PURPOSE In prostate cancer, inactivating mutations result in gene fusion-induced neoantigens and possibly sensitivity to immunotherapy. metastatic hormone-sensitive disease (n = 59), 79.7% had a PSA response, and median PFS was 12.3 months. Of those who received first-line abiraterone and enzalutamide for metastatic castration-resistant prostate malignancy (mCRPC; n = 34), 41.2% had a PSA response, and median PFS was 5.3 months. Of those ARN-509 reversible enzyme inhibition who received a first taxane chemotherapy for mCRPC (n = 22), 31.8% had a PSA response, and median PFS was 3.8 months. Eleven men received a PARP inhibitor (olaparib [n = 10], rucaparib [n = 1]), and none experienced a PSA response (median PFS, 3.6 months). Nine men received a PD-1 inhibitor as fourth- to sixth-line systemic therapy (pembrolizumab [n = 5], nivolumab [n = 4]); 33.3% had a PSA response, and median PFS was 5.4 months. CONCLUSION deficiency in immunotherapy sensitivity. INTRODUCTION Clinically relevant genomic classifications of many cancers are progressively aiding in the selection of optimal systemic therapies, which have heralded the era of precision oncology. In advanced prostate malignancy, however, the clinical power of germline and somatic genetic testing is limited to the detection of mismatch repair (MMR) deficiency mutations (which may predict responsiveness to PD-1 inhibitors, eg, pembrolizumab)1,2 or the detection of homologous recombination deficiency (HRD) mutations (which may predict sensitivity to investigational poly [ADP-ribose] polymerase [PARP] inhibitors, eg, olaparib, or platinum brokers).3C5 Furthermore, while immune checkpoint blockade has resulted in unprecedented gains in a growing number of tumor types, the use of CTLA-4- and/or PD-1-targeting agents in unselected patients with metastatic castration-resistant prostate cancer (mCRPC) has been met with limited success.6,7 To this end, identification of additional molecular subsets of mCRPC that may benefit from immune system checkpoint inhibition is paramount.8 encodes cyclin-dependent kinase 12, a tumor suppressor proteins with diverse features linked to genomic stability.9 Initially, CDK12 was thought to promote DNA fix through the regulation of homologous recombination DNA fix genes (was connected with PARP inhibitor sensitivity in preclinical models.10 Recently, however, it had been suggested that in prostate cancer, CDK12 may function in DNA replication-associated fix primarily, with biallelic inactivation of producing a unique genomic signature seen as a widespread focal tandem duplications that result in gene fusion-induced neoantigens and sensitivity to immune checkpoint inhibitors.11 For the reason that preliminary research, 2 of 4 sufferers with mutations occur in 5%?7% of sufferers with mCRPC,11C13 & most are biallelic inactivations. Because small is well known about the scientific features and prognosis of sufferers with alterations are located in 1%?4% of several other cancer types,12,13 the findings of the study (particularly regarding PARP inhibitor and PD-1 inhibitor awareness) may possess implications for a variety of additional malignancies. Strategies We executed a retrospective Fgfr2 evaluation that started with an interrogation of ARN-509 reversible enzyme inhibition the tumor genomic databases from 9 academic medical centers. We searched for patients with recurrent or metastatic prostate malignancy who experienced at least monoallelic loss-of-function mutations, as detected using a clinical-grade (eg, Clinical Laboratory Improvement Amendments-certified) commercial or in-house genomic assay. Pathogenic mutations were defined a priori as those that result in a truncated protein (ie, frameshift, nonsense, splicing mutations) or genomic rearrangements that involve the locus (eg, homozygous deletions, gene fusions, other translocations). After a pathogenic first hit was recognized, a second hit was sought by examining for another pathogenic ARN-509 reversible enzyme inhibition alteration as previously defined, a loss of heterozygosity (LOH) of the wild-type allele, or a missense mutation in the kinase domain name (amino acids 727C1,020) of the protein. Of note, a single missense mutation in the kinase domain name alone was not considered a pathogenic alteration. Next, we abstracted clinical data from your electronic records of patients with confirmed (at least monoallelic) mutations. This involved collection of common clinical characteristics, including age at diagnosis, PSA level at diagnosis, race, family history of malignancy, Gleason score, presence of histologic variants, clinical and/or pathologic stage, presence of metastatic disease at diagnosis, and sites of metastatic disease. We also documented the types and quantity of systemic therapies received for metastatic disease. For each systemic therapy, we collected data about longitudinal PSA levels, radiographic studies, clinical symptoms, and survival status. We decided PSA response rates and progression-free survival (PFS) for each systemic therapy separately. PSA response was defined as a 50% reduction in PSA level compared with baseline values, with a confirmatory PSA value 4.