POSTED: September 04, 2015

Dr. Tomasz Beer On Xtandi

Beer,Tomasz

Dr.Tomasz Beer is Professor of Medicine and Deputy Director of the Knight Cancer Institute at Oregon Health & Science University in Portland. Prostate Forum spoke with him recently about Xtandi for prostate cancer.

 

To read the entire conversation, as well as a conversation with Dr. Emmanuel Antonarakis about Xtandi resistance, download Prostate Forum 16 Number 3.

 

PROSTATE FORUM: Can explain to my readers what your role was in the development and validation of Xtandi (enzalutamide) for metastatic castration-resistant prostate cancer?

 

DR.TOMASZ BEER: I’ve been working with Xtandi from the very first studies in patients-the Phase I trial, which became a Phase I/II clinical trial. We initially joined Memorial Sloan-Kettering Cancer Center and the University of Washington in developing and carrying out that trial. I was the second author after Dr. Howard Scher of Memorial Sloan- Kettering in the Phase I/II paper that reported the results. The very first patients treated with that drug anywhere in the world were treated in New York and here in Oregon.

 

Out of that work came two Phase III clinical trials: one examined Xtandi in metastatic castration-resistant patients that had previously received chemotherapy. Dr. Scher led that trial. Then the other trial tested Xtandi in the pre- chemotherapy setting. I led that one.

 

PROSTATE FORUM: What is Xtandi’s mechanism of action?

 

DR. BEER: Xtandi is a potent blocker of the androgen receptor. Androgens are hormones, and so the signaling induced by androgens occurs through the binding of the ligand or androgen (typically dihydrotestosterone, but other androgens as well) to the androgen receptor.

When that happens, the androgen receptor is activated and moves into the nucleus of the cell, binds to specific sequences in the DNA, recruits relevant co-factors, and then regulates the expression of hundreds of genes. It affects all the things that testosterone does: libido, facial hair, etc.

 

One of the things that testosterone does is promote and develop the prostate gland, and ultimately promote the growth of prostate cancer. Xtandi binds to the androgen receptor and prevents the translocation into the nucleus, prevents the binding of the ligand, and pre- vents the recruitment of co-factors. It has several ways in which it interferes with androgen receptor action.

 

PROSTATE FORUM: On June 1, 2014 you published results in the New England Journal of Medicine showing that Xtandi can be of use in patients on ADT who hadn’t received chemotherapy yet. Can you talk a little bit about those results and what they mean?

 

This was a Phase III clinical trial with co- primary endpoints of overall survival and radiographically documented progression-free survival. These are very meaningful clinical end-points. 1,717 patients across the globe participated, so it was one of the largest studies in prostate cancer ever done-not the largest, but one of the largest. It might very well be the largest in castration-resistant disease. What we found was a significant reduction in the risk of death with a 29% reduction in risk of death and a very large reduction in the risk of dis- ease progression. There was an 81% reduction in risk of progression. The drug was able to control the disease and, as a consequence, extend overall survival.

 

Gratifyingly, we saw a clearly positive result not just through the primary measures, but also through all the secondary and exploratory end points that we used like PSA response rate, skeletal-related complications of malignancy, quality of life deterioration, and responses in measurable disease. All of those things very strongly favored Xtandi over placebo.

 

What all of this really means is that, assuming the FDA concurs, we have a new oral drug that is relatively well-tolerated that can be used in patients before chemotherapy. Xtandi is more convenient and less toxic than chemotherapy (although of course the studies did not compare it directly to chemotherapy– so this is my opinion based on the sum of all available data). It doesn’t take a rocket scientist to figure out that most people would prefer a non-chemotherapy option if it were effective and safe.

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