Targeting arginine metabolism overcomes chemotherapy resistance in aggressive-variant prostate cancers

Aggressive-variant prostate cancers (AVPCs) respond poorly to anti-androgen therapy but show sensitivity to taxane-platinum chemotherapy, though outcomes remain poor. We conducted a phase 2 trial testing induction cabazitaxel plus carboplatin (CabCarb) followed by olaparib maintenance versus observation in men with AVPC. The primary endpoint of improved progression-free survival (PFS) was not met, likely due to the study being underpowered after 38.5% of patients experienced early progression (ChemoPD) prior to randomization. No genomic alterations predicted ChemoPD; however, transcriptomic analysis revealed the enrichment of metabolic pathways, including arginine metabolism, in ChemoPD tumors. These findings were supported by metabolomics data from preclinical models. In AVPC models, arginine depletion with ADI-PEG20 enhanced CabCarb efficacy in vitro and in vivo . Together, these results provide insight into the heterogeneity of AVPCs and establish a rationale for novel combination treatment strategies to overcome chemotherapy resistance.