BET inhibition in treatment of mCRPC

A company called Zenith Epigenetics has recently reported data from a Phase I/II clinical trial of a drug known as ZEN003604 or ZEN-3694 in the treatment of men with metastatic, castration-resistant prostate cancer (mCRPC) who have progressed on treatment with either abiraterone + prednisone or enzlautamide (Xtandi).

ZEN-3694 is a type of product known as a BET inhibitor. This relatively new class of drugs appear to be able to make it more likely that at least some men with advanced prostate cancer may be able to respond better to treatment with drugs like enzalutamide.

Preliminary data from the above-mentioned Phase Ib/IIa trial were reported by Aggarwal et al. in Clinical Cancer Research and also noted in The ASCO Post (for those who can read that publication). Basically, this trial enrolled 75 men who had progressive mCRPC after treatment with either abiraterone acetate + prednisone or enzalutamide and then treated these patients with ZEN-3694 + enzalutamide.

Among these 75 patients:

  • Patients who were in high-risk subgroups, including those with more aggressive disease with lower androgen receptor activity in their tumors, seemed to show particular benefit from this form of treatment, but
  • 14 patients (19 percent) reported severe adverse reactions, including three patients (4 percent) who developed thrombocytopenia.

It is important to note that the same group of authors have also shown that there is a particular genetic profile associated with relatively low levels of androgen receptor activity that seems to contribute to early resistance to drugs like abiraterone and enzalutamide in about 30 percent of men with advanced prostate cancer.

According to one of the senior authors of the paper by Aggarwal et al.

That subset of patients with front-line resistance to enzalutamide or abiraterone and low androgen receptor activity are the ones who appeared to respond best to ZEN-3694 — suggesting a promising treatment approach for this group of patients whose cancers behave quite poorly with currently approved treatments.

What we assume is that Zenith Epigenetics and its advisors are probably trying to develop a new trial (perhaps a randomized Phase II/III trial) of ZEN-3694 + enzalutamide in patients with mCRPC who exhibit this particular genetic profile, in the hope that such patients will be able to demonstrate a relatively high level of response to combination therapy with ZEN-3694 + enzalutamide as opposed to enzalutamide alone. In the meantime, the company will soon be running another trial of ZEN-3694 + enzalutamide in combination with pembrolizumab (Keytruda) — again in patients with mCRPC.

Obviously the potential development of another new type of drug for the treatment of specific subsets of men with advanced forms of prostate cancer shows continuing progress in the attempt to extend survival for some of the most severely affected patients with this disease.

3 Responses

  1. My question is around “low levels of anrogen receptor activity”. Is this related to high or low expresssion of ARs, or is it about how actively they function? How is the level of AR activity measured? How would a man know if he is high or low?

  2. Rick: Since I can’t see the full text of the original article, you’ll have to take those questions up with the authors of the paper.

  3. I also asked Len …. He deduces that somehow the MYC mutation can indicate the level of activity. That’s about as far as I have gotten other than to recoginize it is highly technical and well above my paygrade.

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