Small cell prostatic carcinoma (SCPC) is an aggressive pathology that is managed similarly to small cell lung cancer. SCPC can evolve from prostatic adenocarcinoma in response to androgen deprivation therapy, but in rare cases is present at initial cancer diagnosis. The molecular etiology of de novo SCPC is incompletely understood, due to the scarcity of tumor tissue and the short life expectancy of patients. Through a retrospective search of our regional oncology pharmacy database, we identified 18 patients diagnosed with de novo SCPC between 2004 and 2017. Ten patients had pure SCPC pathology and the remainder had some admixed adenocarcinoma foci, but all were treated with first-line platinum-based chemotherapy. Median overall survival was 28 months. We performed targeted DNA sequencing, whole exome sequencing and mRNA profiling on formalin-fixed paraffin-embedded archival tumor tissue. We observed frequent biallelic deletion and/or mutation of tumor suppressors TP53, RB1 and PTEN, similar to treatment-related SCPC. Indeed, at the RNA level pure de novo SCPC closely resembled treatment-related SCPC. However, five patients had biallelic loss of DNA repair genes including BRCA1, BRCA2, ATM or MSH2/6, potentially underlying the high genomic instability of this rare disease variant. Two patients with pure de novo SCPC harbored ETS gene rearrangements to androgen-driven promoters, consistent with evolution of de novo SCPC from an androgen-driven ancestor. Overall, our results reveal a highly aggressive molecular landscape that underlies this unusual pathologic variant, and propose opportunities for targeted therapy strategies in a disease with few treatment options. This article is protected by copyright. All rights reserved.