Some of my posts over the last week or two have discussed the issue of the development of cross-resistance of two of our newest treatments for advanced prostate cancer.  These drugs are abiraterone (Zytiga) and enzalutamide (Xtandi).

Currently, both of them are approved for use after a man has failed chemotherapy with docetaxel. In addition, abiraterone is also approved for use prior to chemotherapy. This means if one were to strictly follow the FDA label we would all be receiving abiraterone, docetaxel and then enzalutamide.

One of the great concerns we have is whether or not taking one of these drugs before the other will dissipate the efficacy of the second drug.  In this case, will takings abiraterone cause the enzalutamide not be as effective?  The answer is very possibly!

Enzalutamide improves overall survival (OS) in men with metastatic castrate resistant prostate cancer (mCRPC) both before and after docetaxel treatment. In reality we know very little about the optimal sequencing of these drugs and the possible cross-resistance that could develop.

Being concerned about this issue a study was conducted of the biochemical response and OS after enzalutamide treatment in post-chemo mCRPC patients following progression on post-chemo abiraterone treatment.

Study involved twenty-four post-chemotherapy and post-abiraterone mCRPC men with progressive disease.   They received enzalutamide 160 mg/daily in a Danish compassionate-use program sponsored by Astellas Pharma A/S.

They found that with a minimum follow-up of three months the best median PSA response was -22% (-76% to 76%). Forty-six percent of men had a greater than 30% decrease in PSA.

The PSA response to enzalutamide did not correlate to the number of prior cancer treatments (p = 0.57), time from diagnosis to CRPC (p = 0.11), or prior response to docetaxel (p = 0.67). However, eight men treated with second line cabazitaxel (Jevtana) had an inferior PSA response to enzalutamide (p = 0.03), and there was a trend for the PSA response to abiraterone to correlate with the PSA response to the succeeding enzalutamide (B = 0.22, p = 0.05).

The best median alkaline phosphatase response was 0.1% (-67% to 126%). Median OS was 4.8 months.

They concluded that men who have been pre-treated with chemotherapy and abiraterone when then treated with enzalutamide showed less biochemical response to therapy compared to the results from the AFFIRM study where post-chemo abiraterone was not used. The question remains whether this is an effect of cross-resistance or a result of the natural history of the disease needs further elaboration.

Soon, we have every good reason to expect that enzalutamide will also be approved in the pre-chemo setting, so sorting out this issue will become even more germane for our proper care.


J Clin Oncol 32, 2014 (suppl 4; abstr 202):  M. Andreas Roeder, Frederik Birkebæk Thomsen, Klaus Brasso, Per Rathenborg, Michael Borre, Peter Iversen;

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