Bruce Kynaston

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

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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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