Abstract Background: Prostate Small cell carcinoma (SmCC) is a rare and aggressive histologic subtype characterized by rapid progression and limited therapeutic options. The genomic drivers underlying survival heterogeneity remain poorly defined. We aimed to identify genomic alterations associated with survival extremes in patients with prostate SmCC using the AACR Project GENIE database. Methods: Patients with histologically confirmed prostate SmCC were identified from the AACR Project GENIE database. Cases with complete genomic profiling and survival data were included. All patients were deceased at last follow-up (n = 65). Patients were stratified into short survival (15 months, n = 32) and long survival (24 months, n = 18) groups. Demographic characteristics were summarized descriptively. Frequencies of recurrent genomic alterations were compared between groups to identify associations with survival. Results: Median age at diagnosis was 67. 5 years for short-survivors and 67. 05 years for long-survivors (range 47–85 vs 54–82). Aggressive prostate SmCC encompasses frequent genetic alterations in tumor suppressor pathway, and the differences are clearly observed between the two survival groups. TP53 mutations were significantly enriched among short-survivors (15 months) (68. 8% vs 22. 2%), as were alterations in RB1 (43. 8% vs 11. 1%), supporting a TP53/RB1-driven aggressive molecular phenotype. PTEN alteration was present in 34. 4% of short-survivors and absent among long-survivors (24 months), indicating the dysregulation of PI3K/AKT/mTOR signaling playing a potential role in early mortality in this population. Less frequent genetic alterations such as ZFHX4 (37. 5% vs 0%) and SPTA1 (23. 1% vs 0%) also appeared exclusive to the poor-survival cohort, although their prognostic significance remains exploratory. Conclusions: In conclusion, analysis of the AACR Project GENIE database reveals a distinct tumor genotype associated with survival extremes in prostate SmCC. Short survivors exhibit a high frequency of alterations in TP53, RB1, and PTEN, which likely drive their aggressive disease course. In contrast, long survivors show a substantially lower burden of tumor suppressor alterations and notably lack PTEN changes, suggesting a biologically distinct subset characterized by reduced genomic instability and more favorable disease behavior, thereby supporting the role of genomic profiling to stratify prognostic risk and guide personalized treatment approaches in prostate SmCC. Larger studies are needed to validate these associations and to aid in the development of novel treatments. Citation Format: Nishanth Thalambedu, Krishna Vasipalli, Sruthi Vellanki, Anup Kumar Trikannad, Anuradha Kunthur, Shi-Ming Tu. Genomic Correlates of Survival in Prostate Small Cell Carcinoma: An Analysis from the AACR Project GENIE Database abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Prostate Cancer Research and Treatment; 2026 Jan 20-22; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86 (2Suppl): Abstract nr A061.
Thalambedu et al. (Tue,) studied this question.