title: Safety and efficacy of maintenance therapy with a nonspecific cytochrome P17 inhibitor (CYP17i) after response/stabilization to docetaxel in metastatic castration-resistant prostate cancer.
abstract: BACKGROUND
  Frontline treatment of metastatic castration-resistant prostate cancer (mCRPC) consists of docetaxel-based chemotherapy. The median time to progression (TTP) from chemotherapy initiation is 6 to 8 months. Ketoconazole, a nonspecific cytochrome P17 inhibitor (CYP17i), blocks adrenal androgen synthesis. Low-dose ketoconazole (LDK), (200 mg three times daily [t.d.s]) has shown activity in mCRPC after progression to androgen deprivation. The role of a CYP17i after docetaxel treatment in the maintenance setting has been unexplored.
  
  
  METHODS
  We identified 38 patients with mCRPC who showed progression to luteinizing hormone releasing-hormone agonists (LHRHa) and who were treated with a median of 7 cycles of frontline three-weekly docetaxel (75 mg/m(2)) plus prednisone (10 mg/d) and LHRHa. Medical charts of 20 patients who showed no progression to docetaxel were reviewed. After the last docetaxel cycle, 10 patients received LDK maintenance treatment plus prednisone (10 mg/d) and LHRHa, whereas 10 patients received LHRHa alone. TTP was the primary endpoint.
  
  
  RESULTS
  After a follow-up of 27 months, disease in all patients receiving LHRHa alone progressed, whereas 8/10 patients progressed to maintenance therapy. Median TTP from docetaxel initiation was 11.5 months (95% confidence interval [CI], 6.3-16.6) for maintenance therapy and 9.2 months (95% CI, 8.5-9.9) for LHRHa alone (P = .047). The maintenance treatment was well tolerated. Only 1 patient experienced a grade 4 adverse event due to a nonsymptomatic pulmonary embolism.
  
  
  CONCLUSIONS
  This is the first study evaluating a CYP17i for maintenance therapy after docetaxel therapy. We showed a 2-month significant benefit in TTP for patients with mCRPC treated with LDK maintenance therapy after docetaxel, with a favorable toxicity profile. A large prospective randomized study using a CYP17i is warranted.
authors.affiliation: Department of Medical Oncology, Clínica Universidad de Navarra, Pamplona, Spain. igbazo@unav.es igbazo@unav.es
authors.forename: Ignacio
authors.initials: I
authors.lastname: Gil-Bazo
authors.forename: Estefanía
authors.initials: E
authors.lastname: Arévalo
authors.forename: Ainhoa
authors.initials: A
authors.lastname: Castillo
authors.forename: María E
authors.initials: ME
authors.lastname: Zudaire
authors.forename: Omar E
authors.initials: OE
authors.lastname: Carranza
authors.forename: Juan P
authors.initials: JP
authors.lastname: Fusco
authors.forename: Eduardo
authors.initials: E
authors.lastname: Castañón
authors.forename: Víctor
authors.initials: V
authors.lastname: Collado-Gómez
authors.forename: Inés
authors.initials: I
authors.lastname: López
authors.forename: Isabel
authors.initials: I
authors.lastname: Gil-Aldea
mesh_terms: D058888:14-alpha Demethylase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D018572:Disease-Free Survival; D000077143:Docetaxel; D007987:Gonadotropin-Releasing Hormone / Q000819:agonists; D006801:Humans; D007654:Ketoconazole / Q000009:adverse effects / Q000627:therapeutic use*; D060046:Maintenance Chemotherapy / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D011241:Prednisone / Q000627:therapeutic use; D017430:Prostate-Specific Antigen / Q000097:blood; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy*; D013254:Steroid 17-alpha-Hydroxylase / Q000037:antagonists & inhibitors*; D043823:Taxoids / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D058888:14-alpha Demethylase Inhibitors; D043823:Taxoids; D000077143:Docetaxel; D007987:Gonadotropin-Releasing Hormone; C501892:CYP17A1 protein, human; D013254:Steroid 17-alpha-Hydroxylase; D017430:Prostate-Specific Antigen; D007654:Ketoconazole; D011241:Prednisone