Galeterone for the treatment of advanced prostate cancer: the evidence to date

Abstract

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.

Keywords: AR splice variants; AR-V7; castration-resistant prostate cancer; galeterone.

Figure 1

Three mechanisms of action of galeterone. Notes: This figure highlights the androgen receptor (AR) activation axis, with conversion of testosterone to dihydrotestosterone (DHT) by the 5α-reductase enzyme, and subsequent AR activation, dimerization, nuclear translocation and activation of transcriptional activation of target genes. The figure also demonstrates potential mechanisms of resistance to AR therapies, including the development of AR splice variants (AR-V) and AR mutations. Finally, it highlights galeterone’s mechanisms of action in each of these AR signaling pathways implicated in resistance to novel androgen/AR-directed therapies: 1) CYP lyase inhibition; 2) AR antagonism to both full-length and mutant AR; and 3) degradation of the AR, including AR splice variants. Abbreviation: Enz, enzalutamide.

Figure 2

ARMOR3-SV: Phase III randomized trial design and study endpoints. Note: Data from Taplin et al. Abbreviations: CRPC, castration-resistant prostate cancer; AR-V7, androgen receptor splice variant 7.