Radium-223/Sipuleucel-T Combo Puts the Brakes on Bone-Metastatic CRPC

In a presentation at the recent American Society of Clinical Oncology’s annual Genitourinary Cancers Symposium, researchers delivered interim results from the ongoing Study of Sipuleucel-T W/ or W/O Radium-223 in Men With Asymptomatic or Minimally Symptomatic Bone-MCRPC (NCT02463799).

Radium-223’s (Ra-223; Provenge, Dendreon) low levels of alpha particle radiation induce double-strand DNA breaks, which leads to cell apoptosis; it was first approved by the FDA in 2013. Sipuleucel-T (SipT; Xofigo, Bayer), which is an immunotherapy manufactured from a patient’s peripheral blood mononuclear cells, activates T cells to spur an immune response; the FDA approved it in 2010. Both are used to treat bone-metastatic castration-resistant prostate cancer (CRPC).

The authors focused on these 2 treatment modalities in bone-metastatic CRPC for 4 main reasons:

1. Radiation therapy boosts immune modulation
2. Tumor antigens’ numbers increase when radiopharmaceutical agents are introduced
3. Ra-223 targets increased bone turnover
4. SipT is approved to treat minimally symptomatic metastatic CRPC

This portion of the study evenly randomized 32 patients between May 2017 and November 2018 to 2 treatment groups: SipT alone or in combination with 6 doses of Ra-223. In the latter group, the SipT was given between the second and third doses of the Ra-223. The mean ages were 71.6 (range, 64-88) and 70.3 (range, 57-86) years in the combination and SipT-alone groups, respectively (P = .59). Most (69% in each group) had a Gleason score of at least 8, indicating high-grade cancer. ECOG Performance Status was 0 in 69% of the combo group and 81% of the SipT-alone group and 1 in 31% and 19%, respectively. The median prostate-specific antigen (PSA) level was 82 and 72 ng/mL, respectively, and the median alkaline phosphatase, 125 U/L in both.

The primary clinical outcome was patient immune response 6 weeks after the first SipT infusion, as measured by PA2024 level, and the secondary outcomes were PSA (>50% decline) response rate, alkaline phosphatase (>30% decline) response rate, time to radiographic/clinical progression-free survival (PFS), and safety/toxicity of the combination.

Compared with SipT alone, treatment with Ra-223 plus SipT resulted in improved clinical outcomes among the patients. However, at the 6-week mark, there was a 25.3% improvement in PA2024 in the SipT-alone arm and 7% with the combination. The remaining results favored the combination, after a median follow-up of 5.3 (range, 2.8-26.6) months:

• PSA: 33% versus 0% (P = .04)
• Alkaline phosphatase: 60% versus 7% (P = .01)
• PFS: 10.7 versus 3.1 months (hazard ratio, 0.35; 95% CI, 0.15-0.81; P = .02)

No safety concerns came to light with the combination treatment, although there were several grade 3 adverse effects: pain (19%) and anemia, nausea, diarrhea, and hypertension (6% each).

“Peripheral immune responses were lower in the SipT + Ra-223 group, although with improved clinical outcomes compared to SipT alone. These data suggest a synergistic effect of the combination, especially with respect to clinical outcomes. Larger randomized studies of this combination are warranted,” the authors concluded.

Reference

Marshall CH, Park JC, DeWeese TL, et al. Randomized phase II study of sipuleucel-T (SipT) with or without radium-223 (Ra223) in men with asymptomatic bone-metastatic castrate-resistant prostate cancer (mCRPC). Presented at: ASCO Annual Genitourinary Cancers Symposium; February 13-15, 2020; San Francisco, CA. Abstract 130. meetinglibrary.asco.org/record/183577/abstract.