Azacitidine favorably modulates PSA kinetics correlating with plasma DNA LINE-1 hypomethylation in men with chemonaive castration-resistant prostate cancer

作者：Sonpavde Guru^*; Aparicio Ana M; Zhan Feng; North Brittany; DeLaune Robert; Garbo Lawrence E; Rousey Steven R; Weinstein Ralph E; Xiao Lianchun; Boehm Kristi A; Asmar Lina; Fleming Mark T; Galsky Matthew D; Berry William R; Von Hoff Daniel D

来源：Urologic Oncology-Seminars and Original Investigations, 2011, 29(6): 682-689.

DOI：10.1016/j.urolonc.2009.09.015

• Azacitidine
• Castration-resistant prostate cancer
• Methylation

Background: Azacitidine is a hypomethylating agent that activates genes repressed by promoter methylation. Preclinically, demethylating agents reverse resistance of prostate cancer to androgen ablation. A phase II trial evaluated azacitidine for men with castration-resistant prostate cancer (CRPC) progressing on combined androgen blockade (CAB).
Methods: Chemonaive patients with CRPC on CAB and PSA-doubling time (DT) < 3 months were eligible. The primary endpoint was prolongation of PSA-DT to >= 3 months. Correlation of biologic activity (fetal hemoglobin, plasma DNA LINE-1 methylation) with prolongation of PSA-DT was tested. CAB was continued and azacitidine 75 mg/m(2) was administered subcutaneously on days 1-5 of each 28-day cycle up to 12 cycles or until clinical progression/intolerable toxicities.
Results: Thirty-six patients were enrolled, 80.6% had metastatic disease, and 34 were evaluable. A PSA-DT >= 3 months was attained in 19 patients (55.8%). Overall median PSA-DT was significantly prolonged compared to baseline (2.8 vs. 1.5 months, P < 0.01). Fourteen patients had some PSA decline during therapy and 1 patient had a >= 30% decline compared with baseline. The median clinical progression-free survival was 12.4 weeks. Grade 3 toxicities included fatigue (12%), and neutropenia (6%), with 4 patients discontinuing due to toxicities. A trend in decreasing plasma DNA LINE-1 methylation was seen with longer treatment duration (P = 0.06), which significantly correlated with prolongation of PSA-DT (P = 0.02).
Conclusions: Azacitidine favorably modulates PSA kinetics in chemonaive CRPC that correlates with decreasing plasma DNA LINE-1 methylation. Given the excellent tolerability, further development of azacitidine for CRPC may be warranted, with exploration of combination regimens.

• 出版日期2011-12