Abstract
Introduction: Inactivating missense mutations in the SPOP gene increase the transcriptional activity of the androgen receptor and sensitivity to hormonal therapies in patients with hormone sensitive prostate cancer (HSPC). However, the relationship of SPOP alterations with differential outcomes by race, particularly in patients with castration-resistant prostate cancer (CRPC), remains unclear.

Patients and methods: We conducted a retrospective case-control analysis of 78 SPOP-mutated (SPOPmut) patients matched to 223 SPOP wild-type (SPOPwt) patients who received first-line ARPI therapy in the CRPC setting. All patients had somatic gene profiling using the Tempus xT or xF NGS assays. We compared PSA declines, time to treatment failure (TTF), progression-free survival (PFS), and overall survival (OS) with ARPI treatment by race and SPOP status.

Results: We identified SPOP mutations in 29% of Black men (n = 10/34) and 20% of White men (n = 30/150). After adjusting for race, visceral metastases, PSA, and M1 at diagnosis, there was no significant difference in TTF (HR 0.80, 95% CI, 0.56-1.15, P = .2), PFS (HR 0.81, 95% CI, 0.58-1.12, P = .2) or OS (HR 0.81, 95% CI, 0.55-1.19, P = .3) by SPOP status. Black men had improved OS with first line ARPI in the CRPC setting (HR 0.44, 95% CI, 0.24-0.79, P = .006) irrespective of SPOP status. PSA declines were more common in SPOPmut patients, with a PSA90 decline in 51% versus 31% (OR 2.35, 95% CI, 1.09-5.12). SPOP mutations were associated with AR ligand-binding domain mutations, APC, and CDKN1B alterations in CRPC.

Conclusion: In this exploratory analysis, we found that Black men have improved survival in the first line mCRPC setting with ARPI therapy, but that SPOP mutations do not explain these differential outcomes despite improved short term PSA declines. Thus, other factors may explain the disparity in outcomes we confirmed in men with CRPC.

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