ASCO 2014 - Abstract 5054

ASCO 2014. Abstact 5054. Sensitivity analyses for radiographic progression-free survival (rPFS): Results from the phase 3 PREVAIL trial comparing enzalutamide to placebo.

Michael J. Morris, Yohann Loriot, Tomasz M. Beer, Celestia S. Higano, Andrew J. Armstrong, Cora N. Sternberg, Johann Sebastian De Bono, Bertrand F. Tombal, Sarah B. Noonberg, Harry H. Mansbach, Suman Bhattacharya, Frank Perabo, De Phung, Dana E. Rathkopf; Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY; Department of Cancer Medicine, INSERM U981, Gustave Roussy, Cancer Campus, Grand Paris, Villejuif, France; Oregon Health & Science University, OHSU Knight Cancer Institute, Portland, OR; Fred Hutchinson Cancer Research Center, Seattle, WA; Duke University, Durham, NC; Hospital San Camillo-Forlanini, Rome, Italy; The Royal Marsden NHS Foundation Trust, Surrey, United Kingdom; Division of Urology, Cliniques Universitaires Saint-Luc, Brussels, Belgium; Medivation, Inc., San Francisco, CA; Astellas Pharma Global Development, Inc., Northbrook, IL; Astellas Pharma Global Development, Inc., Leiderdorp, Netherlands; Memorial Sloan Kettering Cancer Center, New York, NY

Background: In the PREVAIL trial, enzalutamide (ENZ), an androgen receptor inhibitor, significantly improved overall survival (HR: 071, P<0.0001) and rPFS (HR: 0.19, P<0.0001) compared with placebo in asymptomatic/mildly symptomatic chemotherapy-naive men with mCRPC (Beer, ASCO GUCS 2014, LBA1). Sensitivity analyses (SA) were performed to assess the impact of different sources of progression on the prespecified rPFS analysis. We also analyzed concordance between central and local reviewers.

Methods: In this double-blind, placebo-controlled, multinational study (NCT01212991), 1,717 patients were randomized 1:1 to ENZ 160 mg/day (n=872) or placebo (n=845). rPFS was a co-primary endpoint defined as time from randomization to the earliest objective evidence of radiographic progression by central review or death within 169 days of treatment discontinuation. Radiographic progression was defined by PCWG2 guidelines for bone disease or by RECIST 1.1 for soft tissue disease; bone progression was captured using a validated bone scan data capture assay. The primary rPFS analysis was event driven (at least 410 events). 

Results: Concordance between central and local assessment of progression was 87.6%. Results of the SA were statistically significant in favor of ENZ.

Conclusions: rPFS sensitivity analyses in PREVAIL demonstrated a consistent and robust treatment benefit with ENZ. Central and local assessment showed good concordance using a quantitative definition of radiographic progression and validated bone scan data assay. 

This study updated the results of PREVAIL, first presented at GU ASCO, and confirmed the clinical efficacy of enzalutamide in patients who have not yet received docetaxel. The authors confirmed a 29% improvement in survival experienced by patients receiving enzalutamide, compared to those receiving a placebo. A statistically significant and clinically relevant 81% improvement in time to radiographic progression was also confirmed. This data supports the use of enzalutamide, along with abiraterone acetate plus prednisone, as one of two main standards of treatment in docetaxel-naïve patients.

Although the initial indication from the reported HR of enzalutamide suggests that it is more effective than abiratone/prednisone, it is important to note that the comparator was placebo for PREVAIL. Similarly the comparator for the COUGAR-302 study was placebo plus prednisone. In fact, the comparator rPFS estimate in PREVAIL study was only 3.9 months, compared to 8.3 months for the COUGAR-302 study. While it is not possible to make any definitive conclusions from cross-trail comparisons, it appears that both abiraterone/prednisone and enzalutamide may offer similar effects. Irrespective, the PREVAIL study produced a statistically significant OS. For patients who are suffering from a high burden of measurable disease, enzalutamide might be the agent of choice – given its high objective response rate of 59%. Of this objective response rate, 20% were complete radiological responses. This degree of disease regression was not previously observed in phase three studies of CRPC patients.
— CARE Genitourinary Cancer Faculty