Impact of <i>SPOP</i> Mutations on Clinical Outcomes in Metastatic Prostate Cancer.

Abstract

Previous studies suggest that <i>SPOP</i> mutations result in increased sensitivity to androgen receptor pathway inhibitors (ARPIs) but are limited by lack of granular data. We hypothesize that <i>SPOP</i> mutations are associated with improved outcomes across the spectrum of advanced prostate cancer (PC). Using the real-world clinicogenomic Prostate Cancer Precision Medicine Multi-Institutional Collaborative Effort database, we analyzed outcomes based on <i>SPOP</i> mutation status. The primary end point was overall survival (OS) from the diagnosis of metastatic disease. Secondary end points included real-world progression-free survival (PFS) and PSA90 response. Among 2,097 patients with metastatic PC, 5.5% (N = 115) had <i>SPOP</i>-mutated tumors. Compared with <i>SPOP</i> wild-type, patients with <i>SPOP</i> mutations were older at diagnosis (median 65 <i>v</i> 63 years; <i>P</i> = .001) and had higher (≥8) Gleason sum (68% <i>v</i> 54%; <i>P</i> = .02), higher incidence of lung metastasis (17% <i>v</i> 6%; <i>P</i> = .001), and increased frequency of intraductal features (13% <i>v</i> 5%; <i>P</i> < .001). <i>SPOP</i> mutations were associated with improved PSA90 response with first ARPI exposure in the castrate-resistant setting (60% <i>v</i> 40.6%; OR, 2.20 [95% CI, 1.15 to 4.19]; <i>P</i> = .02) but not in the castrate-sensitive setting (78.9% <i>v</i> 71.5%; OR, 1.49 [95% CI, 0.66 to 3.37]; <i>P</i> = .43). Median PFS with first ARPI did not differ in <i>SPOP-</i>mutated versus wild-type group in both the castrate-sensitive (24.2 <i>v</i> 19.2 months; hazard ratio [HR], 0.80 [95% CI, 0.49 to 1.32]; <i>P</i> = .39) and castrate-resistant settings (15.0 <i>v</i> 12.4 months; HR, 0.81 [95% CI, 0.58 to 1.12]; <i>P</i> = .20). In multivariable analysis, <i>SPOP</i> mutations were associated with improved OS (HR, 0.65, <i>P</i> = .02). <i>SPOP</i> mutations were associated with longer OS despite the presence of aggressive clinical features. The distinct clinical and molecular features of <i>SPOP</i>-mutated PC support its consideration as a unique molecular subtype with prognostic implications.