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Clin Cancer Res. 2019 Jan 1;25(1):52-63. doi: 10.1158/1078-0432.CCR-18-1589. Epub 2018 Sep 17.

Epigenetic Therapy with Panobinostat Combined with Bicalutamide Rechallenge in Castration-Resistant Prostate Cancer.

Author information

1
Icahn School of Medicine Mount Sinai, New York, New York. anna.ferrarip@outlook.com.
2
OHSU Knight Cancer Institute, Portland, Oregon.
3
Columbia University Medical Center, New York, New York.
4
Dana-Farber Cancer Institute, Boston, Massachusetts.
5
Perlmutter Cancer Center, NYU Langone Medical Center, New York, New York.
6
Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey.
7
University of Kentucky College of Medicine, Lexington, Kentucky.

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.

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