Repurposing itraconazole as a treatment for advanced prostate cancer

A noncomparative randomized phase ii trial in men with metastatic castration-resistant prostate cancer

Emmanuel Antonarakis, Elisabeth I. Heath, David C. Smith, Dana Rathkopf, Amanda L. Blackford, Daniel C. Danila, Serina King, Anja Frost, A. Seun Ajiboye, Ming Zhao, Janet Mendonca, Sushant Kachhap, Michelle Rudek-Renaut, Michael A Carducci

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)163-173
Number of pages11
JournalOncologist
Volume18
Issue number2
DOIs
StatePublished - 2013

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Itraconazole
Castration
Prostatic Neoplasms
Arm
Disease-Free Survival
Prostate-Specific Antigen
Circulating Neoplastic Cells
Survival Rate
Testosterone
Therapeutics
Medical Futility
Hypokalemia
Anorexia
Exanthema
Serum
Heterografts
Nausea
Androgens
Sulfates
Fatigue

Keywords

  • Angiogenesis
  • Hedgehog pathway
  • Itraconazole
  • Prostate cancer

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Repurposing itraconazole as a treatment for advanced prostate cancer : A noncomparative randomized phase ii trial in men with metastatic castration-resistant prostate cancer. / Antonarakis, Emmanuel; Heath, Elisabeth I.; Smith, David C.; Rathkopf, Dana; Blackford, Amanda L.; Danila, Daniel C.; King, Serina; Frost, Anja; Seun Ajiboye, A.; Zhao, Ming; Mendonca, Janet; Kachhap, Sushant; Rudek-Renaut, Michelle; Carducci, Michael A.

In: Oncologist, Vol. 18, No. 2, 2013, p. 163-173.

Research output: Contribution to journalArticle

Antonarakis, Emmanuel ; Heath, Elisabeth I. ; Smith, David C. ; Rathkopf, Dana ; Blackford, Amanda L. ; Danila, Daniel C. ; King, Serina ; Frost, Anja ; Seun Ajiboye, A. ; Zhao, Ming ; Mendonca, Janet ; Kachhap, Sushant ; Rudek-Renaut, Michelle ; Carducci, Michael A. / Repurposing itraconazole as a treatment for advanced prostate cancer : A noncomparative randomized phase ii trial in men with metastatic castration-resistant prostate cancer. In: Oncologist. 2013 ; Vol. 18, No. 2. pp. 163-173.
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title = "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-na{\"i}ve 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.",
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T2 - A noncomparative randomized phase ii trial in men with metastatic castration-resistant prostate cancer

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AU - Heath, Elisabeth I.

AU - Smith, David C.

AU - Rathkopf, Dana

AU - Blackford, Amanda L.

AU - Danila, Daniel C.

AU - King, Serina

AU - Frost, Anja

AU - Seun Ajiboye, A.

AU - Zhao, Ming

AU - Mendonca, Janet

AU - Kachhap, Sushant

AU - Rudek-Renaut, Michelle

AU - Carducci, Michael A

PY - 2013

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N2 - 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.

AB - 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.

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KW - Hedgehog pathway

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KW - Prostate cancer

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