Samarium-153-EDTMP (Quadramet®) with or without vaccine in metastatic castration-resistant prostate cancer: A randomized Phase 2 trial

// Christopher R. Heery 1 , Ravi A. Madan 2 , Mark N. Stein 3 , Walter M. Stadler 4 , Robert S. Di Paola 3, 7 , Myrna Rauckhorst 2 , Seth M. Steinberg 5 , Jennifer L. Marté 2 , Clara C. Chen 6 , Italia Grenga 1 , Renee N. Donahue 1 , Caroline Jochems 1 , William L. Dahut 2 , Jeffrey Schlom 1 , James L. Gulley 2 1 Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA 2 Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA 3 Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA 4 University of Chicago Medicine, Chicago, IL, USA 5 Biostatistics and Data Management Section, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA 6 National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, MD, USA 7 Current affiliation: University of Kentucky College of Medicine Lexington, KY, USA Correspondence to: James L. Gulley, email: Gulleyj@mail.nih.gov Keywords: therapeutic vaccine, radionuclide, prostate cancer, Quadramet ® , cancer immunotherapy Received: April 19, 2016 Accepted: June 26, 2016 Published: July 28, 2016 ABSTRACT PSA-TRICOM is a therapeutic vaccine in late stage clinical testing in metastatic castration-resistant prostate cancer (mCRPC). Samarium-153-ethylene diamine tetramethylene phosphonate (Sm-153-EDTMP; Quadramet ® ), a radiopharmaceutical, binds osteoblastic bone lesions and emits beta particles causing local tumor cell destruction. Preclinically, Sm-153-EDTMP alters tumor cell phenotype facilitating immune-mediated killing. This phase 2 multi-center trial randomized patients to Sm-153-EDTMP alone or with PSA-TRICOM vaccine. Eligibility required mCRPC, bone metastases, prior docetaxel and no visceral disease. The primary endpoint was the proportion of patients without radiographic disease progression at 4 months. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and immune responses. Forty-four patients enrolled. Eighteen and 21 patients were evaluable for the primary endpoint in Sm-153-EDTMP alone and combination arms, respectively. There was no statistical difference in the primary endpoint, with two of 18 (11.1%) and five of 21 (23.8%) in Sm-153-EDTMP alone and combination arms, respectively, having stable disease at approximately the 4-month evaluation time point ( P = 0.27). Median PFS was 1.7 vs. 3.7 months in the Sm-153-EDTMP alone and combination arms ( P = 0.041, HR = 0.51, P = 0.046). No patient in the Sm-153-EDTMP alone arm achieved prostate-specific antigen (PSA) decline > 30% compared with four patients (of 21) in the combination arm, including three with PSA decline > 50%. Toxicities were similar between arms and related to number of Sm-153-EDTMP doses administered. These results provide the rationale for clinical evaluation of new radiopharmaceuticals, such as Ra-223, in combination with PSA-TRICOM.