Abstract Background: The SPARTAN study recently demonstrated that the addition of APA to androgen deprivation therapy (ADT) improved metastasis-free survival (MFS) and second progression-free survival (PFS2) in pts with nmCRPC defined by conventional imaging. We performed transcriptome-wide profiling of available primary tumor samples from pts in SPARTAN to evaluate predictors of response or resistance to APA + ADT. Methods: We used a commercially available genomic assay (DECIPHER® prostate test, GenomeDx, San Diego, CA) to assess gene expression in archived primary tumors from SPARTAN pts. DECIPHER GC, a 22-marker mRNA-based genomic classifier (GC), was validated for predicting metastatic prostate cancer (Karnes RJ, et al. J Urol. 2013), and basal/luminal (BA/LU) subtyping was validated in prostate cancer (Zhao SG, et al. JAMA Oncol. 2017; Zhang D, et al. Nat Commun. 2016). Pts were stratified into high and low risk for developing metastases based on DECIPHER GC score high (GC > 0.6) and low to average (GC ≤ 0.6), respectively, and into BA and LU subtypes. Gene signatures representing key biological pathways associated with the BA subtype were also assessed. We analyzed the association between GC scores and subtypes and outcomes using a Cox proportional hazards model. Results: A total of 233 pts were assessed; 117 pts had high GC score. Pts with both high and low to average GC score had improved outcomes with APA + ADT vs ADT alone. Pts with poor-prognosis high GC score had improved MFS (HR = 0.21, p < 0.0001) and PFS2 (HR = 0.26, p = 0.0084) with APA + ADT vs ADT, suggesting APA overcomes the negative prognosis in these pts. Approximately 65% of pts (n = 151) had the BA subtype associated with poor prognosis, indicating the high-risk nature of nmCRPC with short PSA doubling time. Key biological pathways associated with the BA subtype in nmCRPC were neuroendocrine differentiation, epithelial-mesenchymal transition, angiogenesis, and inflammation. Pts with the LU subtype, known to be sensitive to ADT, and with the BA subtype, typically resistant to ADT, benefited from APA + ADT vs ADT alone: HR for MFS = 0.22 and 0.34, p = 0.0017 and 0.0001, for LU and BA, respectively. Similar benefit was observed for PFS2. Both LU and BA pts had similar MFS benefit with ADT. LU pts had greater benefit from APA + ADT than BA pts: HR for MFS in LU vs BA subtypes was 0.40, p = 0.0295. Conclusions: Molecular signatures derived from primary tumors, such as DECIPHER GC and BA/LU subtypes, stratify pts with nmCRPC who would benefit from APA + ADT despite the high risk for progression. DECIPHER GC may be useful for identifying pts for early treatment intensification with APA or other agents, and BA/LU subtyping may be an effective approach for pt selection in trials combining novel therapies with APA. Citation Format: Felix Feng, Shibu Thomas, Michael Gormley, Angela Lopez-Gitlitz, Margaret K. Yu, Shinta Cheng, Deborah S. Ricci, Brendan Rooney, Paul N. Mainwaring, David Olmos, Fred Saad, Simon Chowdhury, Boris Hadaschik, Nick Fishbane, Elai Davicioni, Yang Liu, Eric J. Small, Matthew R. Smith. Identifying molecular determinants of response to apalutamide (APA) in patients (pts) with nonmetastatic castration-resistant prostate cancer (nmCRPC) in the SPARTAN study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT129.