RT Journal Article
SR Electronic
T1 Activity of durvalumab plus olaparib in metastatic castration-resistant prostate cancer in men with and without DNA damage repair mutations
JF Journal for ImmunoTherapy of Cancer
JO J Immunother Cancer
FD BMJ Publishing Group Ltd
SP 141
DO 10.1186/s40425-018-0463-2
VO 6
IS 1
A1 Fatima Karzai
A1 David VanderWeele
A1 Ravi A. Madan
A1 Helen Owens
A1 Lisa M. Cordes
A1 Amy Hankin
A1 Anna Couvillon
A1 Erin Nichols
A1 Marijo Bilusic
A1 Michael L. Beshiri
A1 Kathleen Kelly
A1 Venkatesh Krishnasamy
A1 Sunmin Lee
A1 Min-Jung Lee
A1 Akira Yuno
A1 Jane B. Trepel
A1 Maria J. Merino
A1 Ryan Dittamore
A1 Jennifer Marté
A1 Renee N. Donahue
A1 Jeffrey Schlom
A1 Keith J. Killian
A1 Paul S. Meltzer
A1 Seth M. Steinberg
A1 James L. Gulley
A1 Jung-Min Lee
A1 William L. Dahut
YR 2018
UL http://jitc.bmj.com/content/6/1/141.abstract
AB 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.Jung-Min Lee and William L. Dahut contributed equally to this work.Jung-Min Lee and William L. Dahut share senior authorship.Abbreviations:CCyclecDCConventional dendritic cellscGASCyclic GMP-AMP synthaseCTCCirculating tumor cellDDayDCDendritic cellDDRDNA damage repairIFNInterferonirAEImmune-related adverse eventmCRPCMetastatic castration-resistant prostate cancermDCMature dendritic cellMDSCMyeloid derived suppressor cellMDSCMyeloid-derived suppressor cellMMRMismatch repairNKNatural killerPD-1Programmed cell death protein 1pDCPlasmacytoid DCPD-L1Programmed death-ligand 1PSAProstate-specific antigenrPFSRadiographic progression-free survivalRS3PERemitting seronegative symmetrical synovitis with pitting edemaSTINGStimulator of interferon genesTregsRegulatory T cells