ORLANDO, FL, USA (UroToday.com) - Androgen deprivation therapy (ADT) has been the standard-of-care treatment for advanced prostate cancer for a long time.
ADT is effective at inducing tumor shrinkage, but it may also be associated with acute bothersome symptoms including hot flushes, loss of libido, depression, and fatigue. It is important to know that ADT also causes long-term adverse events (AEs) including decreased bone density and increased fracture risk, sarcopenic obesity, insulin resistance, and cardiovascular and sexual dysfunction. Bicalutamide is the first-generation nonsteroidal antiandrogen and it has been used as a single agent to avoid castration. Bicalutamide has demonstrated an improved safety profile compared with ADT in previous studies, especially relating to bone and hormone-suppressive effects, resulting in significant quality-of-life benefits despite an increased incidence of breast pain and gynecomastia compared with ADT. Efficacy, however, has been shown to be inferior to ADT in metastatic prostate cancer. Accordingly, first-generation antiandrogens are recognized as a potential alternative to ADT for locally advanced prostate cancer in clinical guidelines.
Enzalutamide (ENZA, formerly MDV3100) is distinct from antiandrogens and is an oral androgen receptor (AR) inhibitor that targets multiple steps in the AR signaling pathway. It has been approved in the US and shown to increase overall survival (OS) by 4.8 months over a placebo (HR, 0.63) in patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with docetaxel (Scher et al, N Engl J Med 2012;367:1187). Compared with bicalutamide in nonclinical studies, ENZA had higher androgen receptor-binding affinity, prevented nuclear translocation, showed no DNA binding, and induced apoptosis (Tran et al, Science 2009;324:787). Unlike bicalutamide, ENZA has no known agonist activity in models of castration-resistant disease.
In contrast to previous phase II and III studies that only enrolled patients with mCRPC receiving ADT (i.e., testosterone (T) levels < 50 ng/dL), this phase II study assessed the efficacy and safety of ENZA monotherapy in patients with localized, locally advanced, or metastatic prostate cancer who had never received hormone therapy -- presenting with non-castrate T levels (&&8804; 230 ng/dL). Primary endpoint was to evaluate the effect of ENZA on PSA response (>80% decrease at week 25). Secondary endpoints included evaluation of changes in endocrine hormone levels and safety/tolerability.
This was a 25-week, open-label, single-arm, phase II study of patients with hormone-naïve, histologically confirmed prostate cancer (all stages) requiring hormonal treatment, an ECOG PS score of 0, and a life expectancy >1 year. All patients received ENZA 160 mg/d for 25 weeks, without concomitant castration. Sixty-seven patients were enrolled, with a median age of 73 years (range, 48–86 years), 39% had metastases, and 36% had undergone prostatectomy and 24% radiotherapy before study entry. Treatment discontinuation at week 25 was 6% (4/67); reasons for discontinuation included AEs (2), protocol violation (1), and patient’s decision (1). The PSA response rate (>80% PSA decline at week 25) was 93%, with a median change of -99.6% (range, -100.0% to -86.5%) at week 25. Substantial PSA reduction occurred by week 5 and was observed through week 25. Rapid changes were also observed in serum sex hormone levels. The mean increases from baseline to week 25 were 185% (n=58) for luteinizing hormone and 114% (n=63) for serum T. Drug-related AEs were reported by 53 patients (79%), the most common were gynecomastia, fatigue, and hot flush, and most were of grade 1 or 2 severity. One drug-related AE led to treatment discontinuation. There were no drug-related serious AEs reported.
To conclude, ENZA monotherapy (160 mg/d) was associated with significant PSA responses in nearly all noncastrate men with hormone-naïve prostate cancer, including men with advanced disease. Endocrine level changes and the most common drug-related AEs (gynecomastia, fatigue, and hot flush) were consistent with potent AR-signaling inhibition.
Presented by Bertrand Tombal, Michael Borre, Per Rathenborg, Patrick Werbrouck, Axel Heidenreich, Peter Iversen, Edwina S. Baskin-Bey, Frank Perabo, De Phung,and Matthew R. Smith at the 2013 Genitourinary Cancers Symposium - February 14 - 16, 2013 - Rosen Shingle Creek - Orlando, Florida USA
Université Catholique de Louvain, Cliniques Universitaires Saint-Luc, Brussels, Belgium; Department of Urology, Århus University Hospital, Skejby, Denmark; Herlev Hospital, Herlev, Denmark; AZ Groeninge Kortrijk, Kortrijk, Belgium; Klinik und Poliklinik für Urologie, North.-Rhine Westphalia, Germany; Rigshospitalet, University of Copenhagen, Copenhagen, Denmark; Astellas Pharma Europe, Ltd., Staines, United Kingdom; Astellas Pharma Inc., Leiderdorp, Netherlands; Astellas Pharma Europe BV, Leiderdorp, Netherlands; Massachusetts General Hospital Cancer Center, Boston, MA
Written by Anna Forsberg, medical reporter for UroToday.com
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