Background: Inactivating mutations in the SPOP gene, encoding speckled-type poxvirus and zinc-finger protein, are common among men with localized and metastatic prostate cancer, occurring at a frequency of 6-15%. Previous studies have suggested the presence of an inactivating mutation in SPOP results in increased sensitivity to androgen deprivation therapy (ADT). In this multi-institutional clinical-genomic database, we evaluated the impact of SPOP alterations on survival outcomes in men with metastatic prostate cancer. Methods: Retrospective data from the PROMISE Consortium were utilized for this analysis. Eligible patients had metastatic prostate cancer and had undergone standard of care next-generation sequencing (NGS). Patients with inactivating mutations in SPOP were defined as SPOP mutated, where. as those lacking such alterations were defined as SPOP wild-type. The primary endpoint was overall survival defined as the time from diagnosis of metastatic prostate cancer to death from any cause, censored at the date of last follow-up. Secondary endpoints included time from metastatic disease to castration resistance and time from castration resistance to death. Results: Of the 2097 patients with available NGS testing, 5.5% (n=115) had SPOP alterations. The median age at diagnosis was 63 years, 427 were Black, and 83 were Hispanic. At last assessment, 66% had bone metastases, 7% lung metastases, and 5% liver metastases. The most frequent co-occurring alterations in the SPOP-mutated group were: TP53 (30.4%), APC (25.2%), and AR (21.7%). 1832 patients were included in the survival analysis [n=96 (5.2%) with and n=1736 (94.8%) without SPOP alterations]. Median overall survival was numerically longer, though not statistically significant, in the SPOP-mutated compared SPOP-wild-type group (75.9 versus 59.5 months, p=0.12). In patients with metastatic disease, median time to castration resistance was 14.6 months in the SPOP-mutated group versus 12.2 months in the SPOP-wild-type group (p=0.30). Median time from metastatic castration resistant to death was 45.0 months in the SPOP-mutated group and 40.2 months in the SPOP-wild type group. Conclusions: Our hypothesis generating data support that SPOP-mutated prostate cancer likely represents a unique molecular subtype of prostate cancer that may confer prolonged survival. Future studies of novel androgen-receptor targeting treatments should be tested in this molecular population.