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.
Highlights
Despite recent advances in the treatment of prostate cancer, an estimated 27,540 men died of metastatic disease in the U.S in 2015 [1]
Despite the poor accrual of this trial due to newly available active oral agents in the post-docetaxel setting which limited the interpretability of the primary endpoint, we found a significant increase in progression-free survival (PFS)
Sm-153-EDTMP in combination with PSATRICOM appears to lead to clinically meaningful improvement in PFS and is associated with trends to improved prostate-specific antigen (PSA) declines and PSA-specific T-cell responses compared with Sm-153-EDTMP alone
Summary
Despite recent advances in the treatment of prostate cancer, an estimated 27,540 men died of metastatic disease in the U.S in 2015 [1]. In a randomized placebo-controlled phase 2 study in patients (n = 125) with minimally symptomatic or asymptomatic mCRPC, subjects randomized to PSA and a triad of costimulatory molecules (PSA-TRICOM) vaccine had a significantly prolonged median overall survival (OS) compared with those who received empty vector placebo (25.1 vs 16.6 months, hazard ratio (HR) 0.56, stratified log-rank P = 0.0061) [8]. Based on those findings, a multi-national phase 3 clinical trial (NCT 01322490) was initiated and has completed enrollment
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