CHICAGO—Itraconazole, an oral antifungal drug, may keep prostate cancer (PCa) from worsening and delay the need for chemotherapy in men with metastatic castration-resistant PCa (mCRPC), according new data presented at the 47th Annual Meeting of the American Society of Clinical Oncology.

“The most effective therapy we have right now for metastatic prostate cancer is hormone therapy, and when it doesn’t work, the next step is usually chemotherapy,” said lead investigator Emmanuel Antonarakis, MD, Assistant Professor of Oncology at Johns Hopkins Kimmel Cancer Center in Baltimore. “We tested two doses [of itraconazole] and we found that patients who got the high dose were more likely to have a PSA decline of 30% or more.”

Itraconazole is approved by the FDA for treating fungal infections in nails and other organs. In a previous investigation, Johns Hopkins researchers screened a database of more than 3,000 FDA-approved drugs and found that itraconazole appears to block angiogenesis—the only drug in its class to do so—much like the anticancer drug bevacizumab (Avastin). Itraconazole also disrupts a key cancer-initiating biological pathway known as Hedgehog signaling. 

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Dr. Antonarakis’ group enrolled 46 men with mCRPC in a phase 2 trial of oral itraconazole, randomizing patients to receive either a low dose (200 mg/day) or a high dose (600 mg/day) of the drug until disease progression or unacceptable toxicity. The primary endpoint was PSA progression-free survival (PPFS) at 24 weeks.  The high-dose group included 29 men and the low-dose arm included 17 men. The low-dose group was closed early due to a pre-specified futility analysis.

After a median follow-up of 21.6 weeks in the high-dose arm and 11.9 weeks in the low-dose arm, 24 of 29 men and 17 of 17 men, respectively, were evaluable for the primary endpoint.

Eleven of the 24 men (48.8%) in the high-dose group had stable or declining PSA levels by week 24 compared with only two of 17 men (11.8%) in the low-dose arm.

Nearly one-third of the men taking the high dose had PSA reductions of 30% or more. Dr. Antonarakis, who presented the study findings at the meeting, said men with mCRPC receiving no treatment typically would worsen in 8-12 weeks.

In addition, 12 of 14 men taking high-dose itraconazole had lower levels of circulating tumor cells after therapy compared to their baseline levels. “We also tested whether itraconazole acted as hormone therapy by tracking levels of testosterone and DHEA in the blood and we found no reductions of either testosterone or DHEA,” Dr. Antonarakis said. “This finding shows that itraconazole is not just another hormone therapy, and has a unique mechanism of action.”

Common toxicities that occurred in 20% or more of the patients included fatigue, nausea, anorexia, rash, hypokalemia, hypertension, and edema. Most adverse effects were manageable, however, and resolved with potassium replacement pills, anti-hypertensives, and diuretics.

“This is an experimental drug and it should not be used except in clinical trials,” Dr. Antonarakis cautioned. “The next step in development of this drug [as a treatment for mCRPC] will be to test the high dose against placebo in patients with advanced prostate cancer.”