How Often are druggable mutations detectable in Metastatic Castration Resistant Prostate Cancer?

OBJECTIVES: To analyze the type and frequency druggable mutations in patients with progressive metastatic castration-resistant prostate cancer (mCRPC). PATIENTS AND METHODS: From 2018 to 2023, 311 patients with mCRPC underwent molecular panel analysis of archived prostatectomy samples (n=96) or CT-guided biopsies of progressive metastases (n=215).Mutation analysis was performed using NGS with an 18 multiplex PCR amplicon (AR, ATM, AURKA/MYC, BRCA1/2, CDK12, CTNNB1, DLL3, ETS family, FOXA1, FOXO1, MED12, PIK3CA, PTEN, RAD51C, TP53, Wnt-Pathway). Since 2023, we applied the TSO500 panel in selected cases. The HRD score was calculated by combining BRCA1 and BRCA2 mutations (Genomic ScarScore GSS) using the HANDLE HRD Focus Panel. The data were evaluated using the following thresholds: tumor cell content ≥ 30%, GScore positive at ≥ 50, HRD positive: GScore at ≥ 50 or BRCA1/2 category 4/5 mutation. MSI-high and mutations of MSH2, MSH6, PMS2, and MLH1 were analysed. The following databases were reviewed to identify druggable mutations: OncoKB, ClinVar, JAX-CKB, COSMIC, and My Cancer Genome. RESULTS: 299/311 (96%) biopsies had sufficient DNA content for NGS. NGS was performed from prostate (31%), lymph node (30%), visceral (15%), and bone (24%) metastases with informative DNA retrival in 95%, 95%, 92%, and 85%, respectively. 157 patients (50.5%) had no or non druggable mutations, while 154 patients (49.5%) exhibited druggable mutations. HRD gene mutations and inactivating p53 mutations were observed in 66 patients (22%). 3 patients had p53 mutations with gain-of-function resulting in ATM inactivation. 50% of HRD gene mutations iwere pathogen and treated with PARPi resulting in a progression-free survival of 3-28 months. Activating AR mutations and inactivating PTEN/activating PIC3Ca mutations were found in 42 (14%) and 24 (8%) patients, respectively. Switch of treatment for AR mutation resulted in PFS of 6-9 months. Mismatch repair deficiency/MSI high mutations were identified in 3 cases who received pembrolizumab with a PFS of 4-8 months. CONCLUSIONS: NGS analysis in mCRPC reveals mutations in two-thirds of patients, of which 41% are already druggable. Only 50% of druggable mutations are based on BRCA1/2 or ATM. NGS analysis should be integrated into the diagnostic armentarium following failure of first-line systemic therapy for mCRPC.