title: Phase II trial of RAD001 and bicalutamide for castration-resistant prostate cancer.
abstract: Study Type--Therapy (cohort) Level of Evidence 2a. What's known on the subject? and What does the study add? Despite expanding treatment options for castration-resistant prostate cancer (CRPC), therapies with long response duration remain intangible due to prostate cancer cells' natural ability to develop iterative resistance. Androgen receptor (AR) signaling has been shown to play a critical role in CRPC and its expression is regulated by the PI3K-Akt pathway. Thus inhibition of AR signalling and PI3K-Akt-mTOR (a downstream mediator of the PI3K-Akt pathway) pathway is a logical combination in CRPC and we report a phase II trial of RAD001 and bicalutamide. Our study is the first clinical trial report of an AR inhibitor of PI3K-Akt-mTOR. The AR pathway and the PI3K-Akt-mTOR pathway are two of the most relevant growth pathway for CRPC. Despite low efficacy results from our trial there will be significant interest in the field for these data (dose, schedule, response, toxicity, trial design) as newer generations of both AR inhibitors and PI3K-Akt-mTOR inhibitors are in development and likely will be tested in combination in CRPC.
  
  
  OBJECTIVE
  • To determine best overall response and duration of response of RAD001, a selective inhibitor of mammalian target of rapamycin, in combination with bicalutamide in castration-resistant prostate cancer (CRPC). • To characterize the toxicity profile of RAD001 in combination with bicalutamide in patients with CRPC.
  
  
  METHODS
  • A phase II study was conducted to explore the efficacy and tolerability of RAD001 (10 mg daily) in combination with bicalutamide (50 mg daily) in men with progressive CRPC. • The primary endpoint was a composite of prostate-specific antigen (PSA) level and measurable disease response by standard criteria. • This single-stage trial with a sample size of 38 eligible patients provided 90% power to differentiate a response rate of ≥ 40% from a response rate of ≤ 20%, as expected for bicalutamide alone (α= 0.10, power = 0.90).
  
  
  RESULTS
  • In total, 36 men were enrolled, with a median (range) age of 68 (60-72) years and median (range) baseline PSA level of 22.2 (8.4-121.3) ng/mL, and 89% had metastatic disease. • There were 31 (86%) patients had previously used bicalutamide for a median duration of 7.4 months. • There were two patients with a confirmed PSA level decline ≥ 50%. • The median (interquartile range) time to progression was 8.7 (7.9-15.9) weeks. • The most common toxicity was grade 1/2 mucositis, which was observed in 20 (56%) patients.
  
  
  CONCLUSIONS
  • The combination of RAD001 and bicalutamide in men with CRPC was well tolerated but had low activity and failed to achieve the primary endpoint of improved response compared to the results previously achieved for bicalutamide alone in this population.
authors.affiliation: Lank Center for Genitourinary Oncology, Department of Medicine, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Mari
authors.initials: M
authors.lastname: Nakabayashi
authors.forename: Lilian
authors.initials: L
authors.lastname: Werner
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Courtney
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Buckle
authors.forename: William K
authors.initials: WK
authors.lastname: Oh
authors.forename: Glen J
authors.initials: GJ
authors.lastname: Bubley
authors.forename: Julia H
authors.initials: JH
authors.lastname: Hayes
authors.forename: Douglas
authors.initials: D
authors.lastname: Weckstein
authors.forename: Aymen
authors.initials: A
authors.lastname: Elfiky
authors.forename: Danny M
authors.initials: DM
authors.lastname: Sims
authors.forename: Philip W
authors.initials: PW
authors.lastname: Kantoff
authors.forename: Mary-Ellen
authors.initials: ME
authors.lastname: Taplin
mesh_terms: D000230:Adenocarcinoma / Q000097:blood / Q000188:drug therapy*; D000368:Aged; D059002:Androgen Receptor Antagonists / Q000627:therapeutic use; D000813:Anilides / Q000008:administration & dosage / Q000009:adverse effects; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm; D000068338:Everolimus; D006801:Humans; D008297:Male; D008875:Middle Aged; D009570:Nitriles / Q000008:administration & dosage / Q000009:adverse effects; D017430:Prostate-Specific Antigen / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000097:blood / Q000188:drug therapy*; D020123:Sirolimus / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D014105:Tosyl Compounds / Q000008:administration & dosage / Q000009:adverse effects; D016896:Treatment Outcome
chemical_list: D059002:Androgen Receptor Antagonists; D000813:Anilides; D000970:Antineoplastic Agents; D009570:Nitriles; D014105:Tosyl Compounds; D000068338:Everolimus; C053541:bicalutamide; D017430:Prostate-Specific Antigen; D020123:Sirolimus