The effect of prior androgen synthesis inhibition on outcomes of subsequent therapy with docetaxel in patients with metastatic castrate-resistant prostate cancer

Results from a retrospective analysis of a randomized phase 3 clinical trial (CALGB 90401) (Alliance)

Authors


  • The following institutions participated in this study: Alliance Statistics and Data Center, Duke University Medical Center, Durham, NC (Daniel J. Sargent, PhD; supported by National Cancer Institute grant CA33601); Christiana Care Health Services, Inc. Community Clinical Oncology Program (CCOP), Wilmington, Del (Stephen Grubbs, MD; supported by CA45418); Dana-Farber Cancer Institute, Boston, Mass (Harold J. Burstein, MD, PhD; supported by CA32291); Dartmouth Medical School-Norris Cotton Cancer Center, Lebanon, NH (Konstantin Dragnev, MD; supported by CA04326); Duke University Medical Center, Durham, NC (Jeffrey Crawford, MD; supported by CA47577); Greenville CCOP, Greenville, SC (Jeffrey Giguere, MD; supported by CA29165); Heartland Cancer Research CCOP, St. Louis, Mo (Alan P. Lyss, MD; supported by CA114558 to Missouri Baptist Medical Center); Hematology-Oncology Associates of Central New York CCOP, Syracuse, NY (Jeffrey Kirshner, MD; supported by CA45389); Illinois Oncology Research Association, Peoria, Ill (John W. Kugler, MD; supported by CA35113); Kansas City CCOP, Kansas City, Mo (Rakesh Gaur, MD); Massachusetts General Hospital, Boston, Mass (Jeffrey W. Clark, MD; supported by CA32291); Memorial Sloan-Kettering Cancer Center, New York, NY (Clifford A. Hudis, MD; supported by CA77651); Missouri Baptist Medical Center, St. Louis, Mo (Alan P. Lyss, MD; supported by CA114558-02 [a grant only to be used for studies that accrued patients after June 1, 2005; the institution received no grant before 2005, and Missouri was an at-large member]); Monter Cancer Center of North Shore-LIJ Health Systems, Lake Success, NY (Daniel Budman, MD; supported by CA35279); Mount Sinai Medical Center, Miami, Fla (Michael A. Schwartz, MD; supported by CA45564); Mount Sinai School of Medicine, New York, NY (Lewis R. Silverman, MD; supported by CA04457); Nevada Cancer Research Foundation CCOP, Las Vegas, Nev (John A. Ellerton, MD; supported by CA35421); New Hampshire Oncology-Hematology PA, Concord, NH (Douglas J. Weckstein, MD); North Shore University Health System CCOP, Evanston, Ill (David L. Grinblatt, MD); Northern Indiana Cancer Research Consortium CCOP, South Bend, Ind (Rafat Ansari, MD; supported by CA86726); Rhode Island Hospital, Providence, RI (William Sikov, MD; supported by CA08025); Roswell Park Cancer Institute, Buffalo, NY (Ellis Levine, MD; supported by CA59518); Sibley Memorial Hospital, Washington, DC (Frederick Barr, MD); Southeast Cancer Control Consortium Inc. CCOP, Goldsboro, NC (James N. Atkins, MD; supported by CA45808); State University of New York Upstate Medical University, Syracuse, NY (Stephen L. Graziano, MD; supported by CA21060); The Ohio State University Medical Center, Columbus, Ohio (Clara D. Bloomfield, MD; supported by CA77658); University of California at San Diego, San Diego, Calif (Barbara A. Parker, MD; supported by CA11789); University of California at San Francisco, San Francisco, Calif (Charles J. Ryan, MD; supported by CA60138); University of Chicago, Chicago, Ill (Hedy L. Kindler, MD; supported by CA41287); University of Illinois Minority-Based CCOP, Chicago, Ill (David J. Peace, MD; supported by CA74811); University of Iowa, Iowa City, Iowa (Daniel A. Vaena, MD; supported by CA47642); University of Maryland Greenebaum Cancer Center, Baltimore, MD (Martin Edelman, MD; supported by CA31983); University of Minnesota, Minneapolis, Minn (Bruce A. Peterson, MD; supported by CA16450); University of Nebraska Medical Center, Omaha, Neb (Apar Ganti, MD; supported by CA77298); University of North Carolina at Chapel Hill, Chapel Hill, NC (Thomas C. Shea, MD; supported by CA47559); University of Oklahoma, Oklahoma City, Okla (Shubham Pant, MD; supported by CA37447); University of Vermont, Burlington, Vt (Steven M. Grunberg, MD; supported by CA77406); Washington University School of Medicine, St. Louis, Mo (Nancy Bartlett, MD; supported by CA77440); Weill Medical College of Cornell University, New York, NY (John Leonard, MD; supported by CA07968); Western Pennsylvania Cancer Institute, Pittsburgh, Pa, John Lister, MD); and Yale University, New Haven, Conn (Lyndsay N. Harris, MD; supported by CA16359).

  • The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute.

Abstract

BACKGROUND

Preliminary data suggest a potential decreased benefit of docetaxel in patients with metastatic, castration-resistant prostate cancer (mCRPC) who previously received abiraterone acetate, a novel androgen synthesis inhibitor (ASI). Cancer and Leukemia Group B (CALGB) trial 90401 (Alliance), a phase 3 trial in patients with mCRPC who received docetaxel-based chemotherapy, offered the opportunity to evaluate effect of prior ketoconazole, an earlier generation ASI, on clinical outcomes after docetaxel.

METHODS

In CALGB trial 90401, 1050 men with chemotherapy-naive mCRPC were randomized to receive treatment with docetaxel and prednisone that included either bevacizumab or placebo. In total, 1005 men (96%) had data available regarding prior ketoconazole therapy. The observed effects of prior ketoconazole on overall survival (OS), progression-free survival (PFS), prostate-specific antigen (PSA) decline, and the objective response rate (ORR) were assessed using proportional hazards and Poisson regression methods adjusted for validated prognostic factors and treatment arm.

RESULTS

Baseline characteristics between patients who did (N = 277) and did not (N = 728) receive prior ketoconazole therapy were similar. There were no statistically significant differences between patients who did and those who did not receive prior ketoconazole therapy with respect to OS (median OS, 21.1 months vs 22.3 months, respectively; stratified log-rank P = .635), PFS (median PFS, 8.1 months vs 8.6 months, respectively; stratified log-rank P = .342), the proportion achieving a decline ≥50% in PSA (61% vs 66%, respectively; relative risk, 1.09; adjusted P = .129), or ORR (39% vs 43%, respectively; relative risk, 1.11; adjusted P = .366).

CONCLUSIONS

As measured by OS, PFS, PSA, and the ORR, there was no evidence that prior treatment with ketoconazole had an impact on the clinical outcomes of patients with mCRPC who received subsequent docetaxel-based therapy. The current results highlight the need for prospective studies to assess for potential cross-resistance with novel ASIs and to define the optimal sequence of therapy in mCRPC. Cancer 2013;119:3636–3643. © 2013 American Cancer Society.

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