Prospective clinical trial of disulfiram plus copper in men with metastatic castration-resistant prostate cancer

Tian Zhang, Julie Kephart, Elizabeth Bronson, Monika Anand, Christine Daly, Ivan Spasojevic, Subha Bakthavatsalam, Katherine Franz, Hannah Berg, Georgia S. Karachaliou, Olga G. James, Lauren Howard, Susan Halabi, Michael R. Harrison, Andrew J. Armstrong, Daniel J. George

Research output: Contribution to journalArticlepeer-review

Abstract

Background: In preclinical models of prostate cancer (PC), disulfiram (DSF) reduced tumor growth only when co-administered with copper (Cu), and Cu uptake in tumors is partially regulated by androgen-receptor signaling. However, prior trials of DSF in PC used DSF as monotherapy. Objective: To assess the safety and efficacy of concurrent administration of DSF with Cu, we conducted a phase 1b clinical trial of patients with metastatic castration-resistant prostate cancer (mCRPC) receiving Cu with DSF. Design, setting, and participants: Patients with mCRPC were treated in two cohorts: mCRPC with nonliver/peritoneal metastases (A), and mCRPC with liver and/or peritoneal metastases (B). Baseline Cu avidity was measured by 64CuCl2 PET scan. Intravenous (IV) CuCl2 was given weekly for three doses with oral daily DSF followed by daily oral Cu gluconate and DSF until disease progression. DSF and metabolite diethyldithiocarbamic acid methyl ester (Me-DDC) levels in plasma were measured. DSF and Me-DDC were then assessed for cytotoxicity in vitro. Results: We treated nine patients with mCRPC (six on cohort A and three on cohort B). Bone and nodal metastases showed differential and heterogeneous Cu uptake on 64CuCl2 PET scans. No confirmed PSA declines or radiographic responses were observed. Median PFS was 2.8 months and median OS was 8.3 months. Common adverse events included fatigue and psychomotor depression; no Grade 4/5 AEs were observed. Me-DDC was measurable in all samples (LOQ = 0.512 ng/ml), whereas DSF was not (LOQ = 0.032 ng/ml, LOD = 0.01 ng/ml); Me-DDC was not cytotoxic in vitro. Conclusions: Oral DSF is not an effective treatment for mCRPC due to rapid metabolism into an inactive metabolite, Me-DDC. This trial has stopped enrollment and further work is needed to identify a stable DSF formulation for treatment of mCRPC.

Original languageEnglish (US)
Pages (from-to)858-866
Number of pages9
JournalProstate
Volume82
Issue number7
DOIs
StatePublished - May 15 2022
Externally publishedYes

Keywords

  • copper PET imaging (64CuCl2 PET)
  • diethyldithiocarbamic Acid Methyl Ester (Me-DDC)
  • disulfiram (DSF)
  • metastatic castration-resistant prostate cancer (mCRPC)

ASJC Scopus subject areas

  • Oncology
  • Urology

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