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Ref Type Journal Article
PMID (30514390)
Authors Karzai F, VanderWeele D, Madan RA, Owens H, Cordes LM, Hankin A, Couvillon A, Nichols E, Bilusic M, Beshiri ML, Kelly K, Krishnasamy V, Lee S, Lee MJ, Yuno A, Trepel JB, Merino MJ, Dittamore R, Marté J, Donahue RN, Schlom J, Killian KJ, Meltzer PS, Steinberg SM, Gulley JL, Lee JM, Dahut WL
Title Activity of durvalumab plus olaparib in metastatic castration-resistant prostate cancer in men with and without DNA damage repair mutations.
Journal Journal for immunotherapy of cancer
Vol 6
Issue 1
Date 2018 Dec 04
URL
Abstract Text 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.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.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.Durvalumab plus olaparib has acceptable toxicity, and the combination demonstrates efficacy, particularly in men with DDR abnormalities.ClinicalTrials.gov identifier: NCT02484404 .

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown prostate cancer not applicable Durvalumab + Olaparib Phase II Actionable In a Phase II trial, Imfinzi (durvalumab) plus Lynparza (olaparib) resulted in a decrease in PSA greater than or equal to 50% in 53% (9/17) of patients with metastatic castrate-resistant prostate cancer, with radiographic response in 4 of those 9, a median radiographic progression-free survival (PFS) of 16.1 mo., and a 12-mo. PFS probability of 83.3% in patients with mutations in DNA damage response (DDR) genes, compared to 36.4% in patients without DDR gene mutations (PMID: 30514390; NCT02484404). 30514390