THE "NEW" PROSTATE CANCER INFOLINK

Not so long ago (back in late 2013), Schweizer et al. reported data from a very small trial of an old drug called disulfiram (also known as Antabuse) in the treatment of men with progressive prostate cancer after first-line therapy.

Disulfiram is known to be a potent inhibitor of prostate cancer cell growth in vitro (i.e., in Petrie dishes in the laboratory). Although its mechanisms of anticancer activity are not well understood, the investigators hoped that disulfiram might prove useful as a treatment for selected men with progressive forms of prostate cancer.

A total of 19 patients actually received treatment in two cohorts. The men in cohort 1 received disulfiram at a dose of 250 mg daily; those in cohort 2 were treated with disulfiram 500 mg daily.

Alas, the data generated by Schweizer et al. were less than compelling:

• Only 2/9 patients in cohort 1 and 3/10 patients in cohort 2 showed any indication of the postulated therapeutic effect.
• Only 5/9  patients in cohort 1 (and no patients on cohort 2) stayed on treatment for as much as 6 months.
• Of the 5 patients who stayed on therapy for 6 months, all 5 had demonstrated PSA progression within that 6-month period.
• There were no changes in the PSA kinetics of the patients in either cohort.
• A total of 6/19 patients (3/9 patients in cohort 1 and 3/10 patients in cohort 2) exhibited grade 3 adverse effects to disulfiram therapy.

The authors concluded that:

Given the toxicities and no clinical benefits, further development of disulfiram should not be pursued in this population.

However, it is now being suggested that testing of disulfiram should be restarted … based on the idea that if prostate cancer tumors simultaneously stimulated with high levels of copper ions, then disulfiram will be more active in these patients. Apparently, when a copper supplement is administered in combination with disulfiram, the combination results in dramatic reductions in prostate tumor growth among animal models with advanced disease.

Now the medical use of copper compounds dates back to the time of Hippocrates in about 400 BCE, and copper is known to be involved in lots of biochemical reactions that are important to human cell function. Copper toxicity is rare in the general population, and copper levels are tightly regulated in the body. However, The “New” Prostate Cancer InfoLink is concerned that a trial like this one is still liable to come with significant risk for the trial participants because of the toxicity of disulfiram. In the worst case scenario, the combination of disulfiram + copper ions could actually increase the toxic impact of the disulfiram.

There is no sign of a trial protocol for the use of disulfiram in combination with copper supplementation (as yet) on the ClinicalTrials.gov web site. Ideally, any trial protocol will be initiated with relatively low doses of disulfiram (i.e., no higher than 250 mg daily) to assess risk for side effects prior to the testing of higher, potentially therapeutic doses. The target group of patients appears to be men with later stages of disease than those treated in the trial by Schweizer et al.

It is worth noting that: (a) Askgaard et al. have shown that disulfiram does appear to have some protective effect in the prevention of prostate cancer. (b) A Phase I trial of the combination of disulfiram + copper gluconate has already been completed in the treatment of about 20 men with treatment-refractory liver cancer (but data from this study are apparently still to be reported).

Filed under: Drugs in development, Living with Prostate Cancer, Management, Treatment | Tagged: activity, advanced, Antabuse, disulfiram, progressive, safety |