title: A phase II trial of temsirolimus in men with castration-resistant metastatic prostate cancer.
abstract: BACKGROUND
  Phosphatase and tensin homologue (PTEN) loss is common in advanced prostate cancer, leading to constitutive activation of the PI3 kinase pathway. Temsirolimus blocks mammalian target of rapamycin (mTOR)/target of rapamycin complex 1 (TORC1), a key signaling node in this pathway; its activity in men with advanced castration-resistant metastatic prostate cancer (mCRPC) is unknown.
  
  
  METHODS
  We conducted a single-arm trial of weekly intravenous temsirolimus administration in men with chemorefractory mCRPC who had ≥ 5 circulating tumor cells (CTCs) at baseline. The primary end point was the change in CTCs at 8 weeks; secondary end points were composite progression-free survival (PFS) (excluding prostate-specific antigen [PSA]), PSA and radiographic response rates, safety, and survival. At PSA/CTC progression, an anti-androgen could be added while continuing temsirolimus.
  
  
  RESULTS
  Eleven patients were accrued out of a planned 20; the trial was stopped prematurely because of lack of efficacy/feasibility. Median age was 61 years, with 55% African-Americans and 36% Caucasian patients. Median baseline PSA level was 390 ng/dL, median baseline number of CTCs was 14 cells; 50% of patients had pain, and 63% had undergone ≥ 2 previous chemotherapy regimens. Median CTC decline was 48% and 3 patients experienced decline in CTCs to < 5. However, 73% of men had a persistently unfavorable number of CTCs (≥ 5) and only 1 patient had a ≥ 30% PSA decline. Median PFS was 1.9 months (95% confidence interval [CI], 0.9-3.1) and median overall survival (OS) was 8.8 months (95% CI, 3.1-15.6). Toxicities included grade 4 hypophosphatemia and central nervous system (CNS) hemorrhage, and frequent grade 3 fatigue, anemia, stomatitis, hypokalemia, weakness, and hyperglycemia.
  
  
  CONCLUSIONS
  Temsirolimus lacked sufficient clinical activity in men with mCRPC, despite transient CTC improvements in some men. Future studies should focus on combination approaches or novel PI3K pathway inhibitors.
authors.affiliation: Duke Cancer Institute and the Duke Prostate Center, Duke University, Durham NC; Department of Medicine, Division of Medical Oncology, Duke University, Durham NC; Department of Surgery, Division of Urology, Duke University, Durham NC; Duke University Medical Center, Duke University, Durham NC. Electronic address: andrew.armstrong@duke.edu.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Armstrong
authors.forename: Tong
authors.initials: T
authors.lastname: Shen
authors.forename: Susan
authors.initials: S
authors.lastname: Halabi
authors.forename: Gabor
authors.initials: G
authors.lastname: Kemeny
authors.forename: Rhonda L
authors.initials: RL
authors.lastname: Bitting
authors.forename: Patricia
authors.initials: P
authors.lastname: Kartcheske
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Embree
authors.forename: Karla
authors.initials: K
authors.lastname: Morris
authors.forename: Carolyn
authors.initials: C
authors.lastname: Winters
authors.forename: Tracy
authors.initials: T
authors.lastname: Jaffe
authors.forename: Mark
authors.initials: M
authors.lastname: Fleming
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: George
mesh_terms: D000328:Adult; D000368:Aged; D001859:Bone Neoplasms / Q000556:secondary; D018450:Disease Progression; D018572:Disease-Free Survival; D006801:Humans; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D008875:Middle Aged; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors; D009360:Neoplastic Cells, Circulating; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017430:Prostate-Specific Antigen / Q000097:blood; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000401:mortality; D047428:Protein Kinase Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use*; D020123:Sirolimus / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D013534:Survival; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D017211:Treatment Failure
chemical_list: D046912:Multiprotein Complexes; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; C401859:temsirolimus; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D017430:Prostate-Specific Antigen; D020123:Sirolimus
keywords: Castration-resistant; Circulating tumor cells; Epithelial-mesenchymal transition; Metastatic prostate cancer; N-cadherin; Prostate-specific antigen; Temsirolimus; mTOR