title: Clinical activity of enzalutamide in Docetaxel-naïve and Docetaxel-pretreated patients with metastatic castration-resistant prostate cancer.
abstract: BACKGROUND
  Two randomized clinical trials have demonstrated a survival advantage with enzalutamide over placebo in both docetaxel (D)-pretreated and D-naïve metastatic castration-resistant prostate cancer (mCRPC) patients. Cross-resistance between androgen receptor-directed therapies and taxanes has been suggested, possibly leading to lower efficacy of enzalutamide in the post-D setting.
  
  
  METHODS
  We aimed to examine the impact of prior D treatment on the clinical activity of enzalutamide in patients with mCRPC. We retrospectively reviewed an institutional database to identify men with mCRPC treated with standard-of-care enzalutamide. Patients were classified as D-naïve or D-pretreated. The efficacy end points were prostate-specific antigen (PSA) response rates (≥ 50% PSA decline), time to PSA progression (TTPP) and clinical/radiographic progression-free survival (PFS) in response to enzalutamide. Differences between groups (D-naïve and D-pretreated) were assessed by univariate and multivariable analyses using logistic and Cox regression models.
  
  
  RESULTS
  One-hundred-seven (107) consecutive patients were included: 60 were D-pretreated and 47 were D-naïve. PSA responses were 43.2% in D-naïve patients and 25.4% in D-pretreated patients (P = 0.089). Median TTPP was 7.2 months (95% CI = 4.5 - 17.2) in the D-naïve group versus 2.6 mo (95% CI = 1.9 - 3.5) in the D-pretreated group (P < 0.0001). Median PFS was not reached for D-naïve men and was 3.3 mo (95% CI = 2.5 - 4.8) for D-pretreated men (P < 0.0001). After adjusting for potential confounders including prior abiraterone use, differences remained statistically significant for TTPP (HR = 2.32; 95% CI = 1.19 - 4.50; P = 0.013) and marginally significant for PFS (HR = 1.90; 95% CI = 0.94 - 3.84; P = 0.073) in multivariable analyses. Among patients who achieved a PSA response to enzalutamide (n = 34), results suggested a trend towards shorter duration of response in D-pretreated patients.
  
  
  CONCLUSIONS
  The clinical activity of enzalutamide appears to be blunted in patients who have previously received docetaxel chemotherapy. These results support the concept of cross-resistance between these two agents.
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland.
authors.forename: Rosa
authors.initials: R
authors.lastname: Nadal
authors.forename: Zhe
authors.initials: Z
authors.lastname: Zhang
authors.forename: Hibba
authors.initials: H
authors.lastname: Rahman
authors.forename: Michael T
authors.initials: MT
authors.lastname: Schweizer
authors.forename: Samuel R
authors.initials: SR
authors.lastname: Denmeade
authors.forename: Channing J
authors.initials: CJ
authors.lastname: Paller
authors.forename: Michael A
authors.initials: MA
authors.lastname: Carducci
authors.forename: Mario A
authors.initials: MA
authors.lastname: Eisenberger
authors.forename: Emmanuel S
authors.initials: ES
authors.lastname: Antonarakis
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001549:Benzamides; D018450:Disease Progression; D018572:Disease-Free Survival; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009570:Nitriles; D010669:Phenylthiohydantoin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D016016:Proportional Hazards Models; D017430:Prostate-Specific Antigen / Q000187:drug effects*; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy*; D012189:Retrospective Studies; D043823:Taxoids / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D009570:Nitriles; D043823:Taxoids; D000077143:Docetaxel; D010669:Phenylthiohydantoin; C540278:enzalutamide; D017430:Prostate-Specific Antigen
keywords: clinical activity; cross-resistance; docetaxel; enzalutamide; prostate cancer