Castration-Resistant Prostate Cancer Refractory to Second-Generation Androgen Receptor Axis-Targeted Agents: Opportunities and Challenges

Abstract

Second-generation androgen receptor axis-targeted (ARAT) agents, namely abiraterone and enzalutamide, enable stronger blockade of the androgen receptor (AR) axis and longer survival of men with castration-resistant prostate cancer (CRPC). However, the extent of the improved survival remains insufficient and the majority of patients eventually develop resistance to these novel agents. Some patients develop resistance against ARAT treatment through mechanisms termed “complete AR independence” or “AR indifference”, and no longer require activation of the AR axis. However, a considerable proportion of CRPC patients remain persistently dependent on AR or its downstream signaling pathways. Ligand-independent activation of the AR, an AR axis-dependent mechanism, is mediated by truncated forms of ARs that lack the ligand-binding domain (LBD), arising as products of AR splicing variants or nonsense mutations of AR. Post-translational modifications of ARs can also contribute to ligand-independent transactivation of the AR. Other mechanisms for AR axis activation are mediated by pathways that bypass the AR. Recent studies revealed that the glucocorticoid receptor can upregulate a similar transcription program to that of the AR, thus bypassing the AR. ARAT agents are essentially ineffective for CRPC driven by these AR-independent mechanisms. This review article describes recent efforts to overcome these refractory machineries for the development of next-generation AR axis blockade in CRPC.

TERF1 downregulation promotes the migration and invasion of the PC3 prostate cancer cell line as a target of miR‑155

“…Guo et al (46) reported contradictory roles of Notch signaling, where it served as a tumor-promoting role in human acute lymphoblastic leukaemia or tumor-suppressive role in basal cell carcinoma. Furthermore, studies have reported synergistic positive results in PCa cells when Notch signaling inhibitors were combined with androgen deprivation therapy (47,48).…”

Emerging Therapeutic Activity of Davallia formosana on Prostate Cancer Cells through Coordinated Blockade of Lipogenesis and Androgen Receptor Expression

“…Nevertheless, the majority of patients who take these new drugs experience transiently clinical and survival benefits. The disease eventually relapses and develops resistance to the next-generation agents [7]. Therefore, seeking alternative therapeutic approaches or finding better drugs to effectively treat this lethal progression are urgent needs.…”

PSMA ADC monotherapy in patients with progressive metastatic castration‐resistant prostate cancer following abiraterone and/or enzalutamide: Efficacy and safety in open‐label single‐arm phase 2 study

“…Although these drugs have demonstrated substantial efficacy in patients with advanced PC, 7 non-responsiveness to therapy, development of resistance after the initial response, and disease progression remain major challenges. [8][9][10][11] Similarly, treatment with docetaxel or cabazitaxel, while providing some overall survival benefit to subjects with advanced disease is not curative. 12,13 Therefore, the development of new agents and treatment strategies for CRPC remain important goals towards addressing this unmet medical need.…”

“…A new generation of hormonal therapies, such as abiraterone, enzalutamide, and apalutamide are now available for the treatment of advanced prostate cancer (PC). Although these drugs have demonstrated substantial efficacy in patients with advanced PC, non‐responsiveness to therapy, development of resistance after the initial response, and disease progression remain major challenges . Similarly, treatment with docetaxel or cabazitaxel, while providing some overall survival benefit to subjects with advanced disease is not curative .…”