Genomic Determinants of Lethality and Therapeutic Vulnerability in Castration-Resistant Prostate Cancer

Despite extensive characterization, the molecular determinants that shape disease progression and therapeutic outcomes in metastatic castration-resistant prostate cancer (mCRPC) remain incompletely defined. This large, multi-institutional analysis reveals that the genomic determinants of outcomes in primary prostate cancer are distinct from those in castration-resistant disease. We identify androgen-regulated MYC fusions as potent primary genetic drivers catalyzing early progression. Additionally, across independent mCRPC cohorts, we validate TP53, RB1, and CDKN1B alterations as the strongest genetic drivers of poor survival. Mechanistically, CDKN1B loss induces an AR-positive epithelial-mesenchymal transition rather than neuroendocrine differentiation, while TP53 loss triggers whole-genome duplication and subsequent adaptive copy-number gains. Within TP53-altered tumors, AR amplifications confer improved survival while AR mutations are protective regardless of TP53 status. Integrating these genomic events with transcriptomic phenotypes, we derive CAPrisk, a multi-omic prognostic classifier. CAPrisk stratifies patients with mCRPC into three risk groups with >33-month survival differences and predicts outcomes across androgen receptor pathway inhibitors, taxanes, PARP-inhibitors, and radium-223. Together, these findings expand the clinical utility of genomic profiling in advanced prostate cancer and establish a framework for risk stratification in lethal disease. IN BRIEF (eTOC BLURB)Rebernick et al. analyze a multi-institutional cohort of 1,331 prostate cancer samples and identify the genomic determinants of progression to lethal, castration-resistant disease. They define rare AR-regulated MYC fusions and haploinsufficient CDKN1B loss as drivers of poor outcome while highlighting AR alterations as predictors of improved prognosis. They develop CAPrisk, a multi-omic classifier that stratifies patient outcomes across androgen receptor pathway inhibitors, taxanes, PARP-inhibitors, and radium-223. HIGHLIGHTS- AR-regulated MYC fusions are rare ([~]2%) truncal events driving aggressive disease. - Distinct AR alterations drive favorable outcomes in TP53-altered and non-altered contexts. - Haploinsufficient CDKN1B loss predicts poor survival in AR-positive tumors. - A multi-omic model predicts outcomes across four standard-of-care therapies. MI-OncoSeq TeamChandan Kumar, Erica Rabban, Kayla Muschong, Lakshmi P. Kunju, Javed Siddiqui, Yu Ning, Rui Wang, Fengyun Su, Yelena Kleyman-Smith, Josh N. Vo, Jin Chen, Rahul Mannan Stand Up To Cancer TeamWassim Abida, Joanna Cyrta, Glenn Heller, Davide Prandi, Joshua Armenia, Ilsa Coleman, Matteo Benelli, Eliezer M. Van Allen, Andrea Sboner, Tarcisio Fedrizzi, Juan Miguel Mosquera, Brian D. Robinson, Navonil De Sarkar, Lakshmi P. Kunju, Scott Tomlins, Daniel Nava Rodrigues, Massimo Loda, Anuradha Gopalan, Victor E. Reuter, Colin C. Pritchard, Joaquin Mateo, Diletta Bianchini, Susana Miranda, Suzanne Carreira, Pasquale Rescigno, Julie Filipenko, Jacob Vinson, Robert B. Montgomery, Himisha Beltran, Elisabeth I. Heath, Howard I. Scher, Philip W. Kantoff, Mary-Ellen Taplin, Nikolaus Schultz, Johann S. deBono, Francesca Demichelis, Peter S. Nelson, Mark A. Rubin, Charles Sawyers