Enzalutamide Before Chemo Slows Metastatic Prostate Cancer

Nick Mulcahy

January 28, 2014

The ability of the oral therapy enzalutamide (Xtandi, Medivation/Astellas) to delay disease progression in men with metastatic prostate cancer and extend their time to the treatment of last resort, chemotherapy, is "quite striking," said one of the drug's investigators today.

Tomasz Beer, MD, from the Knight Cancer Institute at Oregon Health & Science University in Portland reported updated results from the placebo-controlled phase 3 trial known as PREVAIL, in which enzalutamide was used prior to chemotherapy in metastatic castration-resistant disease.

He spoke about enzalutamide, which is a second-generation androgen-receptor blocker, at a presscast ahead of the Genitourinary Cancers Symposium, which takes place January 30 through February 1 in San Francisco, California.

The new data update the top-line results from this trial released in October 2013, when the trial was stopped early due to benefit, as reported by Medscape Medical News .

The manufacturer is planning to use these new data to apply for an extension of the indication, for use of enzalutamide prior to chemotherapy.

The drug is already approved for use in prostate cancer, but its current indication is for second-line therapy in men with metastatic castration-resistant prostate cancer who had previously received docetaxel. This indication was approved by the US Food and Drug Administration (FDA) in August 2012, and was recently approved in the European Union.

Use Before Chemotherapy

The PREVAIL study was conducted in men with advanced disease that had progressed on androgen deprivation therapy.

Dr. Beer explained that enzalutamide was compared with placebo and not with chemotherapy in PREVAIL because the study population consisted of men with asymptomatic or minimally symptomatic advanced prostate cancer. Such men "typically" do not have chemotherapy at this point in their disease, he said.

The updated results show that enzalutamide delayed the radiographically detected progression of the disease by 81% (rPFS: hazard ratio [HR], 0.19; P < .0001). The median rPFS for the placebo arm was 3.4 months but has not yet been reached in the treatment arm.

Additionally, enzalutamide stopped or slowed cancer growth in soft tissue in 59% of patients (20% complete responses and 39% partial responses) compared with 5% of patients on placebo.

These benefits ultimately meant that, on average, patients treated with enzalutamide received chemotherapy about 17 months later than those in the placebo arm (28 months vs 10.8 months; HR, 0.35; P < .0001).

Dr. Beer also updated the survival data for the 1717 trial participants, who were randomized to enzalutamide (160 mg orally once daily) or placebo between September 2010 and September 2012. Patients in both arms also received standard hormone therapy.

At a median follow-up of 20.2 months, 28% of enzalutamide patients and 35% of placebo patients have died.

This translated into a 29% reduction in risk for death (overall survival: HR, 0.71; P < .0001). The estimated median overall survival was 32.4 months in the enzalutamide arm vs 30.2 months in the placebo arm, but the data are maturing and the upper limits of survival have not yet been reached in either arm.

First-Line Use

Currently in the United States, the first-line treatment for metastatic castration-resistant prostate cancer is limited to either chemotherapy regimens containing docetaxel or abiraterone (Zytiga; Janssen), which had this extension to its indication approved in December 2012.

Enzalutamide is poised to become, pending FDA approval for this indication extension, another systemic therapy option in this first-line setting.

The possibility of approval for enzalutamide invites comparisons with abiraterone in this setting. But Dr. Beer refused to indulge reporters' requests for such a summary, citing the inappropriateness of such cross-trial comparisons and the absence of an FDA approval for first-line enzalutamide.

However, he went onto say that some of the conveniences of enzalutamide, "may play a role in decision-making in the clinic."

For instance, enzalutamide is not coadministered with steroids, as is abiraterone (with prednisone). Also, there are no diet restrictions with enzalutamide, as there are with abiraterone, he said.

Time will tell how enzalutamide and abiraterone are used in this patient population, suggested Dr. Beer, saying that both drugs have "emerged very rapidly" and the clinical assessments and understandings of the pair are "just beginning."

There is a large clinical opportunity for enzalutamide, should its approval be expanded, said Charles Ryan, MD, from the Helen Diller Family Comprehensive Cancer Center at the University of California, San Francisco. He was not involved with the study and moderated the press conference.

Dr. Ryan said that more than 50,000 men a year in the United States live with castration-resistant metastatic prostate cancer. "Although chemotherapy is held up as a benchmark for this disease, the reality is less than 50%...of men with castration-resistant metastatic prostate cancer receive chemotherapy," he commented.

Well Tolerated in This Study

Enzalutamide was well tolerated in the study, with the same percentage (6%) of patients in both arms leaving the study because of side effects.

There were more grade 3+ adverse events with enzalutamide vs placebo (43% vs 37%).

The most common side effects of all grades included fatigue (36% vs 26%), constipation (22% vs 17%), back pain (27% vs 22%) and arthralgia (20% vs 16%).

The median time to reporting an adverse event was 17.1 months for enzalutamide and 5.4 months for placebo.

One patient in each arm had a seizure, Dr. Beer reported. However, in both cases, the patients had a history of seizures.

Enzalutamide is a second-generation androgen-receptor blocker and has proven more potent than the first generation of these agents such as bicalutamide, flutamide, and nilutamide.

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