Activity of durvalumab plus olaparib in metastatic castration-resistant prostate cancer in men with and without DNA damage repair mutations 11 Medical and Health Sciences 1112 Oncology and Carcinogenesis

Fatima Karzai, David James VanderWeele, Ravi A. Madan, Helen Owens, Lisa M. Cordes, Amy Hankin, Anna Couvillon, Erin Nichols, Marijo Bilusic, Michael L. Beshiri, Kathleen Kelly, Venkatesh Krishnasamy, Sunmin Lee, Min Jung Lee, Akira Yuno, Jane B. Trepel, Maria J. Merino, Ryan Dittamore, Jennifer Marté, Renee N. DonahueJeffrey Schlom, Keith J. Killian, Paul S. Meltzer, Seth M. Steinberg, James L. Gulley, Jung Min Lee, William L. Dahut*

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

72 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article number141
JournalJournal for immunotherapy of cancer
Volume6
Issue number1
DOIs
StatePublished - Dec 4 2018

Keywords

  • Abiraterone
  • Anti-PD-L1
  • Durvalumab
  • Enzalutamide
  • Immunotherapy
  • Olaparib
  • PARP inhibitor
  • mCRPC

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Molecular Medicine
  • Oncology
  • Pharmacology
  • Cancer Research

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