Azacitidine favorably modulates PSA kinetics correlating with plasma DNA LINE-1 hypomethylation in men with chemonaïve castration-resistant prostate cancer.
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
Chemonaïve 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 chemonaïve 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.
Sonpavde
Guru
G
US Oncology Research, Inc., The Woodlands, TX 77380, USA. Guru.Sonpavde@USOncology.com
Aparicio
Ana M
AM
Zhan
Feng
F
North
Brittany
B
Delaune
Robert
R
Garbo
Lawrence E
LE
Rousey
Steven R
SR
Weinstein
Ralph E
RE
Xiao
Lianchun
L
Boehm
Kristi A
KA
Asmar
Lina
L
Fleming
Mark T
MT
Galsky
Matthew D
MD
Berry
William R
WR
Von Hoff
Daniel D
DD
D000230:Adenocarcinoma / Q000097:blood / Q000188:drug therapy* / Q000235:genetics; D000368:Aged; D000369:Aged, 80 and over; D000726:Androgen Antagonists / Q000627:therapeutic use; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D001374:Azacitidine / Q000627:therapeutic use*; D002369:Castration; D019175:DNA Methylation / Q000187:drug effects*; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D053208:Kaplan-Meier Estimate; D020084:Long Interspersed Nucleotide Elements / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000235:genetics
D000726:Androgen Antagonists; D000964:Antimetabolites, Antineoplastic; D017430:Prostate-Specific Antigen; D001374:Azacitidine