We identified resistance mechanisms to abiraterone acetate/prednisone (AA/P) in patients with metastatic castration-resistant prostate cancer (mCRPC) in the PROMOTE (Prostate Cancer Medically Optimized Genome-Enhanced Therapy) study. We analyzed whole-exome sequencing (WES) and RNA-seq data from 83 patients with metastatic biopsies pre (V1) and after 12 weeks of AA/P treatment (V2). Resistance was determined by time to treatment change (TTTC). At V2, 18 and 11 out of 58 patients had either short (median 3.6 months; range 1.4-4.5) or long- (median 29 months; range 23.5-41.7) term responses, respectively. Non-responders had low expression of TGFBR3 and increased activation of the Wnt pathway, cell cycle, upregulation of AR variants, both pre and post-treatment, with further deletion of AR inhibitor CDK11B post-treatment. Deletion of androgen processing genes, HSD17B11, CYP19A1 were observed in non-responders post-treatment. Genes involved in cell cycle, DNA repair, Wnt-signaling, and Aurora kinase pathways were differentially expressed between the responder and non-responder at V2. Activation of Wnt signaling in non-responder and deactivation of MYC or its target genes in responders was detected via Somatic Copy Number (SCN) loss, somatic mutations, and transcriptomics. Upregulation of genes in the AURKA pathway are consistent with the activation of MYC regulated genes in non-responders. Several genes in the AKT1 axis had increased mutation rate in non-responders. We also found evidence of resistance via PD1 overexpression in responders. Implications: Finally, we identified candidates drugs to reverse AA/P resistance : topoisomerase inhibitors and drugs targeting the cell cycle via the MYC/AURKA/AURKB/TOP2A and/or PI3K/AKT1/MTOR pathways.