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A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
Published on: March 6, 2018
Repurposing itraconazole as a treatment for advanced prostate cancer: a noncomparative randomized phase II trial in
Emmanuel S Antonarakis1, Elisabeth I Heath, David C Smith
1Prostate Cancer Research Program, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, 1650 Orleans Street, CRB1-1M45, Baltimore, Maryland 21231-1000, USA. eantona1@jhmi.edu
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.
Insights
High-dose itraconazole demonstrated modest antitumor activity in men with metastatic castration-resistant prostate cancer. The 600 mg/day dose showed significant prostate-specific antigen progression-free survival, unlike the lower dose.
Area of Science:
- Oncology
- Pharmacology
Background:
- Itraconazole, an antifungal, inhibits angiogenesis and Hedgehog signaling.
- Preclinical models show itraconazole delays tumor growth in prostate cancer xenografts.
Purpose of the Study:
- Evaluate the antitumor efficacy of two oral itraconazole doses in men with metastatic prostate cancer.
- Assess prostate-specific antigen progression-free survival (PPFS) at 24 weeks as the primary endpoint.
Main Methods:
- A noncomparative, randomized phase II study assigned 46 chemotherapy-naïve metastatic castration-resistant prostate cancer (CRPC) patients to low-dose (200 mg/day) or high-dose (600 mg/day) itraconazole.
- Endpoints included PPFS, progression-free survival (PFS), PSA response rates, circulating tumor cell (CTC) enumeration, and serum androgen levels.
Main Results:
- High-dose itraconazole achieved a 48.0% PPFS rate at 24 weeks, compared to 11.8% for the low-dose arm.
- Median PFS was 35.9 weeks for high-dose vs. 11.9 weeks for low-dose. PSA response rates were 14.3% and 0%, respectively.
- Itraconazole favorably affected CTC counts and suppressed Hedgehog signaling but did not reduce testosterone levels. Common toxicities were observed.
Conclusions:
- High-dose itraconazole (600 mg/day) exhibits modest antitumor activity in metastatic CRPC patients.
- This activity is not attributed to testosterone suppression.
- Further investigation into itraconazole's role in prostate cancer treatment is warranted.
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