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

    7 Scopus citations

    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

    ASJC Scopus subject areas

    • Oncology
    • Cancer Research

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  • Cite this

    Ferrari, A. C., Alumkal, J., Stein, M. N., Taplin, M. E., Babb, J., Barnett, E. S., Gomez-Pinillos, A., Liu, X., Moore, D., DiPaola, R., & Beer, T. T. (2019). Epigenetic therapy with panobinostat combined with bicalutamide rechallenge in castration-resistant prostate cancer. Clinical Cancer Research, 25(1), 52-63. https://doi.org/10.1158/1078-0432.CCR-18-1589