Results Of The Randomized Phase Ii Study Of Sipuleucel-T (Sip-T) +/- Radium-223 (Ra-223) In Men With Bone-Metastatic Castration Resistant Prostate Cancer.

5563 Background: It has been suggested that immune modulation can be augmented by radiation, possibly by enhancing tumor-antigen display. SipT-induced antigen-specific immune responses in mCRPC patients correlate with survival. We hypothesized that the combination of Ra223 and SipT would enhance SipT-related immune response and improve outcomes compared to SipT alone. Methods: Patients with asymptomatic, bone-predominant mCRPC, without visceral mets >1.0 cm, were randomized (1:1) to SipT alone or with 6 doses of Ra223 (NCT02463799). Men in the SipT+Ra223 arm started SipT between the 2nd and 3rd dose of Ra223. The primary immunologic endpoint was PA2024-specific T-cell proliferation 6 wks after the first SipT 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 PFS, PSA response (≥50% decline), AlkPhos response (≥30% decline), and safety. Results: 32 men were randomized, 16 per arm. Baseline characteristics in SipT+Ra223 and SipT arms were similar: age (median 71 vs. 70 yrs), Gleason (8-10: 69% vs. 69%), baseline PSA (med 25 vs. 33 ng/mL), AlkPhos (med 89 vs. 92 U/L) and ECOG score (≥1: 31% vs. 19%). There was no significant difference in prior use of abi/enza (38% vs. 44%), or chemo (0% vs. 25%). At 6 weeks, absolute PA2024-specific T-cell proliferation was 2.1-fold higher in the Sip-T arm compared to the SipT+Ra223 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 Sip-T arm compared to the SipT+Ra223 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 SipT+Ra223 arm (9.3 vs. 3.2 months; HR 0.26, 95% CI 0.11–0.61; P=0.007). PSA and AlkPhos responses were better in the SipT+Ra223 arm (PSA50: 5/15=33% vs. 0/14=0%; P=0.04; AlkPhos30: 9/15=60% vs. 1/15=7%; P=0.01). There was no difference in SREs (13% vs. 7%). Conclusions: SipT+Ra223 was associated with improved clinical outcomes and a higher rate of PSA responses compared to SipT alone, although surprisingly, the SipT 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. Clinical trial information: NCT02463799 .