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.

Abstract

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.

• Authors: G Sonpavde, V Matveev, J M Burke, J R Caton, M T Fleming, T E Hutson, M D Galsky, W R Berry, P Karlov, J T Holmlund, B A Wood, M Brookes, L Leopold
• Journal: Annals of oncology : official journal of the European Society for Medical Oncology (Ann Oncol) Vol. 23 Issue 7 Pg. 1803-8 (Jul 2012) ISSN: 1569-8041 [Electronic] England
• PMID: 22112969 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Placebos
• Proto-Oncogene Proteins c-bcl-2
• Taxoids
• Docetaxel
• Gossypol
• gossypol acetic acid
• Prednisone

Topics

• Adenocarcinoma (drug therapy, mortality, secondary)
• Aged
• Aged, 80 and over
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Bone Neoplasms (drug therapy, mortality, secondary)
• Docetaxel
• Gossypol (administration & dosage, analogs & derivatives)
• Humans
• Kaplan-Meier Estimate
• Lymphatic Metastasis
• Male
• Middle Aged
• Neoplastic Cells, Circulating
• Orchiectomy
• Placebos (administration & dosage)
• Prednisone (administration & dosage)
• Prostatic Neoplasms (drug therapy, mortality, pathology)
• Proto-Oncogene Proteins c-bcl-2 (antagonists & inhibitors)
• Taxoids (administration & dosage)
• Treatment Outcome