Epigenetic therapy with panobinostat combined with bicalutamide rechallenge in castration-resistant prostate cancer

Anna C. Ferrari, Joshi Alumkal, Mark N. Stein, Mary Ellen Taplin, James Babb, Ethan S. Barnett, Alejandro Gomez-Pinillos, Xiaomei Liu, Dirk Moore, Robert DiPaola, Tomasz (Tom) Beer

    Research output: Contribution to journalArticle

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    Abstract

    Purpose: This study assesses the action of panobinostat, a histone deacetylase inhibitor (HDACI), in restoring sensitivity to bicalutamide in a castration-resistant prostate cancer (CRPC) model and the efficacy and safety of the panobinostat/bicalutamide combination in CRPC patients resistant to second-line antiandrogen therapy (2ndLAARx). Patients and Methods: The CWR22PC xenograft and isogenic cell line were tested for drug interactions on tumor cell growth and on the androgen receptor (AR), AR-splice variant7, and AR targets. A phase I trial had a 3 3 panobinostat dose-escalation design. The phase II study randomized 55 patients to panobinostat 40 mg (A arm) or 20 mg (B arm) triweekly 2 weeks with bicalutamide 50 mg/day in 3-week cycles. The primary endpoint was to determine the percentage of radiographic progression-free (rPF) patients at 36 weeks versus historic high-dose bicalutamide. Results: In the model, panobinostat/bicalutamide demonstrated synergistic antitumor effect while reducing AR activity. The dose-limiting toxicity was not reached. The probability of remaining rPF exceeded protocol-specified 35% in the A arm and 47.5% and 38.5% in the B arm. The probabilities of remaining rPF were 47.5% in the A arm and 38.5% in the B arm, exceeding the protocol-specified threshold of 35%. A arm/B arm: adverse events (AE), 62%/19%; treatment stopped for AEs, 27.5%/11.5%; dose reduction required, 41%/4%; principal A-arm grade 3 AEs, thrombocytopenia (31%) and fatigue (14%). Conclusions: The 40 mg panobinostat/bicalutamide regimen increased rPF survival in CRPC patients resistant to 2ndLAARx. Panobinostat toxicity was tolerable with dose reductions. Epigenetic HDACI therapy reduces AR-mediated resistance to bicalutamide in CRPC models with clinical benefit in patients. The combination merits validation using a second-generation antiandrogen.

    Original languageEnglish (US)
    Pages (from-to)52-63
    Number of pages12
    JournalClinical Cancer Research
    Volume25
    Issue number1
    DOIs
    StatePublished - Jan 1 2019

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    Castration
    Epigenomics
    Prostatic Neoplasms
    Arm
    Androgen Receptors
    Androgen Antagonists
    Histone Deacetylase Inhibitors
    Therapeutics
    bicalutamide
    panobinostat
    Drug Interactions
    Heterografts
    Disease-Free Survival
    Fatigue
    Safety
    Cell Line
    Growth

    ASJC Scopus subject areas

    • Oncology
    • Cancer Research

    Cite this

    Epigenetic therapy with panobinostat combined with bicalutamide rechallenge in castration-resistant prostate cancer. / Ferrari, Anna C.; Alumkal, Joshi; Stein, Mark N.; Taplin, Mary Ellen; Babb, James; Barnett, Ethan S.; Gomez-Pinillos, Alejandro; Liu, Xiaomei; Moore, Dirk; DiPaola, Robert; Beer, Tomasz (Tom).

    In: Clinical Cancer Research, Vol. 25, No. 1, 01.01.2019, p. 52-63.

    Research output: Contribution to journalArticle

    Ferrari, AC, Alumkal, J, Stein, MN, Taplin, ME, Babb, J, Barnett, ES, Gomez-Pinillos, A, Liu, X, Moore, D, DiPaola, R & Beer, TT 2019, 'Epigenetic therapy with panobinostat combined with bicalutamide rechallenge in castration-resistant prostate cancer', Clinical Cancer Research, vol. 25, no. 1, pp. 52-63. https://doi.org/10.1158/1078-0432.CCR-18-1589
    Ferrari, Anna C. ; Alumkal, Joshi ; Stein, Mark N. ; Taplin, Mary Ellen ; Babb, James ; Barnett, Ethan S. ; Gomez-Pinillos, Alejandro ; Liu, Xiaomei ; Moore, Dirk ; DiPaola, Robert ; Beer, Tomasz (Tom). / Epigenetic therapy with panobinostat combined with bicalutamide rechallenge in castration-resistant prostate cancer. In: Clinical Cancer Research. 2019 ; Vol. 25, No. 1. pp. 52-63.
    @article{bcea60c0b44f4af3ad2384a6f9573f03,
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    abstract = "Purpose: This study assesses the action of panobinostat, a histone deacetylase inhibitor (HDACI), in restoring sensitivity to bicalutamide in a castration-resistant prostate cancer (CRPC) model and the efficacy and safety of the panobinostat/bicalutamide combination in CRPC patients resistant to second-line antiandrogen therapy (2ndLAARx). Patients and Methods: The CWR22PC xenograft and isogenic cell line were tested for drug interactions on tumor cell growth and on the androgen receptor (AR), AR-splice variant7, and AR targets. A phase I trial had a 3 3 panobinostat dose-escalation design. The phase II study randomized 55 patients to panobinostat 40 mg (A arm) or 20 mg (B arm) triweekly 2 weeks with bicalutamide 50 mg/day in 3-week cycles. The primary endpoint was to determine the percentage of radiographic progression-free (rPF) patients at 36 weeks versus historic high-dose bicalutamide. Results: In the model, panobinostat/bicalutamide demonstrated synergistic antitumor effect while reducing AR activity. The dose-limiting toxicity was not reached. The probability of remaining rPF exceeded protocol-specified 35{\%} in the A arm and 47.5{\%} and 38.5{\%} in the B arm. The probabilities of remaining rPF were 47.5{\%} in the A arm and 38.5{\%} in the B arm, exceeding the protocol-specified threshold of 35{\%}. A arm/B arm: adverse events (AE), 62{\%}/19{\%}; treatment stopped for AEs, 27.5{\%}/11.5{\%}; dose reduction required, 41{\%}/4{\%}; principal A-arm grade 3 AEs, thrombocytopenia (31{\%}) and fatigue (14{\%}). Conclusions: The 40 mg panobinostat/bicalutamide regimen increased rPF survival in CRPC patients resistant to 2ndLAARx. Panobinostat toxicity was tolerable with dose reductions. Epigenetic HDACI therapy reduces AR-mediated resistance to bicalutamide in CRPC models with clinical benefit in patients. The combination merits validation using a second-generation antiandrogen.",
    author = "Ferrari, {Anna C.} and Joshi Alumkal and Stein, {Mark N.} and Taplin, {Mary Ellen} and James Babb and Barnett, {Ethan S.} and Alejandro Gomez-Pinillos and Xiaomei Liu and Dirk Moore and Robert DiPaola and Beer, {Tomasz (Tom)}",
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    AU - Ferrari, Anna C.

    AU - Alumkal, Joshi

    AU - Stein, Mark N.

    AU - Taplin, Mary Ellen

    AU - Babb, James

    AU - Barnett, Ethan S.

    AU - Gomez-Pinillos, Alejandro

    AU - Liu, Xiaomei

    AU - Moore, Dirk

    AU - DiPaola, Robert

    AU - Beer, Tomasz (Tom)

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    N2 - Purpose: This study assesses the action of panobinostat, a histone deacetylase inhibitor (HDACI), in restoring sensitivity to bicalutamide in a castration-resistant prostate cancer (CRPC) model and the efficacy and safety of the panobinostat/bicalutamide combination in CRPC patients resistant to second-line antiandrogen therapy (2ndLAARx). Patients and Methods: The CWR22PC xenograft and isogenic cell line were tested for drug interactions on tumor cell growth and on the androgen receptor (AR), AR-splice variant7, and AR targets. A phase I trial had a 3 3 panobinostat dose-escalation design. The phase II study randomized 55 patients to panobinostat 40 mg (A arm) or 20 mg (B arm) triweekly 2 weeks with bicalutamide 50 mg/day in 3-week cycles. The primary endpoint was to determine the percentage of radiographic progression-free (rPF) patients at 36 weeks versus historic high-dose bicalutamide. Results: In the model, panobinostat/bicalutamide demonstrated synergistic antitumor effect while reducing AR activity. The dose-limiting toxicity was not reached. The probability of remaining rPF exceeded protocol-specified 35% in the A arm and 47.5% and 38.5% in the B arm. The probabilities of remaining rPF were 47.5% in the A arm and 38.5% in the B arm, exceeding the protocol-specified threshold of 35%. A arm/B arm: adverse events (AE), 62%/19%; treatment stopped for AEs, 27.5%/11.5%; dose reduction required, 41%/4%; principal A-arm grade 3 AEs, thrombocytopenia (31%) and fatigue (14%). Conclusions: The 40 mg panobinostat/bicalutamide regimen increased rPF survival in CRPC patients resistant to 2ndLAARx. Panobinostat toxicity was tolerable with dose reductions. Epigenetic HDACI therapy reduces AR-mediated resistance to bicalutamide in CRPC models with clinical benefit in patients. The combination merits validation using a second-generation antiandrogen.

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