Repurposing itraconazole as a treatment for advanced prostate cancer: a noncomparative randomized phase II trial in men with metastatic castration-resistant prostate cancer

Abstract

Background: The antifungal drug itraconazole inhibits angiogenesis and Hedgehog signaling and delays tumor growth in murine prostate cancer xenograft models. We conducted a noncomparative, randomized, phase II study evaluating the antitumor efficacy of two doses of oral itraconazole in men with metastatic prostate cancer.

Patients and methods: We randomly assigned 46 men with chemotherapy-naïve metastatic castration-resistant prostate cancer (CRPC) to receive low-dose (200 mg/day) or high-dose (600 mg/day) itraconazole until disease progression or unacceptable toxicity. The primary endpoint was the prostate-specific antigen (PSA) progression-free survival (PPFS) rate at 24 weeks; a 45% success rate in either arm was prespecified as constituting clinical significance. Secondary endpoints included the progression-free survival (PFS) rate and PSA response rate (Prostate Cancer Working Group criteria). Exploratory outcomes included circulating tumor cell (CTC) enumeration, serum androgen measurements, as well as pharmacokinetic and pharmacodynamic analyses.

Results: The high-dose arm enrolled to completion (n = 29), but the low-dose arm closed early (n = 17) because of a prespecified futility rule. The PPFS rates at 24 weeks were 11.8% in the low-dose arm and 48.0% in the high-dose arm. The median PFS times were 11.9 weeks and 35.9 weeks, respectively. PSA response rates were 0% and 14.3%, respectively. In addition, itraconazole had favorable effects on CTC counts, and it suppressed Hedgehog signaling in skin biopsy samples. Itraconazole did not reduce serum testosterone or dehydroepiandrostenedione sulfate levels. Common toxicities included fatigue, nausea, anorexia, rash, and a syndrome of hypokalemia, hypertension, and edema.

Conclusion: High-dose itraconazole (600 mg/day) has modest antitumor activity in men with metastatic CRPC that is not mediated by testosterone suppression.

Conflict of interest statement

Disclosures of potential conflicts of interest may be found at the end of this article.

Figures

Figure 1.

Consort diagram.

Figure 2.

Clinical effects of itraconazole. (A): Kaplan–Meier curves of PPFS in men receiving low-dose and high-dose itraconazole. (B): Kaplan–Meier curves of PFS in each treatment arm. (C): Waterfall plots showing best PSA responses among men receiving low-dose and high-dose itraconazole. The asterisk denotes a clipped PSA value. Prior treatment with ketoconazole is indicated by the hashed bars. (D): Waterfall plots showing best objective responses in measurable lesions according to Response Evaluation Criteria in Solid Tumors, version 1.0. Prior treatment with ketoconazole is indicated by the hashed bars (and daggers). Abbreviations: CI, confidence interval; PFS, progression-free survival; PPFS, PSA progression-free survival; PSA, prostate-specific antigen.

Figure 3.

Endocrine effects of itraconazole. (A): Effect of low- and high-dose itraconazole on serum testosterone concentrations (data are shown as medians and interquartile ranges). (B): Effect of low- and high-dose itraconazole on serum DHEA-S concentrations. (C): Effect of low- and high-dose itraconazole on serum aldosterone concentrations. (D): Effect of low- and high-dose itraconazole on plasma ACTH concentrations. Abbreviations: ACTH, adrenocorticotropic hormone; DHEA-S, dehydroepiandrostenedione-sulfate.

Figure 4.

GLI1 modulation by itraconazole. (A): Waterfall plots showing GLI1 modulation in skin punch biopsies, depicted as fold change in GLI expression post-treatment compared with baseline values. (B): Kaplan–Meier curves depicting PPFS according to GLI1 modulation status. (C): Kaplan–Meier curves depicting PFS according to GLI1 modulation status. (D): Scatterplot showing the association between GLI1 modulation and PSA change. Abbreviations: PFS, progression-free survival; PPFS, PSA progression-free survival; PSA, prostate-specific antigen.

Figure 4.

Continued.