Cediranib, a pan-vascular endothelial growth factor receptor inhibitor, suppresses expression of homologous recombination repair (HRR) genes and increases sensitivity to poly-(ADP-ribose) polymerase inhibition in preclinical models. We investigated whether cediranib combined with olaparib improves the clinical outcomes of patients with prostate cancer.
Patients with progressive metastatic castration-resistant prostate cancer (mCRPC) were randomly assigned 1:1 to arm A: cediranib 30 mg once daily plus olaparib 200 mg twice daily or arm B: olaparib 300 mg twice daily alone. The primary end point was radiographic progression-free survival (rPFS) in the intention-to-treat patients. The secondary end points were rPFS in patients with HRR-deficient and HRR-proficient mCRPC.
In the intention-to-treat set of 90 patients, median rPFS was 8.5 (95% CI, 5.4 to 12.0) and 4.0 (95% CI, 3.2 to 8.5) months in arms A and B, respectively. Cediranib/olaparib significantly improved rPFS versus olaparib alone (hazard ratio [HR], 0.617; 95% CI, 0.392 to 0.969; P = .0359). Descriptive analyses showed a median rPFS of 10.6 (95% CI, 5.9 to not assessed [NA]) and 3.8 (95% CI, 2.33 to NA) months (HR, 0.64; 95% CI, 0.272 to 1.504) among patients with HRR-deficient mCRPC, and 13.8 (95% CI, 3.3 to NA) and 11.3 (95% CI, 3.8 to NA) months (HR, 0.98; 95% CI, 0.321 to 2.988) among patients with BRCA2-mutated mCRPC in arms A and B, respectively. The incidence of grades 3-4 adverse events was 61% and 18% in arms A and B, respectively.
Cediranib combined with olaparib improved rPFS compared with olaparib alone in men with mCRPC. This combination was associated with an increased incidence of grades 3-4 adverse events. BRCA2-mutated subgroups treated with olaparib with or without cediranib were associated with a numerically longer median rPFS.
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2022 Oct 18 [Epub ahead of print]
Joseph W Kim, Rana R McKay, Marc R Radke, Shilin Zhao, Mary-Ellen Taplin, Nancy B Davis, Paul Monk, Leonard J Appleman, Primo N Lara, Ulka N Vaishampayan, Jingsong Zhang, Asit K Paul, Glenn Bubley, Eliezer M Van Allen, Serhan Unlu, Ying Huang, Massimo Loda, Geoffrey I Shapiro, Peter M Glazer, Patricia M LoRusso, S Percy Ivy, Yu Shyr, Elizabeth M Swisher, Daniel P Petrylak
Medical Oncology Yale School of Medicine and Yale Cancer Center, New Haven, CT., Division of Hematology-Oncology, Department of Medicine, University of California San Diego, San Diego, CA., Department of Obstetrics and Gynecology, University of Washington, Seattle, WA., Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN., Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA., Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN., Division of Medical Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH., Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA., Department of Internal Medicine, UC Davis Comprehensive Cancer Center, Sacramento, CA., Department of Internal Medicine/Oncology, University of Michigan, Ann Arbor, MI., Genitourinary Oncology Program, H. Lee Moffitt Cancer Center, Tampa, FL., Virginia Commonwealth University, Richmond, VA., Department of Medicine, Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Boston, MA., Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, and Meyer Cancer Center, New York, NY., Therapeutic Radiology, Yale School of Medicine and Yale Cancer Center, New Haven, CT., Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD.