Dr Garmezy on JNJ-6143's Novel Mechanism in Advanced Prostate Cancer

This is part 2 of a 2-part interview. Watch part 1 here.

Benjamin Garmezy, MD, associate director of Genitourinary Cancer Research at Sarah Cannon Research Institute, discusses the novel mechanism of action of JNJ-6143, an investigational oral therapy being evaluated in advanced prostate cancer. In this interview with Targeted Onc^TM, he explains how the first-in-class regulated induced proximity targeting chimera (RIPTAC) molecule brings together androgen receptor (AR) and BRD4 to disrupt cancer cell survival.

The discussion focuses on how JNJ-6143's dual-protein targeting mechanism may offer a different approach to treating advanced prostate cancer, particularly in patients with genomic alterations associated with treatment resistance.

Garmezy explains that JNJ-6143 forms a ternary complex by binding to AR, a tumor-specific antigen, and BRD4, a protein essential for cell survival. Through this interaction, the molecule effectively locks the 2 proteins together, preventing BRD4 from performing its normal functions within the cell. This disruption ultimately leads to cancer cell death.

“If you prevent BRD4 from doing its function within the cell, the cell dies,” Garmezy says.

He highlights the potential significance of this mechanism given the activity observed across several high-risk genomic alterations in heavily pretreated patients. These include BRCA1/2, TP53, and PTEN alterations, RB loss, AR ligand-binding domain mutations, and AR-V7 expression. Garmezy suggests that JNJ-6143's novel mechanism of action may help explain why activity has been observed despite the presence of these alterations, which can contribute to treatment resistance.

Garmezy also discusses the encouraging early balance of safety and efficacy observed with JNJ-6143 in phase 1 testing. Although he describes the findings as exciting, he emphasizes that the results remain preliminary and must be evaluated in later-phase clinical trials, given the small number of patients studied.

Beyond its potential role in advanced prostate cancer, Garmezy highlights the broader implications of RIPTAC technology. Because the approach uses targeted protein interactions to disrupt essential cellular functions, he believes it could have applications across other solid tumors.

He emphasizes the importance of continued investigation to determine how this novel platform could advance cancer treatment and potentially expand therapeutic options across oncology.