Predictive molecular alterations of prostate cancer brain metastases based on a companion diagnostic assay

The current first-line treatment standard for patients with metastatic prostate cancer (mPCa), is a combination of androgen deprivation therapy (ADT) and androgen receptor pathway inhibitors (ARPI), plus the addition of docetaxel for fit patients with high-volume or high-risk disease. This upfront treatment is highly effective, however, the emergence of acquired resistance is nearly universal, upon which, molecular predictive biomarkers are needed for further targeted therapies. Genomic studies have identified a population of 20-30% prostate cancer (PCa) patients harboring tumor DNA damage repair (DDR) alterations. Recent clinical trials have shown that treatment with PARP inhibitors (PARPi) achieve high response rates in tumors with BRCA1- and BRCA2-pathogenic alterations. Patients with metastatic castration-resistant PCa (mCRPC) harboring these alterations showed the highest overall survival benefit. Prostate cancer brain metastases (PCBM) is a usual exclusion criterion for clinical trials in part due to expected poor outcome. Recent work from our group in Switzerland has shown that 19.6% of patients with prostate cancer brain metastases (PCBM) had genomic alterations in homologous recombination repair (HRR) genes. However, the study was done using a research genomic assay. To maximize clinical relevance, in this work we analyzed 46 men suffering from PCBM from the same cohort using the FDA approved companion diagnostic FoundationOne®CDx assay. We found that 12/44 patients (27.3%), from which a metastatic sample was available, harbored qualifying alterations for PARPi therapy. Additionally, we found 7/44 patients (15.9%) qualifying for immune check-point inhibitors therapy. We anticipate that these findings will improve the rate of molecular testing in mCRPC patients with brain metastases and advance personalized management of these patients.