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Enzalutamide MDV3100 pill for metastatic PCa review by Nick Mulcahy of MedScape


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#1 Bruce Kynaston

Bruce Kynaston

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Posted 29 September 2012 - 03:00 PM

From Medscape Medical News:


Second Pill for Prostate Cancer Also Prolongs Survival
Nick Mulcahy

September 27, 2012 — Enzalutamide (Xtandi, Astellas), the once-daily oral
therapy, significantly prolongs survival in men with metastatic castrationresistant
prostate cancer after chemotherapy, according to a study published
in the September 27 issue of the New England Journal of Medicine.

The median overall survival was 18.4 months in the enzalutamide group and
13.6 months in the placebo group. This translates into a 37% reduction in the
risk for death (hazard ratio, 0.63; P < .001), say the investigators, led by
Howard I. Scher, MD, from the Memorial Sloan-Kettering Cancer Center in
New York City.

The pill, formerly known as MDV3100, was approved for the treatment of
metastatic castration-resistant prostate cancer by the US Food and Drug
Administration in August. It became the second oral therapy to be approved
in this setting; abiraterone acetate was approved in 2011. With abiraterone,
survival was prolonged 4.6 months, which is comparable to the 4.8 months
seen with enzalutamide.

As reported by Medscape Medical News, results from this pivotal phase 3
trial, known as A Study Evaluating the Efficacy of the Investigational Drug
MDV3100 (AFFIRM), were published online in August. The overall survival
results of the trial, which was stopped early, have not changed.

Enzalutamide adds to the treatment that can be offered to patients with
advanced prostate cancer, an expert writes in an accompanying editorial.
"It will be used sequentially with other active agents, such as docetaxel,
abiraterone, cabazitaxel, radium-223, and immunotherapy," says Nicholas J.
Vogelzang, MD, from the Comprehensive Cancer Centers of Nevada in Las
Vegas.

The effectiveness of enzalutamide in patients who previously received
abiraterone is unknown, Dr. Vogelzang notes, but the 2 agents are
"theoretically not cross-resistant" because they have different mechanisms of
action.

Dr. Vogelzang adds that this trial has "strikingly positive results" and that the
new drug "will become widely used."

One of the striking results, he explains, is related to the toxicity of the drug.
The incidence of grade 3 or higher adverse events was lower in the
enzalutamide group than in the placebo group (45.3% vs 53.1%). This
"suggests that the 'toxicity' of placebo is related to underlying disease-related
symptoms," observed Dr. Vogelzang.

Patients in the trial were randomly assigned in a 2:1 ratio to receive
enzalutamide (160 mg orally once daily in four 40 mg capsules) or matched
placebo capsules.

In the intention-to-treat population, 308 of 800 patients in the enzalutamide
group and 212 of 399 patients in the placebo group died (39% vs 53%).
Selecting Patients?

Dr. Vogelzang explains that 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."

Unfortunately, there is currently no method to clinically assess which patients
have active androgen receptors. However, there is some promising research
on a biomarker that might eventually translate into a clinical tool, he writes.
All patients deserve a therapeutic trial of enzalutamide.

For the moment, "all patients deserve a therapeutic trial of enzalutamide," he
says.
He explains that enzalutamide works differently than abiraterone, which
inhibits androgen synthesis and lowers testosterone levels to "nearly
undetectable levels."

Enzalutamide does not lower androgen levels; instead, it inhibits androgenreceptor
signaling and the binding of androgens, both of which are required for
tumor-cell growth. These inhibitory actions take place "even in patients with
androgen-receptor overexpression and resistance to other antiandrogens," he
writes.

Notably, in this study, prostate-specific antigen (PSA) levels increased in a
majority of patients who had disease progression while receiving
enzalutamide. This "suggests the tumors remained driven by androgen and
androgen receptors," Dr. Scher and colleagues report.

They conclude that these phase 3 trial data "confirm the central role of the
androgen receptor and androgen-receptor signaling in the progression of
prostate cancer."

They also offer a historic perspective.

The study participants had all been treated with conventional androgendeprivation
therapy and had castrate levels of testosterone (below 50 ng/dL
[1.7 nmol/L]). Nonetheless, because their disease progressed, it was deemed
castration-resistant

"Castration-resistant disease was previously considered to be a hormonerefractory
disease," they write. They explain that their new results show that
there is more than one way to administer hormone treatment. "The survival
benefit in this study substantiates preclinical work showing that androgenreceptor
signaling contributes to disease progression despite castrate levels
of testosterone and previous conventional antiandrogen therapy," they note.

More Results

The overall survival benefit was consistent across all subgroups, including
age, baseline pain intensity, geographic region, and type of disease
progression at entry, the authors report.

The superiority of enzalutamide over placebo was shown for all secondary
end points.

Secondary End Points in the 2 Groups (P < .001 for All)
End Point Enzalutamide, Placebo
PSA-Level Response Rate (%) 54, 2
Soft-Tissue Response Rate (%) 29, 4
FACT-P Quality-of-Life Response (%) 43, 18
Time to PSA Progression (Months) 8.3, 3.0
Radiographic Progression-Free Survival (Months) 8.3, 2.9
Time to First Skeletal-Related Event (Months) 16.7, 13.3

The benefits of enzalutamide were observed even though a greater proportion
of patients in the placebo group received subsequent systemic therapies for
prostate cancer, the authors point out.

Specifically, 42% of enzalutamide patients went on to receive abiraterone or
another therapy, compared with 61% of placebo patients.

Importantly, seizures were reported in 5 of 800 patients (0.6%) receiving
enzalutamide (several of whom had predisposing conditions or received
concomitant treatments). "Caution should be used in administering
enzalutamide to patients with a history of seizure or who have other
predisposing factors, including underlying brain injury, stroke, brain
metastases, or alcoholism, or to patients receiving concomitant medication
that may lower the seizure threshold," say the authors.

The study was funded by Medivation and Astellas Pharma Global
Development. Dr. Scher reports financial relationships with Medivation and
multiple other companies. Some of his coauthors report financial relationships
and others report being company employees.
N Engl J Med. 2012;367:1187-1197, 1256-1257.




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