Clinicogenomic Differences Between Early-Onset (EO-PCa) and Late-Onset Prostate Cancer (LO-PCa): A Large-Scale Retrospective Cohort Study

Background
EO-PCa is increasingly recognized as a biologically distinct entity, but its clinical behavior, molecular features, and outcomes relative to LO-PCa are incompletely characterized.

Methods
The Tempus Lens Platform (Tempus AI, Inc., Chicago, IL) was used to query the de-identified, multimodal database for patients (pts) diagnosed with metastatic prostate cancer (N= 6,967) tested with Tempus xT (DNA-seq) and xR (RNA-seq). Eligible pts had a sample collected within 60 days of diagnosis and were stratified by onset age (EO-PCa ≤55 years; LO-PCa >55 years). Clinicogenomic characteristics were compared using Wilcoxon rank-sum tests or chi-squared tests as appropriate. Real-world overall survival (rwOS) was defined as the time from sample collection to death or loss to follow up. Median rwOS (mOS) was estimated using Kaplan-Meier (KM) curves and compared using log-rank tests. Hazard ratios (HR) were estimated using Cox proportional hazards models. Risk set adjustment was used to account for immortal time bias.

Results
EO-PCa comprised 8.4% of cases and was more common in Black than white pts (24% vs 18%, p=0.004). Metastatic disease at diagnosis was observed in 83% of EO-PCa vs 87% of LO-PCa. Pts with EO-PCa had higher median PSA levels [median 87 ng/mL vs 71 ng/mL, p=0.009] and were more likely to undergo primary treatment (radiotherapy: 37% vs 26%; prostatectomy: 19% vs 10%, p<0.001). EO-PCa was enriched for germline BRCA2 variants (4.8% vs 2.6%, p=0.019) and TMPRSS2 (40% vs 35%, p=0.015) and ERG fusions (41% vs 37%, p=0.031). FOXA1 (15% vs 9.4%, p<0.001) and SPOP mutations (11% vs. 8.2%, p=0.033) were more common in LO-PCa. EO-PCa was associated with longer mOS [42 vs 32 months, HR = 1.51 (95% CI 1.26-1.81), p<0.001]. SPOP alterations were prognostic for favorable mOS (LO-PCa: 52 months vs 30.7 months, p<0.001; EO-PCa: 67.1 months vs 41.7 months, p= 0.41). TP53 alterations were prognostic for worse mOS (LO-PCa: mOS 25.9 months vs 37.9 months, p<0.001; EO-PCa: mOS 33.8 vs 55.9 months, p<0.001).

Conclusions
EO-PCa exhibits distinct clinical and molecular characteristics compared to LO-PCa. OS appears to be driven by a combination of age and tumor biology.