Prognostic Significance of Alterations on Outcomes in Metastatic Prostate Cancer.

[PURPOSE] Emerging evidence suggests that inactivation may be a strong predictor of poor survival for men with prostate cancer (PC); however, large-scale validation is lacking.

[METHODS] We analyzed whether alterations are associated with inferior survival in advanced PC and evaluated the impact of co-occurring genomic alterations on outcomes using retrospective data from the Veteran's Health Administration and Veterans Affairs Multi-Omics Analysis Platform for Prostate Cancer from 2016 to 2023.

[RESULTS] The primary outcome was overall survival (OS) from onset of metastatic castration-resistant prostate cancer (mCRPC), as well as OS from initiation of life-prolonging therapy other than androgen deprivation therapy, and time to development of mCRPC. Eighty-seven (3.5%) of the 2,512 included patients had an alteration detected. The median age at diagnosis in the -altered group was 71 (IQR, 65-76) years, and 68 (IQR, 62-73) years in the wild-type group. The median overall survival from diagnosis of mCRPC was 1.31 years (95% CI, 0.89 to 1.84) in those with an alteration compared with 2.99 years (95% CI, 2.79 to 3.23). alteration alone conferred similar poor prognosis when compared with patients who had combined and alterations. A dose effect was seen with increasing numbers of tumor suppressor genes (TSGs-, , and ) conferring poorer outcomes. The median survival of patients from diagnosis of mCRPC with zero, one, two, and three TSGs was 3.74, 2.61, 1.61, and 0.87 years, respectively. alterations were not associated with significantly worse outcomes unless accompanied by alteration.

[CONCLUSION] In this large, real-world cohort of men with mCRPC, alterations emerged as a strong indicator of poor prognosis and can be used to stratify studies alone or in conjunction with other TSG alterations.