Impact of SPOP Mutations on Clinical Outcomes in Metastatic Prostate Cancer
Recommended Citation
Kilari D, Henderson NC, Yamamoto K, Yao Y, Hwang C, Barata PC, Bilen MA, Graham L, Garje R, Rothstein S, Haider S, Park JJ, Raychaudhuri R, Pilling A, Chin E, Koshkin VS, Tripathi A, Cackowski FC, Nauseef JT, Sokolova A, Ayanambakkam A, Zakharia Y, Schweizer MT, Armstrong AJ, Dorff TB, Reichert ZR, and McKay RR. Impact of SPOP Mutations on Clinical Outcomes in Metastatic Prostate Cancer. JCO Precis Oncol 2025;9:e2500590.
Document Type
Article
Publication Date
12-1-2025
Publication Title
JCO Precis Oncol
Keywords
Humans, Male, Repressor Proteins, Prostatic Neoplasms, Aged, Middle Aged, Mutation, Nuclear Proteins, Neoplasm Metastasis
Abstract
PURPOSE: Previous studies suggest that SPOP mutations result in increased sensitivity to androgen receptor pathway inhibitors (ARPIs) but are limited by lack of granular data. We hypothesize that SPOP mutations are associated with improved outcomes across the spectrum of advanced prostate cancer (PC).
METHODS: Using the real-world clinicogenomic Prostate Cancer Precision Medicine Multi-Institutional Collaborative Effort database, we analyzed outcomes based on SPOP 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.
RESULTS: Among 2,097 patients with metastatic PC, 5.5% (N = 115) had SPOP-mutated tumors. Compared with SPOP wild-type, patients with SPOP mutations were older at diagnosis (median 65 v 63 years; P = .001) and had higher (≥8) Gleason sum (68% v 54%; P = .02), higher incidence of lung metastasis (17% v 6%; P = .001), and increased frequency of intraductal features (13% v 5%; P < .001). SPOP mutations were associated with improved PSA90 response with first ARPI exposure in the castrate-resistant setting (60% v 40.6%; OR, 2.20 [95% CI, 1.15 to 4.19]; P = .02) but not in the castrate-sensitive setting (78.9% v 71.5%; OR, 1.49 [95% CI, 0.66 to 3.37]; P = .43). Median PFS with first ARPI did not differ in SPOP-mutated versus wild-type group in both the castrate-sensitive (24.2 v 19.2 months; hazard ratio [HR], 0.80 [95% CI, 0.49 to 1.32]; P = .39) and castrate-resistant settings (15.0 v 12.4 months; HR, 0.81 [95% CI, 0.58 to 1.12]; P = .20). In multivariable analysis, SPOP mutations were associated with improved OS (HR, 0.65, P = .02).
CONCLUSION: SPOP mutations were associated with longer OS despite the presence of aggressive clinical features. The distinct clinical and molecular features of SPOP-mutated PC support its consideration as a unique molecular subtype with prognostic implications.
Medical Subject Headings
Humans; Male; Repressor Proteins; Prostatic Neoplasms; Aged; Middle Aged; Mutation; Nuclear Proteins; Neoplasm Metastasis
PubMed ID
41348987
Volume
9
First Page
2500590
Last Page
2500590
