Randomized phase II trial of docetaxel plus prednisone in combination with
placebo or AT-101, an oral small molecule Bcl-2 family antagonist, as first-line
therapy for metastatic castration-resistant prostate cancer.
Author(s): Sonpavde G, Matveev V, Burke JM, Caton JR, Fleming MT, Hutson TE, Galsky MD,
Berry WR, Karlov P, Holmlund JT, Wood BA, Brookes M, Leopold L.
Affiliation(s): Texas Oncology and US Oncology Research, Houston, TX, USA.
guru.sonpavde@usoncology.com
Publication date & source: 2012, Ann Oncol. , 23(7):1803-8
BACKGROUND: AT-101 (A), a small molecule oral inhibitor of the Bcl-2 family, has
activity alone and in combination with docetaxel (Taxotere) and prednisone (DP)
in metastatic castration-resistant prostate cancer (mCRPC). A randomized,
double-blind, placebo-controlled phase II trial compared DP combined with either
AT-101 (A) or placebo in chemonaive mCRPC.
PATIENTS AND METHODS: Men with progressive mCRPC despite androgen deprivation
were eligible and randomized 1:1. Patients received docetaxel (75 mg/m2 day 1)
and prednisone 5 mg orally twice daily every 21 days with either AT-101 (40 mg)
or placebo twice daily orally on days 1-3. The primary end point was overall
survival (OS).
RESULTS: Two hundred and twenty-one patients were randomly assigned. Median OS
for AT-101 plus docetaxel-prednisone (ADP) and placebo-DP was 18.1 versus 17.8
months [hazard ratio (HR) 1.07, 95% confidence interval 0.72-1.55, P=0.63].
Secondary end points were also not statistically different. Grade 3/4 toxic
effects for ADP versus placebo-DP were cardiac events (5% versus 2%), lymphopenia
(23% versus 16%), neutropenia (47% versus 40%), ileus (2% versus 0%) and
pulmonary embolism (6% versus 2%). In a subgroup of high-risk mCRPC (n=34),
outcomes appeared to favor ADP (median OS 19 versus 14 months).
CONCLUSIONS: AT-101 was tolerable but did not extend OS when combined with DP in
mCRPC; a potential benefit was observed in high-risk patients.
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