I don’t understand why if I have hormone resistant advanced prostate cancer why the new drugs, Zytiga and Xtandi work. These drugs are still hormone therapies, is my prostate cancer hormone resistant? I recently received an email asking me this question and I thought it might be a question many people have, so I am going to answer this on the blog.

First, I want to be clear, yes Zytiga and Xtandi are both hormonal therapies that do work for many men when their cancer has been classified as hormone resistant.

The failure of Lupron etc. and Casodex does not mean that our cancer no longer is dependent upon testosterone. What it really means is that our cancer now has adapted itself and become more sensitive to lower levels of testosterone and is able to find alternative sources of testosterone. Simply put, the Lupron and Casodex are no longer powerful enough to do the job.

This change is the result of three different mechanisms. We have now found out that prostate cancer cells themselves are capable of making their own testosterone, making them independent of outside sources; the cancer cells often are able to modify their androgen receptor so that Casodex encourages the cancer growth by treating the drug as if it were testosterone. (This is why in many men stopping Casodex will initiate a positive response) and the androgen receptor becomes more sensitive so that it needs much lower levels of testosterone to continue growing.

To be accurate it is quite uncommon for prostate cancer to become androgen independent. This understanding of the progression of prostate has led us to the new forms of hormone therapy using Zytiga and Xtandi

Zytiga (given along with prednisone) was the first FDA-approved drug to respond to this understanding. Zytiga ‘s mechanism of operation is simple, it is much more efficient at blocking testosterone production then Lupron. Its most important difference is that it blocks testosterone production throughout the body; including the adrenal glands and the cancer cell itself. Zytiga is more efficient at lowering the levels of testosterone production in the entire body (not just from the testis).

The other new hormone therapy drug is known as Xtandi and it has a different mechanism of action from Zytiga and the other hormone therapy drugs. Xtandi has been called a “Super Casodex” because like Casodex, it binds to the androgen receptor, however Xtandi is five fold better at competing with testosterone for the androgen receptor than is Casodex. Xtandi uses different pathways that are used by Lupron and Casodex and is able to work even while Lupron and Casodex have failed.

The bottom line is that it is a misnomer to call prostate cancer that has begun to progress in the face of Lupron (etc.) and Casodex hormone resistant. In fact prostate cancer at this stage is still dependent on the androgens, but the cancer has actually developed additional pathways around these first stage treatments so that it can continue to progress. Zytiga and Xtandi respond to these new pathways, but they too only respond for a limited time as this cancer is able to develop even more new pathways.

Joel T. Nowak, M.A., M.S.W.