Enzalutamide and abiraterone both target androgen receptor signaling but via different mechanisms. The mechanism of action of one drug may counteract the resistance pathways of the other. We sought to determine whether the addition of abiraterone acetate and prednisone (AAP) to enzalutamide prolongs overall survival (OS) in patients with metastatic castration-resistant prostate cancer (mCRPC) in the first-line setting.
Men with untreated mCRPC were randomly assigned (1:1) to receive first-line enzalutamide with or without AAP. The primary end point was OS. Toxicity, prostate-specific antigen declines, pharmacokinetics, and radiographic progression-free survival (rPFS) were also examined. Data were analyzed using an intent-to-treat approach. The Kaplan-Meier estimate and the stratified log-rank statistic were used to compare OS between treatments.
In total, 1,311 patients were randomly assigned: 657 to enzalutamide and 654 to enzalutamide plus AAP. OS was not statistically different between the two arms (median, 32.7 [95% CI, 30.5 to 35.4] months for enzalutamide v 34.2 [95% CI, 31.4 to 37.3] months for enzalutamide and AAP; hazard ratio [HR], 0.89; one-sided P = .03; boundary nominal significance level = .02). rPFS was longer in the combination arm (median rPFS, 21.3 [95% CI, 19.4 to 22.9] months for enzalutamide v 24.3 [95% CI, 22.3 to 26.7] months for enzalutamide and AAP; HR, 0.86; two-sided P = .02). However, pharmacokinetic clearance of abiraterone was 2.2- to 2.9-fold higher when administered with enzalutamide, compared with clearance values for abiraterone alone.
The addition of AAP to enzalutamide for first-line treatment of mCRPC was not associated with a statistically significant benefit in OS. Drug-drug interactions between the two agents resulting in increased abiraterone clearance may partly account for this result, although these interactions did not prevent the combination regimen from having more nonhematologic toxicity.
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2023 Mar 30 [Epub ahead of print]
Michael J Morris, Glenn Heller, David W Hillman, Olivia Bobek, Charles Ryan, Emmanuel S Antonarakis, Alan H Bryce, Olwen Hahn, Himisha Beltran, Andrew J Armstrong, Lawrence Schwartz, Lionel D Lewis, Jan H Beumer, Brooke Langevin, Eric C McGary, Paul T Mehan, Amir Goldkorn, Bruce J Roth, Han Xiao, Colleen Watt, Mary-Ellen Taplin, Susan Halabi, Eric J Small
Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY., Alliance Statistics and Data Management Center, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY., Alliance Statistics and Data Management Center, Mayo Clinic, Rochester, MN., Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN., Division of Hematology and Medical Oncology, Mayo Clinic, Phoenix, AZ., University of Chicago Medical Center, Chicago, IL., Department of Medical Oncology, Dana-Farber/Partners Cancer Care, Boston, MA., Duke Cancer Institute Center for Prostate and Urologic Cancers, Division of Medical Oncology, Department of Medicine, Duke University, Durham, NC., Department of Radiology, Columbia University Irving Medical Center, New York, NY., Norris Cotton Cancer Center, The Geisel School of Medicine at Dartmouth and The Dartmouth-Hitchcock Medical Center, Lebanon, NH., University of Pittsburgh, Pittsburgh, PA., Center for Translational Medicine, University of Maryland School of Pharmacy, Baltimore, MD., Division of Medical Oncology, Kaiser Permanente (SCAL) and Kaiser Permanente School of Medicine, Cadillac, CA., Missouri Baptist Hospital, St Louis, MO., Division of Medical Oncology, Department of Medicine, Keck School of Medicine and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA., Washington University School of Medicine, St Louis, MO., University of Chicago, Chicago, IL., Alliance Statistics and Data Management Center, and Department of Biostatistics and Bioinformatics, Duke University, Durham, NC., UCSF Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA.