Activity of durvalumab plus olaparib in metastatic castration-resistant prostate cancer in men with and without DNA damage repair mutations.

BACKGROUND: Checkpoint inhibitors have not been effective for prostate cancer as single agents. Durvalumab is a human IgG1-K monoclonal antibody that targets programmed death ligand 1 and is approved by the U.S. Food and Drug Administration for locally advanced or metastatic urothelial cancer and locally advanced, unresectable stage 3 non-small cell lung cancer. Olaparib, a poly (ADP-ribose) polymerase inhibitor, has demonstrated an improvement in median progression-free survival (PFS) in select patients with metastatic castration-resistant prostate cancer (mCRPC). Data from other trials suggest there may be improved activity in men with DNA damage repair (DDR) mutations treated with checkpoint inhibitors. This trial evaluated durvalumab and olaparib in patients with mCRPC with and without somatic or germline DDR mutations. METHODS: Eligible patients had received prior enzalutamide and/or abiraterone. Patients received durvalumab 1500 mg i.v. every 28 days and olaparib 300 mg tablets p.o. every 12 h until disease progression or unacceptable toxicity. All patients had biopsies of metastatic lesions with an evaluation for both germline and somatic mutations. RESULTS: Seventeen patients received durvalumab and olaparib. Nausea was the only nonhematologic grade 3 or 4 toxicity occurring in > 1 patient (2/17). No patients were taken off trial for toxicity. Median radiographic progression-free survival (rPFS) for all patients is 16.1 months (95% CI: 4.5-16.1 months) with a 12-month rPFS of 51.5% (95% CI: 25.7-72.3%). Activity is seen in patients with alterations in DDR genes, with a median rPFS of 16.1 months (95% CI: 7.8-18.1 months). Nine of 17 (53%) patients had a radiographic and/or PSA response. Patients with fewer peripheral myeloid-derived suppressor cells and with alterations in DDR genes were more likely to respond. Early changes in circulating tumor cell counts and in both innate and adaptive immune characteristics were associated with response. CONCLUSIONS: Durvalumab plus olaparib has acceptable toxicity, and the combination demonstrates efficacy, particularly in men with DDR abnormalities. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02484404 .

A specific missense mutation in GTF2I occurs at high frequency in thymic epithelial tumors.

We analyzed 28 thymic epithelial tumors (TETs) using next-generation sequencing and identified a missense mutation (chromosome 7 c.74146970T>A) in GTF2I at high frequency in type A thymomas, a relatively indolent subtype. In a series of 274 TETs, we detected the GTF2I mutation in 82% of type A and 74% of type AB thymomas but rarely in the aggressive subtypes, where recurrent mutations of known cancer genes have been identified. Therefore, GTF2I mutation correlated with better survival. GTF2I ß and δ isoforms were expressed in TETs, and both mutant isoforms were able to stimulate cell proliferation in vitro. Thymic carcinomas carried a higher number of mutations than thymomas (average of 43.5 and 18.4, respectively). Notably, we identified recurrent mutations of known cancer genes, including TP53, CYLD, CDKN2A, BAP1 and PBRM1, in thymic carcinomas. These findings will complement the diagnostic assessment of these tumors and also facilitate development of a molecular classification and assessment of prognosis and treatment strategies.

ERBB4 mutation analysis: emerging molecular target for melanoma treatment.

Recent sequencing efforts in melanoma have elucidated many previously unknown molecular pathways and biological mechanisms involved in melanoma development and progression and have yielded a number of promising targets for molecular therapy. As sequencing technologies have become more sophisticated and have revealed an ever-increasing complexity of the genetic landscape of melanoma, it has become clear that sequencing methods applied to clinical specimens have to reliably capture not only recurrent "hotspot" mutations like BRAFV600 and NRASQ61 or "mini-hotspot" mutations like exon 11 and 13 c-KIT but also heterogeneous somatic mutations dispersed across multiple functionally conserved regions of genes or entire genes. One such example in melanoma is the ERBB4 receptor, or HER4, a member of the Erb receptor family, which has recently been shown to be a major oncogenic "driver" in melanoma. Mutated ERBB4 signaling activates both aberrant ERBB4 and PI3K-AKT signal transduction, mediates sensitivity to small-molecule inhibition with the dual-tyrosine kinase inhibitor lapatinib, and has recently also been implied in oncogenic glutamatergic signaling in melanoma. Mutations involving the ERBB4 gene act as "gain-of-function" mutations and predominantly involve the extracellular domains of the receptor. Additional sequencing efforts have recently identified recurrent mutations ("mini-hotspots") or mutation clusters which affect the regulation of, e.g., ligand binding, arrangement of extracellular domain alignment, or intramolecular tether formation.In this chapter, we describe the methods used to determine the mutation status of all exons of the ERBB4 gene in clinical specimens obtained from patients afflicted by metastatic melanoma. Upon slight modifications, this protocol can also be used for mutational analysis of other oncogenes affected by "non-hotspot" mutations dispersed across multiple exons. This sequencing technique has successfully been applied within a clinical trial selecting patients with ERBB4-mutant melanoma for lapatinib treatment. With the increasing emergence of low-frequency oncogenes affected by heterogeneous activating mutations located in different exons and regions this method will provide a mean to translate the promise of recently obtained genetic knowledge into clinical genotype-directed targeted therapy trials.