title: Phase 2 Study of the Safety and Antitumor Activity of Apalutamide (ARN-509), a Potent Androgen Receptor Antagonist, in the High-risk Nonmetastatic Castration-resistant Prostate Cancer Cohort.
abstract: Apalutamide is a potent androgen receptor (AR) antagonist that targets the AR ligand-binding domain and prevents AR nuclear translocation, DNA binding, and transcription of AR gene targets.
  
  
  
  To evaluate the activity and safety of apalutamide in patients with high-risk nonmetastatic castration-resistant prostate cancer (nmCRPC).
  
  
  
  We conducted a multicenter phase 2 study of nmCRPC patients with a high risk for progression (prostate-specific antigen [PSA] ≥8 ng/ml or PSA doubling time [PSA DT] ≤10 mo).
  
  
  
  Patients received 240mg/d apalutamide while continuing on androgen-deprivation therapy.
  
  
  
  Primary end point was 12-wk PSA response (Prostate Cancer Working Group 2 criteria). Secondary end points included safety, time to PSA progression (TTPP), and metastasis-free survival (MFS).
  
  
  
  A total of 51 patients were enrolled; four patients with metastatic disease were excluded from the efficacy analysis. Patient characteristics included median age, 71 yr; Eastern Cooperative Oncology Group performance status 0 (76%); Gleason score ≤7 (57%); median PSA 10.7 ng/ml; and PSA DT ≤10 mo (45%). At median follow-up of 28.0 mo, 18 patients (35%) remained in the study. Overall, 89% of patients had ≥50% PSA decline at 12 wk. Median TTPP was 24.0 mo (95% confidence interval [CI], 16.3 mo-not reached [NR]); median MFS was NR (95% CI, 33.4 mo-NR). Most of the patients discontinued study treatment (n=33) due to disease progression (n=11 [22%]) or adverse events (AEs) (n=9 [18%]). The most common AE was fatigue (any grade, n=31 [61%]) although grade ≥3 fatigue was uncommon (n=2 [4%]). These represent the first apalutamide nmCRPC patient clinical data.
  
  
  
  In high-risk nmCRPC patients, apalutamide was safe with robust activity based on durable PSA responses and disease control.
  
  
  
  Antitumor activity and the safety of apalutamide in patients with nonmetastatic castration-resistant prostate cancer support continued development in this setting.
  
  
  
  ClinicalTrials.gov identifier NCT01171898.
authors.affiliation: Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA, USA. Electronic address: smith.matthew@mgh.harvard.edu.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Smith
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Emmanuel S
authors.initials: ES
authors.lastname: Antonarakis
authors.affiliation: UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA.
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Ryan
authors.affiliation: Cancer Centers of North Carolina, Raleigh, NC, USA.
authors.forename: William R
authors.initials: WR
authors.lastname: Berry
authors.affiliation: Carolina Urologic Research Center, Myrtle Beach, SC, USA.
authors.forename: Neal D
authors.initials: ND
authors.lastname: Shore
authors.affiliation: University of Wisconsin Carbone Cancer Center, Madison, WI, USA.
authors.forename: Glenn
authors.initials: G
authors.lastname: Liu
authors.affiliation: Oregon Health & Science University, Knight Cancer Institute, Portland, OR, USA.
authors.forename: Joshi J
authors.initials: JJ
authors.lastname: Alumkal
authors.affiliation: University of Washington, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: Celestia S
authors.initials: CS
authors.lastname: Higano
authors.affiliation: Aragon Pharmaceuticals, San Diego, CA, USA.
authors.forename: Edna
authors.initials: E
authors.lastname: Chow Maneval
authors.affiliation: Janssen Research & Development, Spring House, PA, USA.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Bandekar
authors.affiliation: Janssen Biologics, B.V., Leiden, The Netherlands.
authors.forename: Carla J
authors.initials: CJ
authors.lastname: de Boer
authors.affiliation: Janssen Research & Development, Los Angeles, CA, USA.
authors.forename: Margaret K
authors.initials: MK
authors.lastname: Yu
authors.affiliation: Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY, USA.
authors.forename: Dana E
authors.initials: DE
authors.lastname: Rathkopf
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D059002:Androgen Receptor Antagonists / Q000627:therapeutic use*; D018572:Disease-Free Survival; D006801:Humans; D007610:Kallikreins / Q000097:blood; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D017430:Prostate-Specific Antigen / Q000097:blood; D064129:Prostatic Neoplasms, Castration-Resistant / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D013867:Thiohydantoins / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D059002:Androgen Receptor Antagonists; D013867:Thiohydantoins; C572045:apalutamide; C549870:KLK3 protein, human; D007610:Kallikreins; D017430:Prostate-Specific Antigen
keywords: Antitumor activity; Apalutamide; Castration-resistant prostate cancer; Safety