Mature results of a randomized phase II study of OGX-011 in combination with docetaxel/prednisone versus docetaxel/prednisone in patients with metastatic castration-resistant prostate cancer
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5012 Background: Clusterin is a cytoprotective chaperone protein associated with CRPC progression. OGX is a 2'-methoxyethyl antisense that potentiates chemotherapy in xenografts and inhibits clusterin expression at doses of <640 mg. Methods: Pts with CRPC and chemo-naive received docetaxel (DOC) 75mg/m2 q3w + OGX 640mg IV weekly + prednisone (Arm A) or DOC + prednisone (Arm B) in a single stage randomized phase II design. Primary endpoint was PSA response rate (RR). Progression-free survival (PFS) and overall survival (OS) were secondary endpoints. Planned sample size was 40/arm: Arm A the hypotheses (PSA RR<40% vs. >60%) could be tested at 10% β and 10% α, Arm B the true PSA RR could be estimated with half-width of the 90% CI<13% if PSA RR=40%. Results: 82 pts (41 Arm A, 41 Arm B) were randomized from 09/05–12/06. At this analysis time, all pts are off therapy and 49 have died. One pt was ineligible but included in ITT survival analysis. Baseline characteristics were similar: median age 69 (49–87), PSA >100 μg/L in 51%, Hgb ≥100 g/L in 98%, alk phos >ULN in 44%, LDH >ULN in 36%, ECOG performance status (PS) 0:1 in 51%:49%, bone/lymph node/visceral metastases in 69%/50%/28%. Median cycles for Arm A and B was 9 and 7. Adverse events associated with OGX included fatigue, fever, rigors, diarrhea and rash. Mean serum clusterin change on day 1 cycle 2 was -18% in Arm A and +8% in Arm B (p = 0.0005). PSA RR was 58% (Arm A) and 54% (Arm B). PSA declines at 12 weeks of any/>30%/>50% was observed in 87%/65%/45% (Arm A) and 68%/58%/34% (Arm B). PSA/objective disease progression as best response occurred in 0%/4% (Arm A), and 3%/17% (Arm B). PFS for Arms A and B was 7.3 (5.3–8.8) and 6.1 months (3.7–8.6). Median OS for Arms A and B was 27.5 (19.2-∞) and 16.9 months (12.7–26.0) (unadjusted HR = 0.60 [0.34–1.06], p = 0.07). Variables predictive of OS on multivariate analysis: PS 0 vs 1 (p = 0.0002), presence of visceral metastasis (p = 0.006) and treatment assignment (HR = 0.54 [0.29–0.97], p = 0.04). Conclusions: The PSA RR in both arms met criterion for further study. OGX reduced serum clusterin and OS appears superior with DOC/OGX. This combination warrants further evaluation. Supported by a grant from the NCI-Canada/Canadian Cancer Society. [Table: see text]
