Study: Androgen inhibitor reduces death risk by 27%

Chicago-Presentations of phase III data at the American Society of Clinical Oncology annual meeting in Chicago further support the conclusion that the oral androgen receptor inhibitor enzalutamide (XTANDI) addresses an unmet therapeutic need for metastatic castration-resistant prostate cancer (mCRPC) in the pre-chemotherapy setting.

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Results presented at the AUA annual meeting in Orlando, FL from PREVAIL, the phase III trial of enzalutamide for treatment of mCRPC in chemotherapy-naïve men, showed that enzalutamide significantly decreased the risk of radiographic progression and death and delayed the initiation of chemotherapy compared to placebo; benefits of enzalutamide were seen in men with visceral as well as non-visceral disease; and the treatment was well tolerated (“Androgen inhibitor shows meaningful benefit pre-chemo").

The studies presented at ASCO contained additional findings from PREVAIL, including an updated overall survival (OS) analysis, quality of life data, and sensitivity analyses on radiographic progression.

“Once-daily oral enzalutamide added to androgen deprivation therapy prior to chemotherapy in men with mCRPC provided meaningful clinical benefit in PREVAIL. In addition, enzalutamide is well tolerated for a prolonged period of time, as 42% of men were still on enzalutamide at the data cut-off as compared to 18% of men treated with placebo, with 20% to 30% of men on enzalutamide beyond 2 years, which was very rare with placebo,” said Andrew J. Armstrong, MD, MSc, associate professor of medicine and surgery at Duke University School of Medicine, Durham, NC, who served as a co-author of both studies.

The study randomized 1,717 men, of whom 12% had visceral disease. It was halted and unblinded after a median follow-up of 22 months when a prespecified interim analysis showed statistically significant benefits of enzalutamide in the co-primary endpoints of OS and radiographic progression-free survival (rPFS). In analyses conducted after 540 deaths, the median duration of treatment was 16.6 months in the enzalutamide group versus 4.6 months in the controls. Enzalutamide reduced the risk of radiographic disease progression by 81% and of death by 29% (p<.001 for both endpoints).

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Tx maintains benefit vs. placebo

The updated OS analysis presented by Dr. Armstrong was done as part of a routine regulatory review and was conducted at the time of 116 additional deaths with an additional 4 months of follow-up. The estimated median OS had not yet been reached for enzalutamide, and it maintained its highly significant benefit compared to placebo, reducing the risk of death by 27% (p<.001).

Separately, findings from prespecified sensitivity analyses for rPFS showed enzalutamide’s treatment effect was relatively consistent using modified Prostate Cancer Working Group 2 definitions of progression, regardless of whether progression was determined by central review or investigator assessment.

“rPFS reflected a greater treatment effect than did overall survival in PREVAIL, and the results of these sensitivity analyses demonstrate the benefit of enzalutamide for improving rPFS was robust,” said Michael J. Morris, MD, associate professor of the Genitourinary Oncology Service, Memorial Sloan Kettering Cancer Center, New York, and first author of the second study.

“These data are important in terms of the role of rPFS in the future. As overall survival is becoming less of a relevant endpoint, we need to find another interim metric that is associated with overall survival and understand it as best we can.”

Higher rate of soft-tissue responses with Tx

Other data presented by Dr. Armstrong that were not reported at the AUA meeting showed a significantly higher rate of complete or partial soft-tissue responses (defined by RECIST 1.1 criteria) among enzalutamide patients compared to controls (58.8% vs. 4.9%; p<.001) as well as a significant benefit for reducing the risk of a skeletal-related event by 28% (p<.001).

In addition, enzalutamide significantly prolonged the median time to deterioration in quality of life (defined as a ≥10-point decline in global Functional Assessment of Cancer Therapy–Prostate [FACT–P] score) compared to placebo (11.3 vs. 5.6 months; p<.001), and it was associated with a near doubling of the proportion of patients achieving a positive quality of life response as measured by a ≥10-point change (40% vs. 23%; p<.0001).

“The majority of men in PREVAIL had no or minimal pain at baseline, but the mean global FACT-P score at entry for the population indicated quality of life was diminished in these men,” said Dr. Armstrong.

“In addition, enzalutamide was associated with significant improvements in all FACT-P subscales, which include physical, social, emotional, and functional well-being in addition to a prostate cancer-specific subscale. Enzalutamide delayed the deterioration in quality of life as well, which led to a significant delay in the need for cytotoxic chemotherapy. Future analyses will investigate the individual components of these quality of life metrics that were improved by enzalutamide.”

Data from the PREVAIL trial were published in the New England Journal of Medicine (2014; 371:424-33).

Dr. Armstrong is a consultant/adviser for Amgen, Bristol-Myers Squibb, Dendreon, Janssen, Medivation/Astelllas, and Sanofi. He has received honoraria from Dendreon, Pfizer, and Sanofi and has received research funding from Active Biotech, Dendreon, Janssen, Medivation, Novartis, Pfizer, and Sanofi. Dr. Morris is a consultant/adviser to Bayer, Janssen, and Millennium, and has received research funding from Astellas Pharma, Bayer, and Sanofi.UT

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