title: A phase II study of GW786034 (pazopanib) with or without bicalutamide in patients with castration-resistant prostate cancer.
abstract: BACKGROUND
  Pazopanib is an oral vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor. In this randomized, open label phase II study, pazopanib alone or in combination with bicalutamide was evaluated in patients with chemotherapy-naive castration-resistant prostate cancer (CRPC).
  
  
  METHODS
  Patients received either pazopanib 800 mg daily (arm A) or pazopanib 800 mg plus bicalutamide 50 mg daily (arm B). A 2-stage study design was used, and the primary endpoint was prostate-specific antigen (PSA) response rate (defined as a confirmed ≥ 50% decline from baseline).
  
  
  RESULTS
  A total of 23 patients (arm A, 10; arm B, 13) were accrued. The main grade 3+ toxicities were hypertension, fatigue, decreased lymphocytes, and increased alanine transaminase. Owing to significant toxicity, the protocol was amended after the first 11 patients and the pazopanib starting dose was reduced to 600 mg daily. In arm A, of 9 evaluable patients, there was 1 patient (11%) with a PSA response, 3 (33%) with stable PSA, and 5 (56%) with PSA progression; in arm B, of 12 evaluable patients, there were 2 patients (17%) with PSA responses, 6 (50%) with stable PSA, and 4 (33%) with PSA progression. Median progression-free survival was similar in both arms at 7.3 months (95% CI, 2.5 months to not reached). Long-term stable disease was seen in 4 patients who remained on treatment for 18 months (arm A), 26 months (arm A), 35 months (arm B), and 52 months (arm B).
  
  
  CONCLUSIONS
  In this unselected patient population, pazopanib either alone or in combination with bicalutamide failed to show sufficient activity to warrant further evaluation. However, 4 patients had long-term benefit, suggesting that targeting the VEGFR pathway may still be relevant in selected patients and emphasizing the need for improved predictive markers for patients with CRPC.
authors.affiliation: Princess Margaret Hospital, Phase II Consortium, Toronto, ON.
authors.forename: Srikala S
authors.initials: SS
authors.lastname: Sridhar
authors.affiliation: Princess Margaret Hospital, Phase II Consortium, Toronto, ON.
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Joshua
authors.affiliation: Department of Oncology, Queen's University, Kingston, ON.
authors.forename: Richard
authors.initials: R
authors.lastname: Gregg
authors.affiliation: Department of Oncology, Queen's University, Kingston, ON.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Booth
authors.affiliation: BC Cancer Agency, Vancouver, BC.
authors.forename: Nevin
authors.initials: N
authors.lastname: Murray
authors.affiliation: Princess Margaret Hospital, Phase II Consortium, Toronto, ON.
authors.forename: Jovana
authors.initials: J
authors.lastname: Golubovic
authors.affiliation: Princess Margaret Hospital, Phase II Consortium, Toronto, ON.
authors.forename: Lisa
authors.initials: L
authors.lastname: Wang
authors.affiliation: Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD.
authors.forename: Pamela
authors.initials: P
authors.lastname: Harris
authors.affiliation: BC Cancer Agency, Vancouver, BC. Electronic address: kchi@bccancer.bc.ca.
authors.forename: Kim N
authors.initials: KN
authors.lastname: Chi
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D000813:Anilides / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000627:therapeutic use; D004334:Drug Administration Schedule; D006801:Humans; D007191:Indazoles; D007610:Kallikreins / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009570:Nitriles / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D017430:Prostate-Specific Antigen / Q000378:metabolism; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000378:metabolism; D011743:Pyrimidines / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D013449:Sulfonamides / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D014105:Tosyl Compounds / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D020533:Angiogenesis Inhibitors; D000813:Anilides; D000970:Antineoplastic Agents; D007191:Indazoles; D009570:Nitriles; D011743:Pyrimidines; D013449:Sulfonamides; D014105:Tosyl Compounds; C516667:pazopanib; C053541:bicalutamide; C549870:KLK3 protein, human; D007610:Kallikreins; D017430:Prostate-Specific Antigen
keywords: Angiogenesis inhibitors; CRPC; PSA response; Patient selection