Genomic landscape of CDK12 mutated metastatic castrate-resistant prostate cancer (mCRPC).

Abstract

165 Background: Identifying prostate cancer patients likely to benefit from immune checkpoint inhibitors (ICPI) remains an unmet need. Specific loss-of-function genomic alterations (GA) in CDK12 are associated with focal tandem duplications linked to fusion-induced production of neoantigens and are a promising candidate biomarker for ICPI. Using comprehensive genomic profiling (CGP) we compared the GA landscape of CDK12 altered (CDK12mut+) and unaltered (CDK12mut-) tumors. Methods: 4,918 mCRPC tumors were sequenced using a hybrid capture-based FDA-approved CGP assay. Tumor mutational burden (TMB) was determined on 0.8 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 95 loci. PD-L1 expression was determined by IHC (Dako 22C3) with low tumor cell positive staining -49% and high staining ≥50% expression. Results: Overall, 315 (6.4%) of the mCRPC cases were CDK12mut+ (Table). CDKmut+ cases had significantly fewer GA in TMPRSS2: ERG (P < .0001), TP53 (P < .0001), PTEN (P < .0001), ATM (P = .001), PIK3CA (P = .003), RB1 (P = .02), BRCA2 (P < .0001) and APC (P = .002). CDK12mut+ cases featured higher frequencies only in CCND1 (P < .0001), BRAF (P = .007) and ERBB2 (P < .001) as well as in cell cycle regulatory genes including MDM2/4 (P < .0001), CDK4 (P < .0001) and CDK6 (P = .002). CDK12mut+ cases featured more frequent MSI-H status (P = .007), significantly higher median TMB (P < .001) and more frequent low positive (1-49% staining) PD-L1 expression (P = .02). High (≥50%) PD-L1 expression was rarely identified in either cohort. Conclusions: CDK12mut+ mCRPC demonstrates a unique genomic profile with significant differences compared with CDK12mut- mCRPC. Lower frequencies of GA associated with homologous recombination defect and mTOR pathway may impact the use of platinum agents, as well as PARPi and PIK3CA/Akt/mTOR inhibitors. Opportunities for targeted therapies for BRAF and ERBB2 driven mCRPC may be enriched in the CDK12mut+ tumors and raise the possibility of combination therapy strategies although the numbers of patients are small and validation is needed. The slightly higher MSI High status, median TMB and PD-L1 staining may be associated with additional benefit from ICPI and warrants further prospective investigation. [Table: see text]