NEW ORLEANS, LA USA (UroToday.com) - Mechanisms of castration resistance in prostate cancer include mutation of AR resulting in ligand promiscuity, altered regulation of AR, glucocorticoid crosstalk, AR splice variants, and AR-independent mechanisms. Emmanuel Antonarakis discussed recent findings from his lab demonstrating that abiraterone and enzalutamide response can be predicted by detecting splice variants in AR in patient samples. Full length AR (FL-AR) has 8 exons translating an N-terminal domain, DNA binding domain, hinge, and ligand binding domain. When the last 1-3 exons are lost (AR-V7), the ligand-binding domain is absent, and therefore regulation by androgen is lost. However, the DNA-binding and transactivating domains are still translated, enabling AR to continue to regulate genes in the absence of androgen in a constitutively active manner. Using RTqPCR, his lab was able to identify truncated AR-V7 in circulating tumor cells from patient serum samples. This can segregate patients into FL-AR and AR-V7 groups.
When stratifying patients, by response, in a pilot trial at Johns Hopkins, patients with truncated AR had a much lower progression-free and overall survival with a 4-fold higher risk of death in AR-V7 patients for enzalutamide and 10-fold higher risk of death in patients treated with abiraterone. He then described emerging data that microtubules interact with AR, suggesting that taxane-based therapy may have utility in patients with alternative AR transcripts. He showed that the PSA response rate after docetaxel therapy in a pilot trial was 65% for FL-AR patients and 41% for AR-V7 patients. AR-V7 patients had an inferior PFS but this was not significant. This suggests that ARV7 doesn’t associate with response to taxanes like it does to AR-targeted therapies. Of critical importance, AR-V7 patients treated with taxane-based therapy had better PFS than patients treated with AR-targeting therapy, but FL-AR patients had equivalent PFS when treated with taxanes or abiraterone/enzalutamide. This suggests that docetaxel-based therapy will have efficacy in patients with AR-V7 when abiraterone/enzalutamide do not. It also reinforces the idea that dual therapy may overcome, or preclude, resistance mechanisms.
He closed by intimating that AR-V7 itself might be a therapeutic target. Several AR-V7-targeting drugs are in development. Galeterone biochemically behaves like both abiraterone (inhbiting CYP17) and enzalutamide (by binding with high affinity to AR), and also induces degradation of AR. EPI-506 is the first drug to target the AR N-terminal domain which would extinguish all AR activity (even FL-AR activity). Lastly, BET inhibitors like GS5829 and GSK525762 act through epigenetic mechanisms. He closed by describing an AR-V7 biomarker-driven trial which will only enroll patients with truncated AR for randomization to enzalutamide or galeterone.
Presented by Emmanuel Antonarakis at the American Urological Association (AUA) Annual Meeting - May 15 - 19, 2015 - New Orleans, LA USA
Johns Hopkins Medicine, Baltimore, MD USA
Reported by Phillip Abbosh, MD, PhD, medical writer for UroToday.com