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

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 ⁶⁴ CuCl₂ 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 ⁶⁴ CuCl₂ 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.

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