Tomasz M. Beer, MD
The androgen-receptor blocker enzalutamide (Xtandi) improves survival by nearly 30% in chemotherapy-naïve men with metastatic castration-resistant prostate cancer (mCRPC) and delays progression of their disease by more than 80%, according to findings from a phase III trial announced Tuesday in advance of the 2014 Genitourinary Cancers Symposium.
In light of the results of the PREVAIL study, the drug’s developers, Medivation Inc. and Astellas Pharma, plan to ask the FDA early this year to expand enzalutamide’s indication, a spokeswoman for Astellas said. Orally administered enzalutamide initially was approved in 2012 for patients with mCRPC previously treated with docetaxel and hormonal therapy.
“Enzalutamide is likely to become an important new treatment option that has a significant impact on the progression of prostate cancer,” said Tomasz Beer, MD, FACP, during a press conference before the opening of the symposium, set for January 30-February 1 in San Francisco. “If approved for this indication, it will become an important standard option for use before chemotherapy in patients with asymptomatic or minimally symptomatic advanced prostate cancer.”
Beer, professor of Medicine and deputy director of the Knight Cancer Institute at Oregon Health and Science University, estimated that about 50,000 men each year in the United States potentially could benefit from earlier use of the therapy.
The approval of enzalutamide in this population would be helpful to those who want or need to delay chemotherapy, since there are few or no other treatment options, noted press conference moderator Charles J. Ryan, MD, professor of Clinical Medicine and Urology at the Helen Diller Family Comprehensive Cancer Center at the University of California, San Francisco.
Enzalutamide, a second-generation androgen receptor blocker, offers more potent activity than the first generation of these agents—bicalutamide, flutamide, and nilutamide, according to the American Society of Clinical Oncology (ASCO), one of the symposium’s sponsors, in a written statement.
The drug, which is supplied in 40-mg capsules, has generated enthusiasm at every research milestone. In October 2013, when the PREVAIL trial was stopped early because the endpoints had been met, Beer called the study’s results “unprecedented in this population.”
The multinational, randomized, double-blind, placebo-controlled PREVAIL study included 1717 men with mCRPC who had not received chemotherapy, randomized 1:1 to receive 160 mg per day of enzalutamide or placebo. Participants had previously received treatment, such as surgery or radiation therapy, for their primary tumor, as well as hormone therapy with an LHRH agonist or first-generation antiandrogen, on which their disease had progressed. Some patients continued taking hormonal therapy during the trial.
The two primary endpoints were overall survival (OS) and radiographic progression-free survival (rPFS), measured with regular bone and CT scans. Median follow-up was 20 months.
Investigators found that patients in the enzalutamide arm had a 29% reduction in their risk of death (HR = 0.71; 95% CI: 0.59-0.83; P
< .0001) and an 81% reduction in their risk of radiographic progression (HR = 0.19; 95% CI: 0.15-0.23; P
< .0001) as compared with those in the placebo arm. At the time of the analysis, 28% of enzalutamide patients and 35% of placebo patients had died.
Estimated median OS was 32.4 months in the enzalutamide arm versus 30.2 months in the placebo arm, the investigators reported. Median rPFS was 3.9 months in the placebo arm and had not been reached in the enzalutamide arm, they wrote.
In a finding Beer described as “quite striking,” investigators noted that enzalutamide led to a meaningful reduction in soft-tissue disease from baseline in 59% of patients (20% complete responses and 39% partial responses), compared with 5% of patients in the placebo arm (P
<.0001). And, he said, they observed that enzalutamide significantly delayed the need for chemotherapy. On average, patients receiving the drug needed chemotherapy 17 months later than those who took placebo, representing a 65% increase in time to chemotherapy (P
> .0001), Beer said. Those taking placebo started chemotherapy after a median 10.8 months, while those taking enzalutamide started cytotoxic treatment after a median 28 months, he said.
After an Independent Data Monitoring Committee confirmed that endpoints had been met and called for an early halt to the trial in October, patients taking placebo were offered enzalutamide.
The most common adverse events (AEs) for patients taking enzalutamide included fatigue, constipation, and back and joint pain, and some on the study experienced AEs associated with hormone therapy, such as weight gain and hot flashes. Overall, enzalutamide was well tolerated, with the same percentage of patients (6%) in the enzalutamide and placebo arms leaving the study due to AEs, Beer pointed out.
Two patients on the trial had seizures—one on the placebo arm and one on the enzalutamide arm—but both had a prior history of seizures that had not been disclosed when they enrolled, Beer said. Those were the only incidences of seizures on the trial, resulting in a 0.1%, or “very low,” risk of seizure associated with enzalutamide, he said.
While there is interest in how or whether enzalutamide should be sequenced or combined with another recently approved drug for prostate cancer, the hormonal treatment abiraterone (Zytiga), Beer said those questions have not yet been answered by studies.
If choosing between the two drugs, physicians might consider the fact that abiraterone must be given with prednisone and not concurrently with food, while enzalutamide does not require the same restrictions, Beer said.
A trial comparing a combination of enzalutamide with or without abiraterone plus prednisone in patients with mCRPC has been launched by members of the SWOG cooperative research group, Ryan noted (NCT01949337).
Beer TM, Armstrong AJ, Sternberg CN, et al. Enzalutamide in men with chemotherapy-naïve metastatic prostate cancer (mCRPC): results of phase 3 PREVAIL study. Presented at: 2014 Genitourinary Cancers Symposium; January 30-February 1, 2014; San Francisco, California. Abstract LBA1.
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