SPOP mutations in veterans with metastatic castration-resistant prostate cancer (mCRPC) and the association with race and response to an androgen receptor pathway inhibitor (ARPI).

Inactivating missense mutations in the tumor suppressor gene speckle-type pox virus and zinc finger protein (SPOP) occur in up to 15% of prostate cancer (PC) men. Inactivation of SPOP may result in increased transcription of the androgen receptor. Several race-stratified studies show that Black men with mCRPC have greater PSA declines and improved time to progression when treated with ARPIs relative to White men. Here we compare survival outcomes in Black and White men with mCRPC receiving an ARPI with a documented SPOP mutation, and hypothesize that Black men have better survival. This retrospective cohort was defined as men with mCRPC seen in the Veterans Affairs (VA) health care system between 1/1/2000 - 9/30/2024. The primary outcome was overall survival (OS), calculated from initial diagnosis (dx), ARPI start, and mCRPC date to death or censoring on 12/31/2024. To assess racial differences in OS, we used Kaplan-Meier curves and a Log-Rank test. Of 1043 men with PC and an mutation, 418 had mCRPC and 296 started an ARPI after mCRPC dx. Excluding those treated with ARPI for hormone-sensitive PC, the final cohort includes 101 Veterans (43 Black, 58 White). Black men tended to be younger at dx, less likely to have de novo metastatic disease, and had lower grade group scores (Table). Median follow-up was 26 months (mo) (range: 0-116) for the entire cohort. Time from initial dx to starting an ARPI was longer for Black men relative to White men (91.9 mo +/- 75.0 vs. 72.7 mo +/- 52.6). Median OS for Black and White men, respectively, from initial dx was 239 and 182 mo (p=0.29), from ARPI start was 43 and 46 mo (p=0.69), and from mCRPC date was 55 and 58 mo (p=0.79). Black and White men with an mutation who received an ARPI for the treatment of mCRPC have similar survival outcomes from ARPI start and after developing mCRPC. Black men lived nearly 5 years longer from the time of PC dx, while also starting an ARPI later, compared to White men. This is the largest reported cohort of men with mCRPC and SPOP mutations, and also has the highest representation of Black men. Further studies are planned to better understand the impact of mutations in mCRPC.

Duke Scholars

Author Joseph Junyong Park Medicine, Medical Oncology