# Molecular landscape of prostate cancers with clival metastases

## TL;DR

This study identifies a unique genetic profile in prostate cancers that spread to the clivus, a rare and aggressive condition, offering insights into potential treatment strategies.

## Contribution

The study reveals a distinct molecular signature in prostate cancers with clival metastases, including specific DNA repair and kinase alterations.

## Key findings

- Clival metastases show enrichment of BRAF and CHEK2 alterations and homologous recombination repair.
- These metastases are relatively depleted of AR-related, PI3K pathway, and G2–M pathway alterations.
- Patients with clival metastases had a median survival of 15.3 months after diagnosis.

## Abstract

Clival metastases are a rare and clinically aggressive manifestation of advanced prostate cancer, associated with cranial nerve palsy and poor survival. The molecular features of prostate cancers giving rise to clivus metastases remain unknown.

We performed a multi-center retrospective study across six institutions, identifying prostate cancer patients with radiographically confirmed clival metastases and available next-generation sequencing (NGS) data. Baseline characteristics and clinical outcomes were collected. Genomic alterations from tissue- and/or blood-based assays were aggregated at the patient level and compared with a publicly available metastatic castration-resistant prostate cancer (mCRPC) cohort (SU2C/PCF).

Fifty-nine patients with clival metastases contributed 87 molecular assays. More than half of patients had Gleason grade group 5 cancer and presented with de novo metastatic (M1) disease. The median interval from initial prostate cancer diagnosis to clival metastasis was 71.4 months (95% CI, 42.0-101.7), while median overall survival following clival involvement was only 15.3 months (95% CI, 6.9-22.8). Compared with the SU2C/PCF mCRPC cohort, clival metastases showed significant enrichment of BRAF and CHEK2 alterations as well as homologous recombination repair (HRR) with relative depletion of AR-related, PI3K pathway, and G2–M pathway alterations.

Prostate cancers giving rise to clival metastases exhibit a distinct molecular profile enriched for DNA damage–repair and RAF kinase alterations, suggesting unique metastatic biology and potential therapeutic vulnerabilities.