TY - JOUR
T1 - Galeterone for the treatment of advanced prostate cancer
T2 - The evidence to date
AU - Bastos, Diogo A.
AU - Antonarakis, Emmanuel S.
N1 - Funding Information:
ESA has received funding from the Prostate Cancer Foundation, the Patrick C. Walsh Fund, and NIH grants R01 CA185297 and P30 CA006973.
Publisher Copyright:
© 2016 Bastos and Antonarakis.
PY - 2016/7/15
Y1 - 2016/7/15
N2 - 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.
AB - 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.
KW - AR splice variants
KW - AR-V7
KW - Castration-resistant prostate cancer
KW - Galeterone
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U2 - 10.2147/DDDT.S93941
DO - 10.2147/DDDT.S93941
M3 - Review article
C2 - 27486306
AN - SCOPUS:84978658463
VL - 10
SP - 2289
EP - 2297
JO - Drug Design, Development and Therapy
JF - Drug Design, Development and Therapy
SN - 1177-8881
ER -