The next-generation antiandrogen drugs, XTANDI (enzalutamide), ZYTIGA 
(abiraterone acetate), ERLEADA (apalutamide) and NUBEQA (darolutamide) extend 
survival times and improve quality of life in patients with advanced prostate 
cancer. Despite these advances, resistance occurs frequently and there is 
currently no definitive cure for castration-resistant prostate cancer. Our 
previous studies identified that similar mechanisms of resistance to 
enzalutamide or abiraterone occur following treatment and cross-resistance 
exists between these therapies in advanced prostate cancer. Here, we show that 
enzalutamide- and abiraterone-resistant prostate cancer cells are further 
cross-resistant to apalutamide and darolutamide. Mechanistically, we have 
determined that the AKR1C3/AR-V7 axis confers this cross-resistance. Knockdown 
of AR-V7 in enzalutamide-resistant cells resensitize cells to apalutamide and 
darolutamide treatment. Furthermore, targeting AKR1C3 resensitizes resistant 
cells to apalutamide and darolutamide treatment through AR-V7 inhibition. 
Chronic apalutamide treatment in C4-2B cells activates the steroid hormone 
biosynthesis pathway and increases AKR1C3 expression, which confers resistance 
to enzalutamide, abiraterone, and darolutamide. In conclusion, our results 
suggest that apalutamide and darolutamide share similar resistant mechanisms 
with enzalutamide and abiraterone. The AKR1C3/AR-V7 complex confers 
cross-resistance to second-generation androgen receptor-targeted therapies in 
advanced prostate cancer.