, leading to apoptosis. JNJ-6143, then known as HLD-0915, received FDA fast track designation in August 2025.

Study Design and Patients

The multicenter, first-in-human study enrolled patients with progressive mCRPC who had received at least 1 androgen receptor pathway inhibitor, up to 2 prior taxanes, and up to 1 prior radioligand therapy. Patients received JNJ-6143 orally once daily in 21-day cycles at doses from 12.5 to 150 mg during dose escalation and backfill, followed by a dose optimization phase that randomly assigned patients to 25 or 50 mg. As of the cutoff, 105 patients had been dosed, including 38 at 50 mg.

In the 50-mg cohort, the median age was 73 years (range, 56-90) and the median baseline PSA level was 122.2 µg/L (range, 17.3-2235). Patients had received a median of 4 prior systemic therapies in the metastatic setting (range, 1-9): 54% had received a taxane, 46% had received radioligand therapy, 32% had received both, and 5% had received a PARP inhibitor. Visceral metastases were present in 29%, including liver metastases in 11%. Baseline characteristics were similar across the full population of 105 patients, who had a median of 4 prior metastatic-setting therapies (range, 1-10).

Activity in High-Risk Subgroups

Among 27 patients in the 50-mg cohort with evaluable circulating tumor DNA, PSA50 responses were observed regardless of high-risk genomic features. PSA50 response was achieved in 13 of 15 in patients with AR amplification, 17 of 21 with TP53 alterations, 8 of 10 with PTEN alterations, 9 of 12 with RB1 alterations, and 9 of 11 with BRCA1/2 alterations; 2 of 3 patients with AR ligand-binding domain mutations responded. Among 6 patients with AR-V7–positive circulating tumor cells, 5 (83%) had a PSA50 response.

"These early results with JNJ-6143 are encouraging because we are seeing meaningful anti-tumor activity in patients who have already received multiple therapies," said Johann de Bono, MD, of The Institute of Cancer Research and The Royal Marsden in London, United Kingdom, in the news release.

Safety Findings

At 50 mg, treatment-related adverse events (TRAEs) occurred in 58% of patients, and 2 patients (5%) had grade 3 or higher TRAEs, both of which were reclassified as unrelated to the study drug after the cutoff. The most common TRAEs were hypercholesterolemia (18%), hypertriglyceridemia (16%), nausea (16%), fatigue (13%), and anemia (13%). No serious TRAEs, dose-limiting toxicities (DLTs), or treatment-related deaths occurred at that dose. TRAEs led to dose interruption in 11%, dose reduction in 3%, and discontinuation in 3%.²

Across all 105 patients, grade 3 or higher TRAEs occurred in 17%, serious TRAEs in 3%, and discontinuations because of TRAEs in 5%. One DLT, hepatotoxicity in the setting of extrinsic bile duct compression, occurred at the 100-mg dose, and 1 patient had a fatal treatment-related event, grade 5 acute kidney injury after an acute hemodynamic event during hemodialysis.²

At the cutoff, 66% of all patients and 71% of those treated at 50 mg remained on treatment, with a median follow-up of 5.6 months (range, 0.2-14.5) in the 50-mg cohort.²Garmezy stated that his practice, patients have tolerated the drug well.

Next Steps

Investigators selected 50 mg once daily as the RP2D based on safety, efficacy, and pharmacokinetic data, and a phase 2 study of JNJ-6143 in metastatic prostate cancer (NCT07832292) has been initiated at that dose.^1,2 Garmezy noted that, although early, he believes the balance of safety and efficacy data supports future randomized phase 3 trials.

"The findings give us confidence to further evaluate this new approach for those with difficult-to-treat disease," de Bono said.

REFERENCES

1. Johnson & Johnson reports 75% tumor response rate in advanced prostate cancer with JNJ-6143, a first-in-class RIPTAC™ molecule. News release. Johnson & Johnson. October 25, 2026. Accessed October 30, 2026. https://tinyurl.com/45rj68hn

2. Garmezy B, Sahota S, Wang JS, et al. Safety and efficacy of JNJ-6143, a first-in-class oral AR-targeted regulated induced proximity targeting chimera at the optimal dose for further development in patients with mCRPC/mAPMR, including high-risk molecular features. Presented at: European Society for Medical Oncology Congress 2026; October 23-27, 2026; Madrid, Spain. Abstract 2216O.