title: Randomized phase II trial of Custirsen (OGX-011) in combination with docetaxel or mitoxantrone as second-line therapy in patients with metastatic castrate-resistant prostate cancer progressing after first-line docetaxel: CUOG trial P-06c.
abstract: OBJECTIVE
  Clusterin (CLU) is an antiapoptotic, stress-induced protein conferring treatment resistance when overexpressed. This study tested custirsen, a CLU inhibitor, in patients with metastatic castration-resistant prostate cancer (mCRPC) progressing during or within 6 months of initial docetaxel therapy.
  
  
  METHODS
  Men were randomized to receive either docetaxel + prednisone + custirsen (DPC) or mitoxantrone + prednisone + custirsen (MPC).
  
  
  RESULTS
  Forty-two patients received study treatment. Toxicity was similar in both arms. Twenty patients treated with DPC received a median of 8 cycles; overall survival (OS) was 15.8 months. Median time to pain progression (TTPP) was 10.0 months; 10 of 13 (77%) evaluable patients had pain responses. Three of 13 (23%) evaluable patients had objective partial responses. Prostate-specific antigen (PSA) declines of 90% or more, 50% or more, and 30% or more occurred in 4 (20%), 8 (40%), and 11 (55%) patients, respectively. Twenty-two patients treated with MPC received a median of 6 cycles; OS was 11.5 months. The median TTPP was 5.2 months; 6 of 13 (46%) evaluable patients had pain responses. No objective responses were observed. PSA declines of 50% or more and 30% or more occurred in 6 (27%) and 7 (32%) patients, respectively. Low serum CLU levels during treatment showed superior survival for patients based on modeling with proportional hazard regression with a time-dependent covariate and different landmarks.
  
  
  CONCLUSIONS
  Custirsen plus either docetaxel or mitoxantrone was feasible in patients with progressive mCRPC following first-line docetaxel therapy. Pain relief was higher than expected, with interesting correlations between serum CLU and survival. A phase III trial evaluating the pain palliation benefit of custirsen with taxane therapy is ongoing.
authors.affiliation: CRCUM-Université de Montréal, Hamilton, Ontario, Canada. fred.saad.chum@ssss.gouv.qc.ca
authors.forename: Fred
authors.initials: F
authors.lastname: Saad
authors.forename: Sebastien
authors.initials: S
authors.lastname: Hotte
authors.forename: Scott
authors.initials: S
authors.lastname: North
authors.forename: Bernie
authors.initials: B
authors.lastname: Eigl
authors.forename: Kim
authors.initials: K
authors.lastname: Chi
authors.forename: Piotr
authors.initials: P
authors.lastname: Czaykowski
authors.forename: Lori
authors.initials: L
authors.lastname: Wood
authors.forename: Michael
authors.initials: M
authors.lastname: Pollak
authors.forename: Scott
authors.initials: S
authors.lastname: Berry
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Lattouf
authors.forename: Som D
authors.initials: SD
authors.lastname: Mukherjee
authors.forename: Martin
authors.initials: M
authors.lastname: Gleave
authors.forename: Eric
authors.initials: E
authors.lastname: Winquist
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D051152:Clusterin / Q000037:antagonists & inhibitors / Q000097:blood; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008297:Male; D008875:Middle Aged; D008942:Mitoxantrone / Q000008:administration & dosage*; D009362:Neoplasm Metastasis; D009919:Orchiectomy; D011241:Prednisone / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D043823:Taxoids / Q000008:administration & dosage* / Q000627:therapeutic use; D013873:Thionucleotides / Q000008:administration & dosage*; D016896:Treatment Outcome
chemical_list: D051152:Clusterin; C503781:OGX-011; D043823:Taxoids; D013873:Thionucleotides; D000077143:Docetaxel; D008942:Mitoxantrone; D011241:Prednisone