Azacitidine for castration-resistant prostate cancer progressing on combined androgen blockade

Abstract

5172 Background: Vidaza (azacitidine, Pharmion Corp), a demethylating agent that activates genes repressed by promoter methylation, may induce responses in malignancies. Preclinically, demethylating agents reverse resistance of prostate cancer to androgen ablation. We conducted a phase II trial of azacitidine in CRPC (castration-resistant prostate cancer) progressing on CAB (combined androgen blockade). Methods: Eligibility criteria included chemonaïve metastatic or nonmetastatic CRPC on CAB and PSA-doubling time (DT) <3 months. The primary endpoint was modulation of PSADT; secondary objectives were PSA response, clinical progression-free survival (PFS), survival, and toxicities. Correlation of biologic activity [fetal hemoglobin (HbF), plasma DNA methylation] with outcomes was done. CAB was continued; azacitidine 75 mg/m2 SC was given Days 1–5 of each 28-day cycle up to 12 cycles or until clinical progression/toxicities. Results: The accrual of 36 patients (pts) is complete, and 20 are currently evaluable for PSADT. Most pts (80.6%) had metastases. A PSADT of >3 months was attained in 8 pts (40%) and 7 other pts exhibited some slowing of PSADT compared to baseline. Overall PSADT post-therapy was significantly prolonged compared to baseline (P<0.01). No PSA declines were observed. The median PFS was 13.3 weeks (95% CI: 11.3, 16.4), while 7 of 36 pts (intent-to-treat analysis) had prolonged PFS ranging from 16- 58 weeks. Grade 3 toxicities (no Grade 4) were fatigue (9%), and neutropenia (6%), with 2 pts discontinuing due to toxicities. Increases in HbF were noted in 8 pts. A linear mixed effect model fit for the average methylation level suggested a significant decreasing trend of average LINE methylation in plasma DNA over time. Correlation of biologic activity with outcomes is ongoing. Conclusions: Azacitidine exhibited biologic activity (increases in HbF, decreased plasma DNA methylation), and may have antitumor activity in progressive chemonaïve CRPC (prolongation of PSADT and PFS in selected patients). The toxicity profile was favorable. Updated clinical data and correlative studies from all pts will be presented. These data may warrant the further development of azacitidine for CRPC. This research was supported, in part, by a research grant from Pharmion Corp. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration ASCO Career Development Award