ASCO 2020: Results of the Randomized Phase II Study of Sipuleucel-T +/- Radium-223 in Men with Bone-Metastatic Castration Resistant Prostate Cancer

(UroToday.com) Immune modulation may be enhanced by radiation therapy through a variety of mechanisms, including via enhanced display of tumor-associated antigens. Furthermore, radiopharmaceutical agents have been shown to upregulate tumor antigens in prostate cancer models,¹ and sipuleucel-T-induced antigen-specific immune responses in metastatic castration-resistant prostate cancer (mCRPC) patients correlate with survival. The hypothesis for this study is that the combination of Radium-223 and sipuleucel-T would enhance sipuleucel-T -related immune response and improve outcomes compared to sipuleucel-T alone. Results from this study were presented at the virtual ASCO 2020 by Catherine Marshall, MD, MPH, and colleagues.

For this trial, patients with asymptomatic, bone-predominant mCRPC, without visceral metastases >1.0 cm, were randomized 1:1 to sipuleucel-T alone or with six doses of Radium-223. Men in the sipuleucel-T + Radium-223 arm started sipuleucel-T between the 2^nd and 3^rd dose of Radium-223. The primary immunologic endpoint was PA2024-specific T-cell proliferation six weeks after the first sipuleucel-T infusion. Secondary immune endpoints were PA2024-specific ELISPOT response, PAP-specific proliferation and ELISPOT, humoral responses against both antigens, and antigen spread. Clinical endpoints were radiographic progression-free survival (PFS), prostate-specific antigen (PSA) response (≥50% decline), alkaline phosphatase response (≥30% decline), and safety. Key inclusion criteria included (i) asymptomatic or minimally symptomatic bone-dominant mCRPC, (ii) serologic or radiographic progression of disease, (iii) absolute PSA >=2.0 ng/mL, (iv) ECOG performance status of 0-1, and (v) prior (not concurrent) abiraterone/enzalutamide was permitted. The trial schema is as follows:

There were 32 men were randomized, 16 to each arm. Baseline characteristics in sipuleucel-T + Radium-223 and sipuleucel-T arms were similar: age (median 71 vs. 70 year), Gleason (8-10: 69% vs. 69%), baseline PSA (median 25 vs. 33 ng/mL), alkaline phosphatase (med 89 vs. 92 U/L) and ECOG score (≥1: 31% vs. 19%). There was no significant difference in prior use of abiraterone/enzalutamide (38% vs. 44%), or chemotherapy (0% vs. 25%). At 6 weeks, absolute PA2024-specific T-cell proliferation was 2.1-fold higher in the sipuleucel-T arm compared to the sipuleucel-T + Radium-223 arm (35.6 vs. 16.6; p = 0.03) and remained higher through week 26. Relative to baseline, the 6-week PA2024-specific T-cell proliferation change was 3.6 times greater in the sipuleucel-T arm compared to the sipuleucel-T + Radium-223 arm (p = 0.007) and remained higher through week 14. There were no significant differences in antigen spread or humoral responses. Median radiographic PFS was longer in the sipuleucel-T + Radium-223 arm (9.3 vs. 3.2 months; HR 0.26, 95% CI 0.11–0.61), and PSA and alkaline phosphatase responses were better in the sipuleucel-T + Radium-223 arm (PSA50: 5/15 = 33% vs. 0/14 = 0%; p = 0.04; AlkPhos30: 9/15 = 60% vs. 1/15 = 7%; p = 0.01).

Between the groups, there was no difference in skeletal-related events (13% vs. 7%).

Dr. Marshall concluded noting that sipuleucel-T + Radium-223 was associated with improved clinical outcomes and a higher rate of PSA responses compared to sipuleucel-T alone. Surprisingly, the sipuleucel-T alone arm demonstrated higher peripheral PA2024-specific T-cell proliferation. Since neither agent reliably induces PSA responses alone, these data suggest a synergistic effect of the combination. Larger randomized studies of this combination are planned. 

Presented by: Catherine H. Marshall, MD, MPH, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD

Co-Authors: Jong Chul Park, Wei Fu, Hao Wang, Theodore L. DeWeese, Serina King, Michaella Afful, Julia Hurrelbrink, Charlotte Manogue, Patrick Cotogno, Nancy P. Moldawer, Pedro C. Barata, Charles G. Drake, Edwin Melencio Posadas, Andrew J. Armstrong, A. Oliver Sartor, Emmanuel S. Antonarakis; Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD; Massachusetts General Hospital, Boston, MA; Department of Biostatistics and Bioinformatics, Johns Hopkins University School of Medicine, Baltimore, MD; Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD; The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD; Johns Hopkins University, Baltimore, MD; Duke University, Durham, NC; Tulane University Cancer Center, New Orleans, LA; Office of Clinical Research, Tulane Cancer Center, New Orleans, LA; Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA; Cleveland Clinic, Cleveland, OH; Herbert Irving Comprehensive Cancer Center, New York, NY; Duke Cancer Institute, Durham, NC; Tulane Cancer Center, New Orleans, LA

References:

1. Chakraborty M, Wansley EK, Carrasquillo JA, et al. The use of chelated radionuclide (samarium-153-ethylenediamine tetramethylene phosphonate) to modulate the phenotype of tumor cells and enhance T cell-mediated killing. Clin Cancer Res 2008;14(13):4241-4249.