Second Pill for Prostate Cancer Also Prolongs Survival

Nick Mulcahy

September 27, 2012

September 27, 2012 — Enzalutamide (Xtandi, Astellas), the once-daily oral therapy, significantly prolongs survival in men with metastatic castration-resistant 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 androgen-receptor 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 androgen-deprivation 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 hormone-refractory 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 androgen-receptor 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. Abstract, Editorial