title: A Phase II Study of AT-101 to Overcome Bcl-2--Mediated Resistance to Androgen Deprivation Therapy in Patients With Newly Diagnosed Castration-Sensitive Metastatic Prostate Cancer.
abstract: In a phase II multicenter study, men with castration sensitive metastatic prostate cancer were treated with AT-101, a small molecule Bcl-2 inhibitor, and androgen deprivation therapy. At the end of 7 cycles of therapy in 55 patients, an undetectable PSA was achieved in 31%. However, the combination did not meet the pre-specified level of activity for further development.
  
  
  BACKGROUND
  We conducted a phase II study in men with castration-sensitive metastatic prostate cancer to test the hypothesis that AT-101, a small molecule Bcl-2 inhibitor, has clinical activity in patients initiating androgen deprivation therapy (ADT) for metastatic prostate cancer.
  
  
  METHODS
  Patients with metastatic prostate cancer scheduled to start, or who had recently (within 6 weeks) initiated, ADT were enrolled. ADT with a luteinizing hormone-releasing hormone agonist and bicalutamide was started 6 weeks before initiation of oral AT-101, 20 mg/day for 21 days of a 28-day cycle. The primary endpoint of the study was the percentage of patients with an undetectable prostate-specific antigen (PSA) level (≤ 0.2 ng/mL) after 7.5 months (1.5 months of ADT alone plus 6 months of combined ADT and AT-101). To assess for an association between chromodomain helicase DNA binding protein 1 (CHD1) and drug sensitivity, fluorescence in situ hybridization with confocal microscopy was assessed in a subgroup of patients.
  
  
  RESULTS
  A total of 55 patients were enrolled, with median age of 61 years and a median PSA level of 27.6 ng/dL. Of the 55 patients, 72% had a Gleason score ≥ 8. Three patients had visceral metastases, and the remaining patients had bone or nodal metastasis. An undetectable PSA level was achieved in 31% of the patients. Of the 31 patients, 12 experienced serious adverse events, 7 of which were considered related to study therapy. Most of the related adverse events were gastrointestinal and nervous system disorders. CHD1 assessment was feasible, with a nonsignificant association with therapeutic sensitivity in a small number of patients.
  
  
  CONCLUSIONS
  The combination of ADT and AT-101 did not meet the prespecified level of activity for further development of this combination.
authors.affiliation: Rutgers Cancer Institute of New Jersey, New Brunswick, NJ.
authors.forename: Mark N
authors.initials: MN
authors.lastname: Stein
authors.affiliation: University of Michigan, Ann Arbor, MI.
authors.forename: Maha
authors.initials: M
authors.lastname: Hussain
authors.affiliation: University of Chicago, Chicago, IL.
authors.forename: Walter M
authors.initials: WM
authors.lastname: Stadler
authors.affiliation: UW Carbone Cancer Center, University of Wisconsin, Madison, WI.
authors.forename: Glenn
authors.initials: G
authors.lastname: Liu
authors.affiliation: Rutgers Cancer Institute of New Jersey, New Brunswick, NJ.
authors.forename: Irina V
authors.initials: IV
authors.lastname: Tereshchenko
authors.affiliation: Rutgers Cancer Institute of New Jersey, New Brunswick, NJ.
authors.forename: Susan
authors.initials: S
authors.lastname: Goodin
authors.affiliation: Rutgers Cancer Institute of New Jersey, New Brunswick, NJ.
authors.forename: Chandrika
authors.initials: C
authors.lastname: Jeyamohan
authors.affiliation: Rutgers Cancer Institute of New Jersey, New Brunswick, NJ.
authors.forename: Howard L
authors.initials: HL
authors.lastname: Kaufman
authors.affiliation: Rutgers Cancer Institute of New Jersey, New Brunswick, NJ.
authors.forename: Janice
authors.initials: J
authors.lastname: Mehnert
authors.affiliation: Rutgers Cancer Institute of New Jersey, New Brunswick, NJ. Electronic address: robert.dipaola@rutgers.edu.
authors.forename: Robert S
authors.initials: RS
authors.lastname: DiPaola
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000556:secondary; D000368:Aged; D000369:Aged, 80 and over; D000726:Androgen Antagonists / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000556:secondary; D006072:Gossypol / Q000008:administration & dosage / Q000031:analogs & derivatives; D006801:Humans; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D016896:Treatment Outcome
chemical_list: D000726:Androgen Antagonists; D006072:Gossypol; C028178:gossypol acetic acid
keywords: Chromodomain helicase DNA binding protein (CHD1); R-(−)-gossypol acetic acid; Small molecule Bcl-2 inhibitor