title: Prognostic factors for clinical outcomes in patients with metastatic castration resistant prostate cancer treated with sequential novel androgen receptor-directed therapies.
abstract: BACKGROUND
  Prognostic factors associated with clinical outcomes in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with a novel androgen receptor-directed therapies (ARDT) in the second line setting has not been formally evaluated.
  
  
  METHODS
  We retrospectively reviewed and analyzed medical records of all patients with mCRPC who received sequential treatment with ARDT. We analyzed potential clinical factors associated with post treatment endpoints including 50% decline in prostatic-specific antigen (PSA), PSA-progression-free survival (PFS), clinical or radiographic PFS and overall survival (OS). Prognostic univariate and multivariate Cox proportional hazard models were developed and assessed.
  
  
  RESULTS
  One hundred twenty-six patients with mCRPC treated with a second-line novel ARDT were included. Overall, 50% decline in PSA was observed in 22% of patients and a median PSA-PFS of 2.9 months and a PFS of 3.6 months. After adjusting for potential confounders including prior exposure to docetaxel and number of prior antiandrogen agents, time to development of CRPC was an independent factor associated with PSA-PFS (hazard ratio [HR]: 0.99; 95% confidence interval [CI]: 0.99-1; P = 0.02) and PFS (HR: 0.99; CI: 0.98-1; P= 0.01). PSA response (50% decline) to first-line novel ARDT correlated negatively with PSA-PFS with second-line novel ARDT (HR: 1.7; 95% CI: 1.14-2.53; P = 0.009) and lower pre-treatment levels of albumin were associated with shorter PFS (HR: 0.56; 95% CI: 0.32-0.97; P = 0.03). Performance status, pre-treatment levels of albumin, extent of disease and time to development CRPC were associated with OS.
  
  
  CONCLUSIONS
  Second-line ARDT is associated with modest outcomes in patients with mCRPC. Time to development of CRPC is the strongest predictor of PSA response, PSA-PFS and OS which suggest that intrinsic resistance to AR directed treatment is the major treatment outcome factor in these patients. Future studies in patients receiving long term ARTD should include the identification of predictive biomarkers to facilitate treatment selection.
authors.affiliation: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Rosa
authors.initials: R
authors.lastname: Nadal
authors.affiliation: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Hua-Ling
authors.initials: HL
authors.lastname: Tsai
authors.affiliation: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Victoria J
authors.initials: VJ
authors.lastname: Sinibaldi
authors.affiliation: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Channing J
authors.initials: CJ
authors.lastname: Paller
authors.affiliation: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Emmanuel S
authors.initials: ES
authors.lastname: Antonarakis
authors.affiliation: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Sammuel R
authors.initials: SR
authors.lastname: Denmeade
authors.affiliation: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Carducci
authors.affiliation: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Mario A
authors.initials: MA
authors.lastname: Eisenberger
mesh_terms: D000368:Aged; D000726:Androgen Antagonists / Q000627:therapeutic use*; D018450:Disease Progression; D006801:Humans; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D017430:Prostate-Specific Antigen; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy / Q000473:pathology*; D011944:Receptors, Androgen / Q000032:analysis; D012189:Retrospective Studies; D016896:Treatment Outcome
chemical_list: C410798:AR protein, human; D000726:Androgen Antagonists; D011944:Receptors, Androgen; D017430:Prostate-Specific Antigen
keywords: androgen receptor; castration-resistant prostate cancer; enzalutamide and abiraterone; prognostic factors