title: A Phase II, Randomized, Open-Label Study of Neoadjuvant Degarelix versus LHRH Agonist in Prostate Cancer Patients Prior to Radical Prostatectomy.
abstract: Purpose:Degarelix, a new gonadotropin-releasing hormone (GnRH) receptor antagonist with demonstrated efficacy as first-line treatment in the management of high-risk prostate cancer, possesses some theoretical advantages over luteinizing hormone-releasing hormone (LHRH) analogues in terms of avoiding "testosterone flare" and lower follicle-stimulating hormone (FSH) levels. We set out to determine whether preoperative degarelix influenced surrogates of disease control in a randomized phase II study.Experimental Design:Thirty-nine patients were randomly assigned to one of three different neoadjuvant arms: degarelix only, degarelix/bicalutamide, or LHRH agonist/bicalutamide. Treatments were given for 3 months before prostatectomy. Patients had localized prostate cancer and had chosen radical prostatectomy as primary treatment. The primary end point was treatment effect on intratumoral dihydrotestosterone levels.Results:Intratumoral DHT levels were higher in the degarelix arm than both the degarelix/bicalutamide and LHRH agonist/bicalutamide arms (0.87 ng/g vs. 0.26 ng/g and 0.23 ng/g,P< 0.01). No significant differences existed for other intratumoral androgens, such as testosterone and dehydroepiandrosterone. Patients in the degarelix-only arm had higher AMACR levels on immunohistochemical analysis (P= 0.01). Serum FSH levels were lower after 12 weeks of therapy in both degarelix arms than the LHRH agonist/bicalutamide arm (0.55 and 0.65 vs. 3.65,P< 0.01), and inhibin B levels were lower in the degarelix/bicalutamide arm than the LHRH agonist/bicalutamide arm (82.14 vs. 126.67,P= 0.02).Conclusions:Neoadjuvant degarelix alone, compared with use of LHRH agonist and bicalutamide, is associated with higher levels of intratumoral dihydrotestosterone, despite similar testosterone levels. Further studies that evaluate the mechanisms behind these results are needed.Clin Cancer Res; 23(8); 1974-80. ©2016 AACR.
authors.affiliation: Princess Margaret Cancer Centre, Toronto, Canada.
authors.forename: Rashid K
authors.initials: RK
authors.lastname: Sayyid
authors.affiliation: Princess Margaret Cancer Centre, Toronto, Canada.
authors.forename: Andrew
authors.initials: A
authors.lastname: Evans
authors.affiliation: Princess Margaret Cancer Centre, Toronto, Canada.
authors.forename: Karen
authors.initials: K
authors.lastname: Hersey
authors.affiliation: Princess Margaret Cancer Centre, Toronto, Canada.
authors.forename: Ranjena
authors.initials: R
authors.lastname: Maloni
authors.affiliation: University of British Columbia, Vancouver, Canada.
authors.forename: Antonio
authors.initials: A
authors.lastname: Hurtado-Coll
authors.affiliation: Princess Margaret Cancer Centre, Toronto, Canada.
authors.forename: Girish
authors.initials: G
authors.lastname: Kulkarni
authors.affiliation: Princess Margaret Cancer Centre, Toronto, Canada.
authors.forename: Antonio
authors.initials: A
authors.lastname: Finelli
authors.affiliation: Princess Margaret Cancer Centre, Toronto, Canada.
authors.forename: Alexandre R
authors.initials: AR
authors.lastname: Zlotta
authors.affiliation: Princess Margaret Cancer Centre, Toronto, Canada.
authors.forename: Robert
authors.initials: R
authors.lastname: Hamilton
authors.affiliation: University of British Columbia, Vancouver, Canada.
authors.forename: Martin
authors.initials: M
authors.lastname: Gleave
authors.affiliation: Princess Margaret Cancer Centre, Toronto, Canada. Neil.Fleshner@uhn.ca.
authors.forename: Neil E
authors.initials: NE
authors.lastname: Fleshner
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy*; D000328:Adult; D000368:Aged; D000726:Androgen Antagonists / Q000008:administration & dosage; D000813:Anilides / Q000008:administration & dosage; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage*; D017024:Chemotherapy, Adjuvant / Q000379:methods; D007987:Gonadotropin-Releasing Hormone / Q000819:agonists; D017273:Goserelin / Q000008:administration & dosage; D006801:Humans; D007150:Immunohistochemistry; D016729:Leuprolide / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy / Q000379:methods; D009570:Nitriles / Q000008:administration & dosage; D009842:Oligopeptides / Q000008:administration & dosage* / Q000009:adverse effects; D011468:Prostatectomy; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D011966:Receptors, LHRH / Q000037:antagonists & inhibitors; D046888:Tissue Array Analysis; D014105:Tosyl Compounds / Q000008:administration & dosage
chemical_list: D000726:Androgen Antagonists; D000813:Anilides; D018931:Antineoplastic Agents, Hormonal; D009570:Nitriles; D009842:Oligopeptides; D011966:Receptors, LHRH; D014105:Tosyl Compounds; C431566:acetyl-2-naphthylalanyl-3-chlorophenylalanyl-1-oxohexadecyl-seryl-4-aminophenylalanyl(hydroorotyl)-4-aminophenylalanyl(carbamoyl)-leucyl-ILys-prolyl-alaninamide; D017273:Goserelin; D007987:Gonadotropin-Releasing Hormone; C053541:bicalutamide; D016729:Leuprolide