New paper below. Note that the link is to the full text & some will want to read that.
Resistance to Enzalutamide (Xtandi) and Abiraterone (Zytiga) is often associated with the emergence of, & selection for, the androgen receptor splice variant AR-V7. This is a functional receptor that has no need of an androgen ligand.
"The clinical importance of AR-V7 in the setting of treatment with AR-directed agents was demonstrated in a recent pilot study of patients with mCRPC treated with abiraterone or enzalutamide. In this prospective study, AR-V7 status was determined ... in 62 patients and was associated with clinical outcomes for abiraterone (n=31) or enzalutamide (n=31). In both cohorts, the rate of PSA decline ≥50% (PSA50) was high in the AR-V7 negative patients (52.6% and 68% for enzalutamide and abiraterone, respectively), but no AR-V7-positive patients achieved a PSA50 response."
"Moreover, in both cohorts, the AR-V7-negative group demonstrated a significantly higher disease-free survival and" overall survival.
Galeterone may be the answer. (Although, like the next Microsoft security fix, the next drug is never the complete answer. IMO. "Despite the many advances achieved thus far in the understanding of the biology of mCRPC, it is clear that with more active AR-directed drugs the complexity of the mechanisms of resistance and progression is increasing, and novel approaches are needed to improve patient outcomes.") But it's an important drug.
"In order to evaluate galeterone’s efficacy for AR-V7 positive patients, the first biomarker-driven Phase III randomized trial in mCRPC (Figure 2; ARMOR3-SV, NCT02438007) has been launched and will compare the efficacy of galeterone against enzalutamide in mCRPC patients harboring AR-V7, and hopefully will demonstrate activity in this refractory patient population. Meanwhile, additional Phase II trials are being planned using galeterone in the post-abiraterone and post-enzalutamide populations. Finally, if galeterone is truly capable of targeting and degrading AR-V7 and other splice variants, it remains possible that this agent may theoretically sensitize (or even re-sensitize) CRPC patients to treatment with abiraterone and enzalutamide, although this hypothesis remains to be tested."
Drug Des Devel Ther. 2016 Jul 15;10:2289-97. doi: 10.2147/DDDT.S93941. eCollection 2016.
Galeterone for the treatment of advanced prostate cancer: the evidence to date.
Bastos DA1, Antonarakis ES2.
Major advances have been achieved recently in the treatment of metastatic castration-resistant prostate cancer, resulting in significant improvements in quality of life and survival with the use of several new agents, including the next-generation androgen receptor (AR)-targeted drugs abiraterone and enzalutamide. However, virtually all patients will eventually progress on these therapies and most will ultimately die of treatment-refractory metastatic disease. Recently, several mechanisms of resistance to AR-directed therapies have been uncovered, including the AR splice variant 7 (AR-V7), which is a ligand-independent constitutionally-active form of the AR that has been associated with poor outcomes to abiraterone and enzalutamide. Galeterone, a potent anti-androgen with three modes of action (CYP17 lyase inhibition, AR antagonism, and AR degradation), is a novel agent under clinical development that could potentially target both full-length AR and aberrant AR, including AR-V7. In this manuscript, we will first discuss the biological mechanisms of action of galeterone and then review the safety and efficacy data from Phase I and II clinical studies of galeterone in patients with metastatic castration-resistant prostate cancer. A Phase III study of galeterone (compared against enzalutamide) in AR-V7-positive patients is currently underway, and represents the first pivotal trial using a biomarker-selection design in this disease.
AR splice variants; AR-V7; castration-resistant prostate cancer; galeterone
PMID: 27486306 DOI: 10.2147/DDDT.S93941
[PubMed - in process] Free full text