Novel RIPTAC molecule shows promising activity in heavily pretreated mCRPC

JNJ-6143, a first-in-class oral regulated induced proximity targeting chimera (RIPTAC) molecule, demonstrated activity and an encouraging safety profile in patients with heavily pretreated metastatic castration-resistant prostate cancer (mCRPC), according to updated phase 1 data presented at the 2026 European Society for Medical Oncology (ESMO) Annual Congress in Madrid, Spain.¹

At the recommended phase 2 dose (RP2D) of 50 mg once daily, 77% of evaluable patients achieved a confirmed prostate-specific antigen (PSA) decline of at least 50% (PSA50) and 48% achieved a confirmed decline of at least 90% (PSA90).

“This is a completely new mechanism of action for these patients,” said presenting author Benjamin Garmezy, MD, at ESMO. “JNJ-6143 forms a targeted dual-protein lock and is an oral small molecule that links the tumor-specific androgen receptor to a protein essential for cell survival, in this case, BRD4. This ternary complex formation of JNJ-6143 and BRD4 suppress BRD4 function, leading to cell death in prostate cancer cells, while sparing normal healthy tissues.”

Trial overview

The first-in-human, multicenter phase 1 study (NCT06800313) enrolled patients with progressive mCRPC and a rising PSA level (2 ng/mL or higher for dose escalation; 20 ng/mL or higher for dose optimization) who had received at least 1 androgen receptor pathway inhibitor (ARPI). Up to 2 prior taxanes and 1 prior radioligand therapy (RLT) were permitted, and an Eastern Cooperative Oncology Group performance status of 0 or 1 was required.

The primary objective was safety and tolerability; secondary objectives included pharmacokinetics, pharmacodynamics, and efficacy measured by PSA response, objective response rate (ORR), and circulating tumor DNA (ctDNA).

As of the September 21, 2026, data cutoff, 105 patients had received JNJ-6143 orally once daily in 21-day cycles at doses ranging from 12.5 mg to 150 mg, with dose optimization at 25 mg and 50 mg. Investigators selected 50 mg once daily as the RP2D based on safety, efficacy, and pharmacokinetic data; 38 patients were treated at that dose.

Across all doses, the median age was 72 years and the median number of prior systemic therapies in the metastatic setting was 4 (range, 1 to 10). In total, 66% of patients had received a taxane, 44% had received RLT, 35% had received both, and 10% had received a PARP inhibitor. Further, 27% of patients had visceral disease. The 50-mg cohort was similar, with 54% having received a taxane, 46% RLT, and 29% having visceral disease.

Efficacy data

Among 31 PSA-evaluable patients in the 50-mg cohort, the confirmed PSA50 rate was 77% (24 of 31) and the confirmed PSA90 rate was 48% (15 of 31).

Among 16 patients with measurable disease at the RP2D, the confirmed ORR by RECIST version 1.1 was 69% (11 of 16), comprising complete responses in 13% and partial responses in 56%. The disease control rate was 88% (14 of 16). The median duration of response was 11.0 months (95% CI, 5.9 months to not evaluable). After the data cutoff, 1 patient with stable disease converted to a confirmed partial response, raising the ORR to 75% (12 of 16).² At the 50-mg dose, 71% of patients remained on treatment at a median follow-up of 5.6 months (range, 0.2 to 14.5).

In an exploratory analysis of 27 patients in the 50-mg cohort with baseline ctDNA, PSA50 rates were similar between patients with and without AR amplification (13 of 15 vs 9 of 12) and between those with and without alterations in TP53 (17 of 21 vs 5 of 6), PTEN (8 of 10 vs 14 of 17), RB1 (9 of 12 vs 13 of 15), and BRCA1/2 (9 of 11 vs 13 of 16). Only 3 patients had an AR ligand-binding domain mutation (2 achieved PSA50). PSA50 was also observed in 5 of 6 patients with AR splice variant 7 (AR-V7)–positive circulating tumor cells.

“Importantly, these PSA responses are irrespective of high-risk molecular features,” Garmezy emphasized during the presentation. “You can see no single genomic alteration is indicative of treatment activity or resistance to JNJ-6143, showing similar PSA50 response rates for altered and unaltered patients with these high-risk genomic subsets.”

Safety profile

At the RP2D, any-grade treatment related adverse events (TRAEs) occurred in 58% of patients. The most common in the 50 mg cohort were hypercholesterolemia (18%), hypertriglyceridemia (16%), nausea (16%), fatigue (13%), anemia (13%), and decreased appetite (11%). Two grade 3 or higher TRAEs were reported at the cutoff; both were subsequently reclassified as unrelated to the study drug. No serious TRAEs, dose-limiting toxicities, or treatment-related deaths occurred at 50 mg. TRAEs led to dose interruption in 11%, dose reduction in 3%, and discontinuation in 3% of patients.

Across all dose levels, grade 3 or higher TRAEs occurred in 17% of patients, serious TRAEs in 3%, and TRAE-related discontinuation in 5%. One dose-limiting toxicity (hepatotoxicity in the setting of extrinsic bile duct compression) and 1 treatment-related death (grade 5 acute kidney injury in a patient who experienced an acute hemodynamic event during hemodialysis) were reported.

Based on these results, a phase 2 study (NCT07832292) of JNJ-6143 has been initiated.

“Meeting a critical unmet need in patients in clinics today across the world, this drug has activity irrespective of high-risk genomic features. Because of these results, a phase 2 study has already been initiated at 50 mg once daily dosing,” Garmezy concluded. “I believe JNJ-6143, [with] this balance of early safety and tolerability, has the potential to be a transformative therapy in prostate cancer.”

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REFERENCES

1. 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: 2026 European Society for Medical Oncology Congress. October 23-27, 2026. Madrid, Spain. Abstract 22160. https://s3.eu-central-1.amazonaws.com/m-anage.com.storage.esmo/static/esmo2026_abstracts/2216O.html.pdf

2. 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 28, 2026. https://www.jnj.com/media-center/press-releases/johnson-johnson-reports-75-tumor-response-rate-in-advanced-prostate-cancer-with-jnj-6143-a-first-in-class-riptac-molecule