Abstract A035: Therapeutic targets in androgen deprivation therapy-resistant prostatic carcinoma
Authors: Gatalica Zoran , Stafford Phillip , Contreras Elma , Swensen Jeff , Feldman Rebecca 
Published: March 2020

Background: Androgen deprivation therapy (ADT) for patients with metastatic prostate carcinoma eventually leads to development of castration-resistant prostate cancer (CRPC) with limited therapeutic options. ADT is characterized by the presence of ARv7 splice variant and several resistance mutations in AR gene. We explored potential therapeutic targets in CRPC. Methods: Biopsy samples from 80 patients with prostate carcinomas (39 primary and 41 metastatic samples) were analyzed for mutations using 592 gene NGS panel and a whole transcriptome sequencing (WTS). Tumor mutational burden (TMB) and microsatellite instability (MSI) were calculated from the NGS data. Protein expression of the full length AR and ARv7 variant, as well as mismatch repair (MMR) enzymes (MLH1, MSH2, MSH6 and PMS2) and tumor cells’ (TC) expression of PD-L1 were analyzed using IHC methods. Tests results were correlated with clinical history of androgen deprivation (ADT-Hx). Chi-square analysis was used to compare subgroups. Results: Clinical histories were available for 63 patients (26 with and 37 without ADT-Hx). The median age in this cohort was 67 (range: 45-88). Overall, ARv7 was detected in 20/80 cases. Two out of 15 cases had ARv7 present in biopsies without previous ADT-Hx (one primary prostate and one metastatic bone biopsy). Five patients with ADT-Hx harbored AR gene mutations (ARmut) in exon 8 which are known to confer ADT resistance were detected in the cohort (6% overall; 1 co-occurred with ARv7). Microsatellite instability (MSI-H) was detected in 6 cases (7.5% overall); of note, AR resistance mutation (ARv7 or ARmut) occurred at significantly higher rate in patients with MSI-H/MMRd compared to MSS/MMRp (83%; 5/6 vs. 26%; 19/72, p=0.001). Average total mutational burden (TMB) in microsatellite stable (MSS) cases was low (6/Mb); high TMB (&gt;80th percentile for the prostate carcinoma cohort) was detected in one MSS CRPC. PD-L1 TC-expression was detected in 1 metastatic (ARv7 negative) case. Pathogenic gene fusions were detected in 33 cases, most commonly TMPRSS2:ERG (26/79; 7/17 in ARv7). The most commonly mutated gene was TP53 (30 cases; 9/17 in ARv7). BRCA 1/2 mutations were found in 7 cases (3 in ARv7) and CDK12 mutations in 4 (2 in ARv7) cases. Other DNA repair genes mutations (n=1, each) includied MUTYH, PRKDC, ATM, BRIP1, ERCC2, FANCA and FANCD2. Gene expression analysis identified numerous differently expressed genes between ARv7+/ADT+, ARv7-/ADT+ and ARv7-/ADT- tumor groups, requiring further analysis. Conclusion: Upon failure of ADT, tumor samples from men with CRPC (biopsy positive for ARv7 or ARmut) demonstrate molecular alterations that are potential targets for treatment. Immune-oncology agents in patients harboring evidence of genomic instability (e.g. high MSI or TMB) and PARP inhibitors in patients with alterations in DNA repair pathways (e.g. BRCA1/2, ATM, PRKDC, CDK12, etc.) should be investigated further. Comprehensive tumor profiling is necessary to detect targetable pathways.

Citation Format: Zoran Gatalica, Phillip Stafford, Elma Contreras, Jeff Swensen, Rebecca Feldman. Therapeutic targets in androgen deprivation therapy-resistant prostatic carcinoma [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A035. doi:10.1158/1535-7163.TARG-19-A035