Heat shock protein inhibitors in the management of CRPC and mCRPC: an update

An investigational agent known as ganetespib failed to show significant clinical activity as monotherapy in a heavily pretreated cohort of men with metastatic, castration-resistant prostate cancer (mCRPC) who had received prior, docetaxel-based chemotherapy.

Thakur et al. have reported data from a Phase II clinical trial of ganetespib (a heat shock protein 90 inhibitor) sponsored by the Prostate Cancer Clinical Trials Consortium (PCCTC). Ganetespib had previously shown promising activity in preclinical and pharmacological studies.

The primary endpoint of the Phase II trial was progression-free survival at 6 months from initiation of therapy. All patients had to have mCRPC and progressed after treatment with docetaxel-based chemotherapy. Each patient was treated with ganetespib (200 mg/m2) on days 1, 8, and 15 of each 28-day cycle. Men who were able to tolerate this treatment with ganetespib were maintained on treatment until disease progression.

Here are some of the core study findings:

  • 18 men with mCRPC were recruited into the trial; all had been heavily pretreated.
  • 17/18 men were actually started on treatment.
  • 0/17 men exhibited progression-free survival at 6 months
  • 2/17 men (12 percent) exhibited progression-free survival at > 4 months.
  • The average (median) progression-free survival time was 1.9 months.
  • Frequent types of Grade 3 toxicity were dehydration, diarrhea, and fatigue.

The study was terminated after the first interim analysis, and the authors concluded that, “Ganetespib demonstrated minimal clinical activity in men with mCRPC.”

However, it can not be concluded from this study that heat shock protein inhibitors have no potential in the management of advanced forms of prostate cancer. As the authors note, this was a very heavily pretreated patent cohort, and it is possible that other heat shock protein inhibitors may have greater activity with a lower risk for side effects (when used alone or in combination with other forms of treatment).

As one example, OncoGenex is continuing to study the potential of OGX-427 (apatorsen) in the treatment of men with CRPC. Preliminary data from a Phase II trial of OGX-427 + prednisone have already been reported, and the company is currently enrolling patients into a Phase II trial of OGX-427 in men who are progressing on abiraterone acetate + prednisone (the so-called Pacific trial).

Having said that, it is also clear that heat shock protein inhibitors have not shown the levels of activity in prostate cancer that had once been hoped for.

One Response

  1. I am troubled whenever I see survival pathway inhibitors like this tested singly or sequentially. When one survival pathway is inhibited, I think the cancer will always survive via a different pathway. That implies that blocking multiple pathways simultaneously may be the only way to check the growth of the cancer. Unfortunately, drug companies too often give up on investigational agents after tests like these.

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