Prognostic Significance of <i>RB1</i> Alterations on Outcomes in Metastatic Prostate Cancer.

Abstract

Emerging evidence suggests that <i>RB1</i> inactivation may be a strong predictor of poor survival for men with prostate cancer (PC); however, large-scale validation is lacking. We analyzed whether <i>RB1</i> 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. 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 <i>RB1</i> alteration detected. The median age at diagnosis in the <i>RB1</i>-altered group was 71 (IQR, 65-76) years, and 68 (IQR, 62-73) years in the <i>RB1</i> 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 <i>RB1</i> alteration compared with 2.99 years (95% CI, 2.79 to 3.23). <i>RB1</i> alteration alone conferred similar poor prognosis when compared with patients who had combined <i>PTEN</i> and <i>TP53</i> alterations. A dose effect was seen with increasing numbers of tumor suppressor genes (TSGs-<i>RB1</i>, <i>TP53</i>, and <i>PTEN</i>) 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. <i>BRCA2</i> alterations were not associated with significantly worse outcomes unless accompanied by <i>RB1</i> alteration. In this large, real-world cohort of men with mCRPC, <i>RB1</i> alterations emerged as a strong indicator of poor prognosis and can be used to stratify studies alone or in conjunction with other TSG alterations.