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.
iScience. 2026 Jun 02*** epublish ***
Elavarasan Subramani, Patrick G Pilié, Rebecca Slack-Tidwell, Paul V Viscuse, Xianghong Kuang, Thirukumaran Kandasamy, Dominik Awad, Jenny J Han, Licai Huang, Christine B Peterson, Amado J Zurita, Sumit K Subudhi, Paul G Corn, Rama Soundararajan, Peter Shepherd, Badrajee Piyarathna, Vasanta Putluri, Nagireddy Putluri, Arun Sreekumar, Yuzhuo Wang, Amina Zoubeidi, Iqbal Mahmud, Sara A Martinez, Lin Tan, Philip L Lorenzi, Sreyashi Basu, Sonali Jindal, Padmanee Sharma, Christopher J Logothetis, Timothy C Thompson, Daniel E Frigo, Ana M Aparicio
Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Department of Medicine, University of Virginia, Charlottesville, VA, USA., Department of Statistics, Rice University, Houston, TX, USA., Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA., Dan L Duncan Comprehensive Cancer Center and Advanced Technology Cores, Baylor College of Medicine, Houston, TX, USA., Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada., Metabolomics Core Facility, Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Immunotherapy Platform, James P. Allison Institute, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.