De Novo vs Metachronous Metastatic Prostate Cancer (mPC): A Comprehensive Clinical and Genomic Analysis

Background
The mechanisms underlying survival differences between patients (pts) with de novo vs metastatic mPC at diagnosis are incompletely characterized. This study compared clinicogenomic features between de novo vs metachronous mPC.

Methods
We used the Tempus Lens Platform (Tempus AI, Inc., Chicago, IL) to query the de-identified, multimodal database for pts with mPC (N= 6,306) tested with Tempus xT (DNA-seq) and xR (RNA-seq). Pts were classified as de novo (Stage IV at diagnosis, n=6171) or metachronous (Stage I–III at diagnosis with progression to Stage IV >180 days later, n=135). Immune cell proportions were estimated from RNA using quanTIseq. Differential gene expression analyses were conducted using Wilcoxon rank-sum tests with Benjamini-Hochberg correction. Gene set enrichment analysis was conducted using the Hallmark libraries. Groups were compared using Wilcoxon rank-sum tests or chi-squared tests as appropriate.

Results
Metachronous pts were younger (median 66 vs 68 years, p=0.002) and had lower PSA levels at diagnosis (median 8 vs 89 ng/mL, p<0.001). Treatment with prostatectomy or radiation was more common in metachronous pts (prostatectomy: 57% vs 5.2%, radiotherapy: 92% vs 22%, p<0.001), while treatment with upfront chemotherapy with ADT +/- ARPI was more common in de-novo metastatic pts (15.7% vs 8.1%, p=0.037). Metachronous pts were enriched for APLNR (13% vs 4.7%, p<0.001) and ZMYM3 somatic alterations (11% vs 4.8%, p<0.001), while most canonical prostate cancer drivers (e.g., TP53, PTEN, ERG) had a similar frequency between groups. Metachronous pts demonstrated increased regulatory T cell and natural killer cell infiltration (p<0.001), suggesting a distinct tumor microenvironment. Inflammatory signaling (TNFα/NF-κB) and KRAS-related pathways were also enriched in metachronous pts.

Conclusions
Metachronous mPC is a distinct entity characterized by lower PSA at diagnosis, greater prior local therapy exposure, unique genomic alterations, and a more immunologically active tumor microenvironment compared to de novo disease. Future work should investigate therapeutic vulnerabilities and differences in survival associated with metachronous vs. de novo disease.