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n e w e ng l a n d j o u r na l
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m e dic i n e
edi t or i a l s
Enzalutamide — A Major Advance in the Treatment
of Metastatic Prostate Cancer
Nicholas J. Vogelzang, M.D.
In this issue of the Journal, Scher et al. describe
the strikingly positive results of a phase 3 trial of
a new nonsteroidal antiandrogen agent, enzalutamide, as compared with placebo in metastatic
castration-resistant prostate cancer.1 Not only was
survival significantly improved among patients
who had undergone previous chemotherapy with
docetaxel (a treatment that is a watershed event
in the lives of most patients), but the incidence
of adverse events of grade 3 or higher was lower
among the patients receiving enzalutamide than
among those receiving placebo (a finding that
suggests that the “toxicity” of placebo is related
to underlying disease-related symptoms). How
did the field get to this point, and what are the
next steps forward?
The first nonsteroidal antiandrogen agents —
flutamide, nilutamide, and bicalutamide2 — were
shown to be less effective than castration in
cases of metastatic castration-resistant prostate
cancer, but bicalutamide is still widely used as a
moderately effective secondary hormone therapy
because of an excellent safety profile.3 Dozens
of randomized phase 3 trials then compared
testosterone ablation plus an antiandrogen (termed
combined androgen blockade) with testosterone
ablation alone. Meta-analyses concluded that the
addition of flutamide or nilutamide prolonged
survival by 2 to 5% at 5 years. One study of testosterone ablation alone as compared with testosterone ablation with bicalutamide showed a survival advantage for the combination.4 Therefore,
since the mid-1990s, bicalutamide has been the
standard of care for patients receiving combined
androgen blockade.
Subsequently, the androgen receptor was
shown to be central to the biologic features of
metastatic castration-resistant prostate cancer:
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it was overexpressed as the cancer progressed; it
could mutate, allowing stimulation by a variety
of weak androgens; and it could be activated by
autocrine production of androgens from tumor
cells obtained from patients with the disease.
Chen et al. then conducted an elegant series of
experiments that involved the synthesis of bicalutamide analogues with improved inhibitory capacity5 and ultimately led to the discovery of
enzalutamide. When phase 1 and phase 2 trials
confirmed the safety and activity of enzalutamide,6 the phase 3 trial was launched; the trial
design was virtually identical to that used to obtain Food and Drug Administration (FDA) approval of abiraterone.7
Although abiraterone inhibits androgen synthesis and lowers testosterone levels to nearly
undetectable levels, it does not affect androgenreceptor signaling, which may remain active and
thereby cause disease progression (perhaps by
means of alternative androgenic agonists). En­
zalutamide does not lower androgen levels but
instead inhibits androgen-receptor signaling by
competitively inhibiting the binding of androgens without stimulation of the androgen receptor. Tumor-cell growth then requires androgen
binding to the androgen receptor, followed by
nuclear translocation and DNA binding; enzalutamide inhibits both steps, even in patients with
androgen-receptor overexpression and resistance
to other antiandrogens. These potentially nonoverlapping and synergistic actions of abiraterone
and enzalutamide have led to the proposal for
a phase 3 trial comparing enzalutamide with
enzalutamide plus abiraterone (comparisons with
abiraterone alone would also be interesting)
(Morris M, Memorial Sloan-Kettering Cancer
Center: personal communication).
n engl j med 367;13 nejm.org september 27, 2012
editorials
What are the limitations to the use of enzalutamide (which has just received FDA approval on
the basis of the study by Scher et al.)? First,
enzalutamide is likely to be active in all patients
with metastatic castration-resistant prostate
cancer in whom the androgen receptor is still
driving the disease, regardless of whether the
patients have received treatment with docetaxel.
A phase 3 trial involving patients who have not
been treated with docetaxel is complete and
should be reported shortly (ClinicalTrials.gov
number, NCT01212991).
Second, assessment of androgen-receptor activity in patients with metastatic castration-resistant prostate cancer is not clinically available, so
all patients deserve a therapeutic trial of enzalutamide. However, Tzelepi et al.8 recently reported
that approximately 25% of analyzed tumors obtained from patients with metastatic castrationresistant prostate cancer have no androgen receptors yet show marked up-regulation of the gene
for the ubiquitin-conjugating enzyme E2C and
other mitotic genes that are independent of regulation by androgen receptors. The extrapolation
of these data indicates that such patients will
have no response or only a minimal response to
enzalutamide. Characterization of the spectrum
of enzalutamide activity as a function of the
heterogeneity of the androgen-signaling pathway
should be a priority of future translational trials.
Third, enzalutamide crosses the blood–brain
barrier and apparently leads to sensitization to
seizures in small numbers of patients.1 The ability to cross the blood–brain barrier may be a
therapeutic advantage in patients with advanced
epidural or meningeal disease but calls for caution. Another new nonsteroidal antiandrogen,
ARN-509, seems to have a similar potency but
less penetrance of the central nervous system.9
Fourth, this clinical trial enrolled very few
patients who had previously received abiraterone,
yet abiraterone is used in virtually all patients
with metastatic castration-resistant prostate cancer. The relative effectiveness of enzalutamide in
patients who have previously received abiraterone
is unknown, although as noted above, the two
agents are theoretically not cross-resistant.
In conclusion, enzalutamide, a new, highly
effective, and safe nonsteroidal antiandrogen,
extends survival and will become widely used in
patients with metastatic castration-resistant prostate cancer. It will be used sequentially with other active agents, such as docetaxel, abiraterone,
cabazitaxel, radium-223, and immunotherapy. It
will be studied much earlier in the disease course.
In addition, it is likely to supplant bicalutamide in
combined androgen blockade after appropriate
phase 3 trials have been completed.
Disclosure forms provided by the author are available with the
full text of this article at NEJM.org.
From the Comprehensive Cancer Centers of Nevada, Las Vegas.
1. Scher HI, Fizazi K, Saad F, et al. Increased survival with
enzalutamide in prostate cancer after chemotherapy. N Engl J Med
2012;367:1187-97.
2. Furr BJ, Valcaccia B, Curry B, Woodburn JR, Chesterson G,
Tucker H. ICI 176,334: a novel non-steroidal, peripherally selective antiandrogen. J Endocrinol 1987;113:R7-R9.
3. Small EJ, Vogelzang NJ. Second-line hormonal therapy for
advanced prostate cancer: a shifting paradigm. J Clin Oncol
1997;15:382-8.
4. Akaza H, Hinotsu S, Usami M, et al. Combined androgen
blockade with bicalutamide for advanced prostate cancer: longterm follow-up of a phase 3, double-blind, randomized study for
survival. Cancer 2009;115:3437-45.
5. Chen CD, Welsbie DS, Tran C, et al. Molecular determinants
of resistance to antiandrogen therapy. Nat Med 2004;10:33-9.
6. Scher HI, Beer TM, Higano CS, et al. Antitumour activity of
MDV3100 in castration-resistant prostate cancer: a phase 1-2
study. Lancet 2010;375:1437-46.
7. de Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and
increased survival in metastatic prostate cancer. N Engl J Med
2011;364:1995-2005.
8. Tzelepi V, Zhang J, Lu JF, et al. Modeling a lethal prostate
cancer variant with small-cell carcinoma features. Clin Cancer
Res 2012;18:666-77.
9. Clegg NJ, Wongvipat J, Joseph JD, et al. ARN-509: a novel
antiandrogen for prostate cancer treatment. Cancer Res 2012;72:
1494-503.
DOI: 10.1056/NEJMe1209041
Copyright © 2012 Massachusetts Medical Society.
Tiotropium for Asthma — Promise and Caution
Elisabeth H. Bel, M.D., Ph.D.
Anticholinergic agents have been available for the
treatment of airways obstruction for many de­
cades. For patients with chronic obstructive pulmonary disease (COPD), many practitioners believe
that these drugs have become the bronchodilator of choice. For patients with asthma, anticho-
linergic agents are less popular, probably because
of their slower onset of action as a reliever medication and their generally inferior effect on lung
function and symptoms, as compared with inhaled beta-agonists.
Not surprisingly, long-acting beta-agonists
n engl j med 367;13 nejm.org september 27, 2012
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