The negative results are consistent with the negative results of large phase III trials in which docetaxel plus antiangiogenic agents were used in patients with metastatic castrate-resistant prostate cancer (mCRPC). The negative data underscore that, despite a sound biological rationale and supportive early-phase clinical results, adding antiangiogenic agents to docetaxel for mCRPC is a great challenge.
Inhibition of vascular endothelial growth factor (VEGF) signaling abrogates tumor-induced angiogenesis to constrain tumor growth, and can be exploited therapeutically by using cediranib, an oral tyrosine kinase inhibitor of VEGF receptor signaling. Our preliminary phase I trial data showed that adding cediranib to docetaxel plus prednisone (DP) was safe and feasible, with early evidence for efficacy in patients with metastatic castrate-resistant prostate cancer (mCRPC).
This multicenter phase II trial assessed whether adding cediranib to DP improves efficacy of DP in patients with mCRPC. Chemotherapy-naive patients with mCRPC were randomly assigned to receive either docetaxel (75 mg/m2 intravenously every 3 weeks) with prednisone (5 mg twice daily) plus cediranib (30 mg once daily; the DP+C arm) or DP only (the DP arm). The primary endpoint was to compare 6-month progression-free survival (PFS) rate between the two arms. Secondary endpoints included 6-month overall survival (OS), objective tumor and prostate-specific antigen (PSA) response rates, biomarkers, and adverse events.
The 6-month PFS rate in a total of 58 patients was only numerically higher in the DP+C arm (61%) compared with the DP arm (57%). Similarly, the 6-month OS rate, objective tumor and PSA response rates, and biomarkers were not significantly different between the two arms. Increased baseline levels of interleukin 6 (IL-6), however, were significantly associated with increased risk of progression. Neutropenia was the only grade 4 toxicity (38% in the DP+C arm vs. 18% in the DP arm).
Combining cediranib with docetaxel + prednisone failed to demonstrate superior efficacy, compared with docetaxel + prednisone, and added toxicity. Our data do not support pursuing the combination further in patients with mCRPC.
The oncologist. 2019 May 31 [Epub ahead of print]
Elisabeth Heath, Lance Heilbrun, Heather Mannuel, Glenn Liu, Primo Lara, J Paul Monk, Thomas Flaig, Amado Zurita, Philip Mack, Ulka Vaishampayan, Philip Stella, Daryn Smith, Susan Bolton, Arif Hussain, Anas Al-Janadi, Daniel Silbiger, Muhammad Usman, S Percy Ivy
Department of Oncology, Wayne State University School of Medicine and Karmanos Cancer Institute, Detroit, Michigan, USA ., Department of Oncology, Wayne State University School of Medicine and Karmanos Cancer Institute, Detroit, Michigan, USA., Division of Hematology/Oncology, University of Maryland School of Medicine and Greenebaum Cancer Center, Baltimore, Maryland, USA., Division of Hematology/Oncology, University of Wisconsin School of Medicine and Public Health and Carbone Cancer Center, Madison, Wisconsin, USA., Division of Hematology/Oncology, University of California Davis School of Medicine and Cancer Center, Sacramento, California, USA., Division of Medical Oncology, Ohio State University School of Medicine and Cancer Center - James, Columbus, Ohio, USA., Division of Medical Oncology, University of Colorado School of Medicine, Aurora, Colorado, USA., Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas, USA., IHA Hematology/Oncology, Ypsilanti, Michigan, USA., Michigan State University Breslin Cancer Center, Lansing, Michigan, USA., Case Western Reserve University School of Medicine University Hospitals, Cleveland, Ohio, USA., National Institutes of Health National Cancer Institute, Bethesda, Maryland, USA.