Xtandi

Here’s an article about Xtandi that I wrote for Prostate Forum Volume 14 Number 5, which was published in Fall 2012.

***

“…we will be discussing a drug that represents a major advance in prostate cancer: Xtandi. First, we need to clarify confusion over the naming of this drug. While the brand name is Xtandi, until recently it was known as MDV3100. It also has a generic name, enzalutamide.

Xtandi is now FDA-approved for use after Docetaxel (taxotere). As such, it competes with Zytiga, Provenge, and Jevtana. This poses an interesting question: which drug would you pick first? We will address this by first telling you about Xtandi and then comparing this drug with its competitors.

While it is approved for use after chemotherapy, Xtandi is a form of hormonal therapy. It works by disrupting the function of the androgen receptor through which testosterone and dihydrotestosterone exert their effects on prostate cancer. This drug works after chemotherapy fails because even at that stage between 80-90% of cancers are still dependent on the androgen receptor. The discovery of this fact is revolutionizing prostate cancer treatment. When drugs like Lupron and Casodex have failed, the cancer is not in fact hormone resistant. In fact, the cancer has adapted by becoming even more sensitive to testosterone. This cancer can change to grow at testosterone levels 1/100 to 1/1,000 of that found in a normal adult male. Lupron and Casodex fail because they are not powerful enough. Prostate cancer accomplishes this by several different mechanisms. Prostate cancer cells can make their own testosterone, making them independent of outside sources. The cells can increase the amount of androgen receptor so that it traps enough testosterone to continue to grow, like using a larger sail in a light wind. The cancer cells can also change the androgen receptor so that it treats Casodex or Eulexin as if it were testosterone, so that drugs that are used to block testosterone now act as if they were testosterone! This is why some patients respond when Casodex is stopped. Finally, the androgen receptor can be altered so that it is activated with little or no testosterone. The end result of all of this research is that we now know that it is quite uncommon for prostate cancer to become androgen independent. This led to a blossoming in research to find drugs able to restore hormone-responsiveness in men with advanced prostate cancer.

Zytiga was the first FDA-approved drug to address this problem. Zytiga works by being much more efficient at blocking testosterone production. Furthermore, it blocks testosterone production throughout the body. After Lupron or competing drugs have been administered, testosterone levels are commonly 20-30 ng/dL. Where does the remaining testosterone come from? The adrenal gland is one site. However, there are others. For example, skin can produce testosterone. Even muscle has the capacity to produce testosterone and it does so after intense resistance exercise. However, for our purposes, the most worrisome site is the cancer cell itself. A significant proportion of the cancers progressing on standard hormonal therapy do so at least in part because they are making their own testosterone! Zytiga shuts down testosterone production from all of these other sites. Zytiga only works for a while before the cancer cells again start to grow. While it is still early, I can say that androgen receptor is still present at this point, so true hormone independence still is not common.

Xtandi has an entirely different mechanism of action. Like Casodex, it binds to the androgen receptor and excludes testosterone in the process. Xtandi is five fold better at competing with testosterone for the androgen receptor. After the androgen receptor binds to testosterone, the receptor then binds to DNA and turns on genes that control cancer growth and spread. Xtandi also blocks this process, but Casodex does not. The end result is that Xtandi overcomes a number of the most important pathways prostate cancer uses to grow in the face of Lupron alone or in combination with Casodex.
While the mechanism of action discussion is interesting, how well did the drug work out in the clinic? In a group of post chemotherapy patients, the median survival in the placebo group was 13.6 months compared with 18.4 months in the group receiving Xtandi. This result has caused a bit of excitement, as is a greater survival prolongation than seen with Provenge, Zytiga or Jevtana. I would just caution that that kind of comparison between studies is questionable at best.

In addition to the survival information, Xtandi showed itself to be very well tolerated. Overall side effect incidence was similar to placebo. In fact, the drug appears to be better tolerated than Casodex. Additionally, the drug appears to be safe in patients with mild to moderate liver injury and renal damage. Unlike Zytiga, it can be taken with or without food. While Zytiga interacts adversely with two liver pathways used by many other cancer drugs as well as those for heart disease, Xtandi’s drug interactions are much easier to handle. Xtandi’s major interaction is with CYP2C8 inhibitors. Lopid (gemfibrozil), a cholesterol-lowering drug, is the major problem, but there are many other options. The antibiotic trimethoprim is also a potential problem. Among the supplements, quercetin might also present a problem. However, it looks as if Xtandi has no major interactions with the other drugs used to treat prostate cancer. This makes it a natural to test in combination with Zytiga, Docetaxel, Jevtana, or Provenge. In fact, trials of these combinations appear to be either ongoing or in discussion.

If I had to pick one agent to use post Docetaxel, Xtandi would be my first choice. It is much safer and easier to use than is Zytiga or Jevtana. The clinical trial information make it look at least as active as each of the two other agents. Provenge is difficult because it is so very expensive and patients commonly progress during and after treatment. It is increasingly difficult for me to justify depriving patients of agents like Zytiga or Xtandi so that Provenge can be administered. Fortunately, it appears as if Dendreon is seriously investigating combinations of Provenge with other agents.
For me, the real question is how rapidly we can get this drug approved for use before chemotherapy. As it looks to be safer and likely much more active than then Casodex, I would really like to use this as part of initial hormonal therapy. This is timely because we face a health care disaster of major magnitude because of the end of prostate cancer screening. We are about to face a dramatic increase in the number of men diagnosed with advanced disease who could have been diagnosed via screening and cured with surgery or radiation therapy. We will need new tools like Xtandi.

Drug Naming Conventions

I want to end with a short note on a related topic. The various drug names are quite confusing to patients. I recently had a patient ask me to compare the advantages of MDV3100 with Xtandi. Patient confusion is also compounded by the fact that many physicians insist on using generic as a vaguely anti-pharmaceutical industry stance. Unfortunately, generic names are increasingly difficult to pronounce. My favorite example of this is ipilimumab, a new drug for melanoma. Certainly does not role off the tongue easily, does it? In many ways, focusing on the generic name is a bit of pseudo-sophistication as it is just as much a made up name as the brand name. So, the “real” chemical name for Xtandi is 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluoro-N-methylbenzamide. If you really want to stick it to the pharmaceutical industry, call the drug by its chemical name!

Copyright September 2012  Rivanna Health Publications, Inc.  All rights reserved.


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