Epigenetic Therapy with Panobinostat Combined with Bicalutamide Re-challenge in Castration-Resistant Prostate Cancer

Purpose: To assess the action of panobinostat, a histone deacetylase inhibitor (HDACI), in restoring sensitivity to bicalutamide in a castration-resistant prostate cancer (CRPC) model; to assess the efficacy and safety of the panobinostat/bicalutamide combination in CRPC patients resistant to second-line antiandrogen therapy (2^ndLAARx). Experimental Design: The CWR22PC xenograft and isogenic cell line were tested for drug interactions on tumor cell growth and androgen receptor (AR), AR-splice variant7 and AR targets. A phase I trial had a 3x3 panobinostat dose-escalation design. The phase II randomized 55 patients to panobinostat 40mg (A-arm) or 20mg (B-arm) triweekly x2 weeks with bicalutamide 50mg/day in 3-week cycles. The primary endpoint was percent of patients radiographic progression-free (rPF) at 36 weeks versus historical 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- and B-arms (47.5%; 38.5%). The A-arm but not the B-arm exceeded expectations for times (medians) to rP (33.9 and 10 weeks), and from PSA progression to rP (24 and 5.9 weeks). A-arm/B-arm: adverse events (AEs), 62%/19%; treatment stopped for AEs, 27.5%/11.5%; dose reduction required, 41%/4%. Principal A-arm grade≥3 AEs: thrombocytopenia (31%), fatigue (14%). Conclusions: The 40mg panobinostat/bicalutamide regimen increased radiographic progression-free survival in CRPC patients resistant to 2^ndLAARx. 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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