New Phase 2 trial for JNJ-101556143 aka HLD-0915 in mCRPC / mAPMR Prostate Cancer

A new phase 2 trial will test JNJ-101556143, also known as HLD-0915, in men with metastatic prostate cancer that has become resistant to androgen-pathway treatment. The study plans to enrol about 100 patients and will evaluate whether the drug can produce objective tumour responses, making this a clear step beyond the earlier dose-finding programme.

JNJ-101556143 is the first clinical example of a new drug class known as a RIPTAC, or Regulated Induced Proximity Targeting Chimera. Rather than trying to block the androgen receptor in the usual way, it uses the receptor as a tumour-selective anchor. The molecule binds full-length androgen receptor on one side and BRD4 on the other, forcing the two proteins into an abnormal complex. This interferes with BRD4, a protein essential for cell survival, and can trigger death of the prostate cancer cell.

The concept is particularly attractive in treatment-resistant prostate cancer. Even after drugs such as enzalutamide, apalutamide or abiraterone stop working, many prostate cancers continue to express large amounts of androgen receptor. A RIPTAC does not require AR signalling itself to remain vulnerable to inhibition: it simply uses the continued presence of full-length AR as a handle to bring BRD4 into a lethal interaction. In theory, some of the adaptations that allow prostate cancer to survive conventional AR blockade could therefore become a weakness rather than an advantage.

Preclinical studies supported this idea, showing tumour shrinkage and PSA reductions in mouse models of castration-resistant prostate cancer, including models resistant to androgen-receptor pathway inhibitors. The drug is orally administered and was designed to selectively exploit AR-rich prostate cancer cells while limiting effects on cells with little or no AR expression.

Importantly, there are now also preliminary human data from an ongoing phase 1/2 study.  Among the first 31 heavily pretreated men with mCRPC, 13 patients (42%) achieved a PSA50 response and 7 (23%) achieved PSA90. Among the 22 patients who completed at least two treatment cycles, PSA50 rose to 59% and PSA90 to 32%. All five patients with measurable disease by RECIST reportedly achieved partial responses. Only three treatment-related grade 3 adverse events were reported, all reversible. These results are encouraging but remain early, with a small number of patients and limited follow-up.

The new phase 2 trial will now ask a more direct efficacy question. JNJ-101556143 will be given orally once daily, and the primary endpoint is confirmed objective response rate, assessed independently using RECIST 1.1. Secondary measures include duration of response, radiographic progression-free survival and time to symptomatic progression.

Source.

Clinical trial 1.

Clinical trial 2.