As cancer treatment continues to get more targeted, the search for reliable biomarkers to identify patients most likely to benefit from this novel and expensive therapy is essential. The driving role of the androgen receptor in prostate cancer is well established.
Androgen dependent prostate cancer growth requires first the binding of the androgen to the androgen receptor and then the nuclear translocation of the complex and subsequent binding to DNA. 1 Methods of inhibition have centered on decreasing the production of androgens and preventing the binding of the androgen to the androgen receptor.
Antiandrogens, such as bicalutamide, inhibit androgen-receptor binding through competitive blockade of the androgen receptor. Abiraterone was FDA approved after an expedited 6-month review in 2011 and inhibits cytochrome P450 (CYP17), which is an enzyme required for the synthesis of testicular and extragonadal androgens. This ultimately results in decreasing the amount of available androgens. The drug is currently FDA approved, in combination with prednisone, for metastatic, castration-resistant prostate cancer.
Enzalutamide, a bicalutamide analog, was FDA approved in August 2012 and works by competitively binding to the androgen receptor to prevent binding of androgens. The drug also inhibits the nuclear translocation and interaction of the androgen receptor with DNA. Like abiraterone, enzalutamide is also FDA approved for metastatic, castration-resistant prostate cancer.
Though both abiraterone and enzalutamide have resulted in significant increases in overall survival, approximately 20% to 40% of patients do not respond to either agent. The androgen-receptor splice variant 7 (AR-V7) encodes a truncated androgen receptor that retains the transactivating N-terminal domain, but lacks the ligand-binding domain. This altered variant does not require ligand binding, but is constituently active ultimately promoting transcription and activation of target androgen receptor genes.2 Based on biologic principle, presence of this AR-V7 variant would suggest resistance to agents like abiraterone and enzalutamide. This was assessed in the clinical trial by Dr. Emmanuel Antonarakis, MD, and colleagues, in the September 2014 edition of the New England Journal of Medicine.2
Patients with metastatic castration-resistant prostate cancer initiating therapy with either abiraterone or enzalutamide were enrolled, and circulating tumor cells were assessed for the full-length and AR-V7 androgen receptor variants. Of the 31 patients treated with enzalutamide, 39% had the AR-V7 variant. Of the 31 patients treated with abiraterone, 19% had the AR-V7 variant (total of 18 patients from both groups). The primary endpoint was the proportion of patients with a prostate specific antigen (PSA) response, defined as a decrease of > 50% from baseline and maintained for > 4 weeks (see data table above).
It is notable that presence of the AR-V7 variant resulted in a 0% PSA response rate for both agents, demonstrating 100% specificity along with inferior survival outcomes. This is similar to the original findings correlating presence of a KRAS mutation in metastatic colorectal cancer and the lack of response from the EGFR-direct antibodies cetuximab and panitumumab.3
When results such as this are seen, there is a strong desire to directly translate this into the clinic. However, one must apply the brakes to the enthusiasm, at least temporarily. Larger trials that are already ongoing are needed to replicate these results. Additionally, a reliable, validated commercially available assay to assess the variant in circulating tumor cells--or another method such as tumor sequencing--will be required. Future research will also be needed to determine alternative therapies for patients with the AR-V7 variant. These may include standard chemotherapeutic agents like docetaxel or cabazitaxel, commonly used in prostate cancer, or novel mechanisms like the treatment vaccine sipuleucel-T. Regardless, the expense of all the agents mentioned underscores the importance of trials such as this to optimize the use of targeted agents for patients. These types of trials will be essential as we continue to translate personalized medicine into standard clinical practice.