Men with metastatic castrate resistant prostate cancer (mCRPC) have become fortunate over the last few years as there we now have a number of new drugs available which can extend our life and can also have some palliative effects. However, as we have more treatments being approved, we find that we are faced with a significant issue, how to sequence these drugs.
The major problem causing this sequencing crisis is cross-resistance. The use of each of any of these drugs limits the use of the another drug in men who have failed the original prior therapy. This problem, cross-resistance, is not limited to any one class of these new agents but, rather involves all the approved therapies for mCRPC.
In a retrospective study of 310 men with mCRPC Cheng et al.  showed that prior abiraterone (Zytiga) or docetaxel (chemotherapy) treatment diminished the subsequent enzalutamide (Xtandi) response. This finding confirmed the findings of multiple other smaller studies. Cheng, etal. found that both PSA decline and PSA progression-free survival were both significantly diminished in the men who had already been treated with abiraterone. They also found similar results, but not as dramatic, in men with who had prior docetaxel therapy (chemotherapy) .
There were other studies that also had similar findings in men treated with docetaxel following abiraterone , . Nadal et al.  confirmed decreased efficacy of enzalutamide in docetaxel-treated (chemotherapy) men. Taxane efficacy (chemotherapy efficacy) following the AR targeted therapies (Zytiga and Xtandi) is also decreased, as demonstrated by van Soest et al. , .
This cross-resistance suggests that taxane therapy does in fact have a role in AR axis modulation, which is the basis of these new hormone regulating therapies, Zytiga and Xtandi. This cross-resistance occurs regardless of the sequencing of docetaxel and these new AR targeted therapies.
The one bright spot is that cross-resistance with AR targeted therapies and cabazitaxel (Jevtana) appears to be less significant. This is interesting, as cabazitaxel was originally developed to overcome the resistance to docetaxel therapy. Cabazitaxel was subsequently identified to have a unique mechanism of actions compared to docetaxel , which may account for why it does not have the same cross-resistance with AR targeted therapies.
Van Soest et al.  concurrently evaluated the efficacy of cabazitaxel in enzalutamide naive and enzalutamide resistant tumors in castrated mice. He found that cabazitaxel remained highly effective in enzalutamide resistant tumors, and more importantly, was much more potent than docetaxel independent of the AR pathway. Al Nakouzi et al.  confirmed similar findings in vivo and in vitro. As a result, an ongoing clinical trial is evaluating the role of cabazitaxel in chemotherapy naive mCRPC men.
Following through on these finding raises the question, should cabazitaxel also be evaluated for use prior to the AR targeted therapies as well as in chemotherapy naive men?
Our understanding of cross-resistance has emphasized the need to identify molecules that can inhibit resistance pathways and emphasized the role of combination therapy.
The CHAARTED trial, by treating men with docetaxel and ADT  demonstrated the strength of combination therapy by providing the largest survival benefit of any treatment regimen in advanced prostate cancer. Many doctors are now experimenting with the “off label” use of re-purposed drugs like metformin and clomipramine, as well as the ARV7 inhibitor niclosamide, the NTD inhibitor EPI-001, the AR degradation promoter ASC-J9, and novel agents such as SD70. There is a growing belief that their efficacy may be compounded by their use in combination with the currently approved therapies rather than as competing agents. As such, the best future direction likely lies in novel combination therapies rather than mono-therapies. It is possible that the use of combination therapies, consisting of both FDA approved and off label treatments, might overcome the resistance pathways we currently see with all of our newly approved prostate cancer treatments. Combination therapy has the significant potential to provide important clinical gains in the treatment of mCRPC.
Perhaps understanding the potential of combination therapy will be our next big advancement in the treatment of mCRPC.
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