BACKGROUND: Metastatic disease burden out of proportion to serum PSA has been used as a marker of aggressive phenotype prostate cancer but is not well defined as a distinct subgroup. We sought to prospectively characterize the molecular features and clinical outcomes of Low PSA Secretors. METHODS: Eligible metastatic castration resistant prostate cancer (mCRPC) patients without prior small cell histology underwent metastatic tumor biopsy with molecular characterization. Low PSA secretion was defined as serum PSA < 2, 5, or 10 ng/mL plus >5 metastases with radiographic progression at study entry. Clinical and molecular features were compared between low PSA vs. normal secretors in a post-hoc fashion. RESULTS: 183 patients were enrolled, including 15 (8%) identified as Low PSA Secretors using optimal PSA cut point of 5 ng/mL. Biopsies from Low PSA Secretors demonstrated higher t-SCNC and RB1 loss and lower AR transcriptional signature scores compared with normal secretors. Genomic loss of RB1 and/or TP53 was more common in Low PSA Secretors (80% vs. 41%). Overall survival (OS) was shorter in Low PSA Secretors (median OS = 26.7 vs. 46.0 months, hazard ratio = 2.465 (95% CI: 0.982-6.183). Progression-free survival (PFS) on post-biopsy treatment with AR-targeted therapy was shorter than with chemotherapy (median PFS 6.2 vs. 4.1 months). CONCLUSIONS: Low PSA secretion in relation to metastatic tumor burden may be a readily available clinical selection tool for de-differentiated mCRPC with molecular features consistent with t-SCNC. Prospective validation is warranted.