The antiandrogen therapeutics apalutamide and darolutamide entered the clinic in 
2018 and 2019, respectively, for the treatment of castration-resistant prostate 
cancer (CRPC). Increased expression of the enzyme aldo-keto reductase 1C3 
(AKR1C3) is phenotypic of CRPC. The enzyme acts to circumvent castration by 
producing potent androgens that drive proliferation. Furthermore, AKR1C3 
mediates chemotherapeutic resistance to the standard of care, enzalutamide, a 
structural analogue of apalutamide. Resistance develops in almost all CRPC 
patients within three months of beginning treatment. Herein, we report that both 
apalutamide and the structurally distinct darolutamide induce AKR1C3 expression 
in in vitro models of prostate cancer and are susceptible to AKR1C3-mediated 
resistance. This effect is countered by pretreatment with a potent and highly 
selective AKR1C3 inhibitor, sensitizing high AKR1C3 expressing prostate cancer 
cell lines to the action of both chemotherapeutics with a concomitant reduction 
in expression of AKR1C3 and the biomarker prostate-specific antigen.