Clinical Summary: 

• Benjamin Garmazy, MD, discusses results from a phase 1 study evaluating JNJ-6143, a first-in-class oral androgen receptor-targeted regulated induced proximity targeting chimera (RIPTAC), in heavily pretreated patients with metastatic castration-resistant prostate cancer, including those with high-risk molecular alterations.

• At the preliminary optimal dose of 50 mg daily, JNJ-6143 demonstrated confirmed PSA50 and PSA90 response rates of 71% and 41%, respectively, with partial responses observed in patients with measurable disease and activity across high-risk genomic subgroups.

• These findings support continued development of JNJ-6143 as a novel therapeutic strategy for metastatic castration-resistant prostate cancer, with encouraging preliminary efficacy and tolerability, although larger studies and longer follow-up are needed to establish its clinical benefit.

Benjamin Garmazy, MD, Sarah Cannon Research Institute, Nashville, Tennessee, discusses results from a phase 1 study evaluating JNJ-6143, a first-in-class oral androgen receptor–targeted RIPTAC, in patients with heavily pretreated metastatic castration-resistant prostate cancer. 

Dr Garmazy reviews the novel mechanism of action of JNJ-6143, which induces cancer cell death by bringing androgen receptor and BRD4 proteins together, along with encouraging PSA responses and antitumor activity across high-risk molecular subgroups. He also discusses the preliminary safety profile, dose optimization findings, and ongoing clinical development of this novel therapeutic approach.

Transcript: 

Hello. My name is Benjamin Garmezy. I'm a GU medical oncologist at Sarah Cannon Research Institute in Nashville, Tennessee.

Today, I'm going to be talking more about my ESMO presentation, which was on a new therapy, JNJ-6143. This is a first-in-class, completely novel mechanism of action. It's an oral androgen receptor-targeted Regulated Induced Proximity Targeting Chimera (RIPTAC) molecule in patients with metastatic castration-resistant prostate cancer, or nowadays also known as metastatic APMR.

And we also not only talked about the efficacy, but we included a focus on the fact that these patients also had high-risk molecular features.

So to understand how this new drug works, you have to understand that it's different. So this forms a targeted dual-protein lock. So it's an oral small molecule, and it forms a targeted dual-protein lock by binding to a tumor-specific antigen, in this case, the androgen receptor, and then binding to a protein essential for cell survival, in this case, BRD4. BRD4 is important for transcription within the cell.

And basically, when you lock BRD4 and AR together, forming this ternary complex between AR, JNJ-6143, and BRD4, you induce essentially apoptosis within the cancer cell, leading to cell death.

You know, the study was a phase 1 study, traditional dose escalation with backfill. We looked at ranges from 12.5 mg orally daily to 150 mg orally daily, and then did dose optimization and expansion at 25 and 50 mg.

The eligibility criteria included patients with mCRPC, had to have a rising PSA, had to have seen a prior androgen receptor pathway inhibitor. Many had seen prior taxanes and radioligands as well, so it was a very heavily pretreated population.

The primary objective was safety and tolerability, and then we also looked at pharmacokinetic, pharmacodynamic, and efficacy data as well.

And the recommended phase 2 dose was 50 mg orally once daily. So for the rest of this conversation, we'll just be talking about that dose, the 50-mg dose.

Overall, when you look at the patient population, there were 105 patients. Many of them had seen many prior lines of therapy. The median was four prior lines of systemic therapy.

When you look at the 50-mg dose more closely, 54% had seen prior taxane and 46% had seen prior radioligand. In fact, 32% had seen both. And then some additional patients had seen PARP inhibitors.

Many patients also had visceral disease. About 29% of patients had visceral disease, showing a high-risk population.

And when you look at the safety profile, the safety profile was very clean at the 50-mg dose. There were, in fact, no treatment-related adverse events that were grade 3 or greater. So everything was low-grade that was related to JNJ-6143.

Only one patient actually had to stop therapy in this cohort related to an adverse event. But that was actually after intrapatient dose escalation from 50 to 100 mg, was related to nausea. So actually, it doesn't really fully apply to the 50-mg dosing cohort.

And if you look at the time of the cutoff, which was in September of 2026, at the 50-mg dose, 71% of patients were still ongoing. That was a median follow-up time of 5.6 months. So some maturity left to go. But overall, many patients remained on therapy.

And what I think is really nice is we showed that PSA responses were quite high. We had a PSA50 response rate of 77% and a PSA90 response rate of 48% in patients at the 50-mg dose.

And then what we also showed is that these responses were irrespective of high-risk molecular features. So if you look at AR amplifications, AR ligand-binding domain mutations, TP53, PTEN, RB1, and BRCA1 or 2 alterations, you saw similar PSA50 rates across all of those different high-risk genomic features.

So there was no single molecular subset that explained the efficacy or resistance to the therapy.

And what was also really nice is the durability was there as well. You know, in patients with measurable soft tissue lesions, so RECIST-evaluable criteria, we found a confirmed overall response rate of 69% at the time of the data cutoff, but it's now as high as 75%, with a median duration of response of 11 months. So really, really impressive, with a disease control rate of 88%.

So this is a phase 1 drug, JNJ-6143, with a completely new mechanism of action that forms the targeted dual-protein lock between AR and BRD4.

And what we showed is a really impressive efficacy rate and a really impressive tolerability and safety profile, with no treatment-related adverse events that were high-grade.

Any-grade treatment-related adverse events were less than 60%. Those included some GI side effects. The most common adverse events were hypertriglyceridemia, nausea, decreased appetite, fatigue, hypercholesterolemia, anemia, increased AST. Acute kidney injury was actually not seen, sorry, increased AST. There was an acute kidney injury at a higher dose, but the 50-mg dose, it was incredibly clean.

So you had a really nice balance of efficacy and tolerability. And in my impression, my personal opinion, this should quickly launch into, you know, a regulatory strategy. It's just such a, such a clean, nice molecule.

Phase 2 is already ongoing at the 50-mg once-daily dose. And we look forward to seeing how this new molecule, JNJ-6143, can help patients.

Source: 

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 ESMO Congress. October 23-27, 2026; Madrid, Spain. Abstract 2216O.