Xtandi in prostate cancer patients not treated with docetaxel – pro

image2 - prostate

Enzalutamide (Xtandi, MDV3100) is an androgen receptor antagonist drug reported to cause an up to an 89% decrease in PSA levels after a month of use. It is more potent than Casodex. Enzalutamide has approximately fivefold higher binding affinity for the androgen receptor (AR). It also does not promote translocation of AR to the nucleus and it prevents binding of AR to DNA and AR to coactivator proteins.

In August of 2012, the U.S. Food and Drug Administration approved enzalutamide for the treatment of castration-resistant prostate cancer in patients who failed docetaxel. This was based on the AFFIRM study results. AFFIRM showed that Enzalutamide significantly prolonged the survival of men with metastatic castration-resistant prostate cancer after chemotherapy(Scher et al). The PREVAIL study that is directly investigating Xtandi before docetaxel is still ongoing: A Multinational Phase 3, Randomized, Double-Blind, Placebo-Controlled Efficacy and Safety Study of Oral MDV3100 in Chemotherapy-Naive Patients With Progressive Metastatic Prostate Cancer Who Have Failed Androgen Deprivation Therapy.

There is current evidence to support the use of Xtandi for patients who had not or cannot receive docetaxel. Median time to radiographic progression in one phase II study by Scher, 2010, was 56 weeks for chemo-naive patients and 25 weeks for patients previously treated with chemotherapy. There are several studies, however, that have been initiated. There is a phase II trial began in March 2011 comparing MDV3100 with Casodex in patients patients who have progressed while on LHRH analogue therapy (e,g., leuprorelin) or surgical castration. This ASPIRE trial is an an open-label study intended to evaluate the effects of enzalutamide in about 150 men who are theoretically eligible to receive chemotherapy but have chosen not to do this. Another phase II study, STRIVE trial is a randomized, double-blind, multi-center clinical study of the efficacy and safety study of enzalutamide (160 mg/day) compared to bicalutamide (50 mg/day) in men with recurrent prostate cancer who have serologic and/or radiographic disease progression subsequent to primary androgen deprivation therapy (ADT). The TERRAIN trial, is a randomized, double-blind, multi-center, Phase II trial designed to test the efficacy and safety of enzalutamide compared to bicalutamide (Casodex) in men with metastatic prostate cancer already controlled by either bilateral orchiectomy (surgical castration) or ongoing androgen deprivation therapy with an LHRH agonist or an LHRH antagonist at a stable dose. There are also combination trials.

Recently, results were released of the large phase III PREVAIL trial evaluating enzalutamide against placebo in chemotherapy-naive men with metastatic castration-resistant prostate cancer (mCRPC) amount to another big win for the rationally designed “super-antiandrogen” . An interim analysis uncovered such dramatic improvements with enzalutamide in overall survival and radiographic progression-free survival—the co-primary endpoints of the study—that the investigators stopped the trial early in October 2013 at the behest of the Independent Data Monitoring Committee and offered enzalutamide to the patients who were originally assigned the placebo.
Recenlty FDA approved Xtandi without preceding docetaxel: “XTANDI is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC).”.

Tran C, Ouk S, Clegg NJ, Chen Y, Watson PA, Arora V, Wongvipat J, Smith-Jones PM, Yoo D, Kwon A, Wasielewska T, Welsbie D, Chen CD, Higano CS, Beer TM, Hung DT, Scher HI, Jung ME, Sawyers CL (May 2009). “Development of a second-generation antiandrogen for treatment of advanced prostate cancer”. Science 324 (5928): 787–90.

Howard I Scher MD,Tomasz M Beer MD,Celestia S Higano MD,Aseem Anand MA,Mary-Ellen Taplin MD,Eleni Efstathiou MD,Dana Rathkopf MD,Julia Shelkey BS,Evan Y Yu MD,Joshi Alumkal MD,David Hung MD,Mohammad Hirmand MD,Lynn Seely MD,Michael J Morris MD,Daniel C Danila MD,John Humm PhD,Steve Larson MD,Martin Fleisher PhD,Charles L Sawyers MD,the Prostate Cancer Foundation/Department of Defense Prostate Cancer Clinical Trials Consortium Antitumour activity of MDV3100 in castration-resistant prostate cancer: a phase 1–2 study The Lancet – 24 April 2010 ( Vol. 375, Issue 9724, Pages 1437-1446 ), see also Scher HI, Fizazi K, Saad F, et al. N Engl J Med. 2012;367:1187-1197

William L Dahut,Ravi A Mada Revisiting the ultimate target of treatment for prostate cancer The Lancet – 24 April 2010 ( Vol. 375, Issue 9724, Pages 1409-1410 )

Scher HI, Beer TM, Higano CS, Anand A, Taplin ME, Efstathiou E, Rathkopf D, Shelkey J, Yu EY, Alumkal J, Hung D, Hirmand M, Seely L, Morris MJ, Danila DC, Humm J, Larson S, Fleisher M, Sawyers CL; Prostate Cancer Foundation/Department of Defense Prostate Cancer Clinical Trials Consortium Antitumour activity of MDV3100 in castration-resistant prostate cancer: a phase 1-2 study.
.Lancet. 2010 Apr 24;375(9724):1437-46.

Mukherji D, Pezaro CJ, De-Bono JS. MDV3100 for the treatment of prostate cancer.Expert Opin Investig Drugs. 2012 Feb;21(2):227-33.

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