Randomized Phase II Trial of Sipuleucel-T with or without Radium-223 in Men with Bone-metastatic Castration-resistant Prostate Cancer

Abstract

Purpose: To investigate if radium-223 increases peripheral immune responses to sipuleucel-T in men with bone-predominant, minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC).Methods: 32 patients were randomized 1:1 in this open label, phase 2 multicenter trial. Patients in the control arm received 3 sipuleucel-T treatments, 2 weeks apart. Those in the combination arm received 6 doses of radium-223 monthly, with sipuleucel-T intercalated between the second and fourth doses of radium-223. The primary endpoint was a comparison of peripheral antigen PA2024-specific T cell responses (measured by proliferation index). Secondary endpoints were progression-free survival (PFS), overall survival (OS), and PSA responses. Results:We enrolled 32 patients, followed for a median of 1.6 years. Six weeks after the first sipuleucel-T dose, participants in the control arm had a 3.2-fold greater change in PA2024-specific T cell responses compared to those who received combination treatment (p=0.036). Patients in the combination arm were more likely to have a >50% PSA decline (5 (31%) versus 0 patients; P=0.04), and also demonstrated longer PFS (39 vs 12 weeks; HR 0.32; 95% CI 0.14-0.76) and OS (not-reached vs 2.6 years; HR 0.32; 95% CI 0.08-1.23).

Osteoimmuno-Oncology: Therapeutic Opportunities for Targeting Immune Cells in Bone Metastasis

“…This immunosuppression can, however, be due to concomitant dexamethasone treatment [ 191 ]. Radium-223 has also been studied in combination with sipuleucel-T. Interim results of a phase 2 combination study suggest synergistic effects, but further studies are warranted [ 192 ]. In relation to radium-223, monitoring and maintaining bone health are important in prostate cancer patients [ 193 ].…”

Boosting the Immune Response – Combining the Local and Immune Therapy for Prostate Cancer Treatment

“…Another phase II trial assessed the combination of sipuleucel-T and a radioisotope, radium-223, in patients with mCRPC. Despite paradoxically decreased the immune response in the combination arm, PSA levels were decreased and PFS and OS longer [204]. A case report by Han et al presents a significant clinical response to pembrolizumab and radiation combination in patient heavily treated mCRPC with rectal involvement.…”

“…Table 2 presents a comparison of the immunomodulatory impact of different local therapies on TME. [ 188,192,[201][202][203][204][205][193][194][195][196][197][198][199][200] HIFU: high-intensity focused ultrasound; PDT: photodynamic therapy; IRE: irreversible electroporation; RT: radiotherapy; DC: dendritic cell; CTL: cytotoxic T-lymphocyte; NK: natural killer; IL: interleukin; Treg: regulatory T cell; MDSC: myeloid-derived suppressor cell; APC: antigen-presenting cell; TNF: tumor necrosis factor; MHC: major histocompatibility complex.…”

Immunotherapy in treatment of metastatic prostate cancer: An approach to circumvent immunosuppressive tumor microenvironment

“…A small percentage, 4.8%–2.6% of Sipuleucel‐T‐treated patients showed PSA reductions at least 50% on two visits at least 4 weeks apart, as compared with 1.3%–0% in the placebo group 55,56 . A synergistic effect of the combination of Sipuleucel‐T and Radium‐223 (Ra223) was evaluated in men with asymptomatic bone‐metastatic CRPC in an ongoing phase II clinical trial which has shown much improved PSA reduction (31%, vs. 0% in Sipuleucel‐T only group) and longer progression‐free survival (39 weeks vs. 12 weeks Sipuleucel‐T only group) in combined Sipuleucel‐T/Ra223 treatment group 66 …”