TY - JOUR
T1 - Epigenetic therapy with panobinostat combined with bicalutamide rechallenge in castration-resistant prostate cancer
AU - Ferrari, Anna C.
AU - Alumkal, Joshi J.
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 M.
N1 - Publisher Copyright:
© 2018 American Association for Cancer Research.
PY - 2019/1/1
Y1 - 2019/1/1
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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85059476067&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-18-1589
DO - 10.1158/1078-0432.CCR-18-1589
M3 - Article
C2 - 30224345
AN - SCOPUS:85059476067
SN - 1078-0432
VL - 25
SP - 52
EP - 63
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 1
ER -