title: Radiographic progression by Prostate Cancer Working Group (PCWG)-2 criteria as an intermediate endpoint for drug development in metastatic castration-resistant prostate cancer.
abstract: OBJECTIVE
  To investigate the association of radiographic progression defined by Prostate Cancer Working Group (PCWG)-2 guidelines and overall survival (OS) in men with metastatic castration-resistant prostate cancer (mCRPC).
  
  
  METHODS
  Two trials that used PCWG-2 guidelines to define progression were analysed: a randomized phase II trial (n = 221) comparing first-line docetaxel-prednisone plus AT-101 or placebo, and a phase III trial (n = 873) comparing prednisone plus sunitinib or placebo after docetaxel-based chemotherapy. Cox proportional hazards regression models were used to estimate the association of radiographic progression with OS. Landmark analyses compared progressing patients with those who had not progressed. Sub-analyses compared patients removed from trial for progression vs other reasons.
  
  
  RESULTS
  An increased risk of death was seen for radiographic progression at landmark times from 6 to 12 months with docetaxel-based therapy (hazard ratio [HR] >1.7 at all time-points). An increased risk of death was also seen with post-docetaxel prednisone alone or with sunitinib for progression at landmark times from 2 to 8 months (HR >2.7 at all time-points). Kendall's τ was 0.50 (P < 0.001) in the setting of docetaxel-based therapy and 0.34 (P < 0.001) in the post-docetaxel setting for association between radiographic progression and death amongst patients with both events. Removal from study due to radiographic progression was associated with a significantly lower OS compared with removal for other reasons in both trials. Limitations of a retrospective analysis apply and there was no central radiology review.
  
  
  CONCLUSIONS
  Radiographic progression by PCWG-2 criteria was significantly associated with OS in patients with mCRPC receiving first-line docetaxel-based chemotherapy or post-docetaxel therapy. With external validation as a surrogate endpoint in trials showing survival benefits, the use of radiographic progression-free survival may expedite drug development in mCRPC, which has been hampered by the lack of intermediate endpoints.
authors.affiliation: Department of Medicine, Division of Hematology-Oncology, University of Alabama, Birmingham (UAB) Comprehensive Cancer Center, Birmingham, AL, USA.
authors.forename: Guru
authors.initials: G
authors.lastname: Sonpavde
authors.affiliation: Department of Biostatistics, McMaster University, Hamilton, ON, Canada.
authors.forename: Gregory R
authors.initials: GR
authors.lastname: Pond
authors.affiliation: Department of Medicine, Division of Hematology-Oncology, Duke Prostate Center, Durham, NC, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Armstrong
authors.affiliation: Department of Medicine, Division of Hematology-Oncology, Mt Sinai Tisch Cancer Institute, New York, NY, USA.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Galsky
authors.affiliation: Ascenta Therapeutics, Malvern, PA, USA.
authors.forename: Lance
authors.initials: L
authors.lastname: Leopold
authors.affiliation: Ascenta Therapeutics, Malvern, PA, USA.
authors.forename: Brian A
authors.initials: BA
authors.lastname: Wood
authors.affiliation: Pfizer Inc., Madison, NJ, USA.|ICON Clinical Research Inc., San Diego, CA, USA.
authors.forename: Shaw-Ling
authors.initials: SL
authors.lastname: Wang
authors.affiliation: Pfizer Inc., Madison, NJ, USA.
authors.forename: Jolanda
authors.initials: J
authors.lastname: Paolini
authors.affiliation: Pfizer Inc., Madison, NJ, USA.|Seragon Pharmaceuticals, San Diego, CA, USA.
authors.forename: Isan
authors.initials: I
authors.lastname: Chen
authors.affiliation: Pfizer Inc., Madison, NJ, USA.|Seragon Pharmaceuticals, San Diego, CA, USA.
authors.forename: Edna
authors.initials: E
authors.lastname: Chow-Maneval
authors.affiliation: Department of Medicine, Division of Hematology-Oncology, University of Alabama, Birmingham (UAB) Comprehensive Cancer Center, Birmingham, AL, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Mooney
authors.affiliation: Pfizer Inc., Madison, NJ, USA.
authors.forename: Mariajose
authors.initials: M
authors.lastname: Lechuga
authors.affiliation: Department of Medicine, Division of Hematology-Oncology, Massachusetts General Hospital and the Harvard Medical School, Boston, MA, USA.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Smith
authors.affiliation: Department of Medicine, Division of Hematology-Oncology, Massachusetts General Hospital and the Harvard Medical School, Boston, MA, USA.
authors.forename: M Dror
authors.initials: MD
authors.lastname: Michaelson
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D018450:Disease Progression; D018572:Disease-Free Survival; D000077143:Docetaxel; D055808:Drug Discovery; D006072:Gossypol / Q000008:administration & dosage / Q000031:analogs & derivatives; D006801:Humans; D007211:Indoles / Q000008:administration & dosage; D008297:Male; D011241:Prednisone / Q000008:administration & dosage; D064129:Prostatic Neoplasms, Castration-Resistant / Q000000981:diagnostic imaging* / Q000188:drug therapy* / Q000473:pathology; D011758:Pyrroles / Q000008:administration & dosage; D011859:Radiography; D012189:Retrospective Studies; D000077210:Sunitinib; D015996:Survival Rate; D043823:Taxoids / Q000008:administration & dosage; D013997:Time Factors
chemical_list: D007211:Indoles; D011758:Pyrroles; D043823:Taxoids; D000077143:Docetaxel; D006072:Gossypol; C028178:gossypol acetic acid; D000077210:Sunitinib; D011241:Prednisone
keywords: Prostate Cancer Working Group (PCWG)-2; castration-resistant prostate cancer; metastatic; overall survival (OS); radiographic progression