Sipuleucel-T Plus Radium-223 Improves Clinical Outcomes in Bone-Metastatic CRPC

Emmanuel S. Antonarakis, MD

The addition of radium-223 dichloride (Xofigo) to sipuleucel-T (sip-T; Provenge) resulted in prolonged radiographic progression-free survival (PFS) in patients with bone-metastatic castration-resistant prostate cancer (CRPC), according to Emmanuel S. Antonarakis, MBBCh.

In a phase 2 study, patients with asymptomatic or minimally-symptomatic bone-predominant mCRPC were randomized 1:1 to receive treatment with sip-T alone or combined with 6 doses of radium-223. A total of 32 patients were enrolled to the trial, and the baseline characteristics in the single-agent and combination arms were matched with respect to age (median 70 vs 71 years, respectively), Gleason sum (69% vs 69%), prostate-specific antigen (PSA; median 33 ng/mL vs median 25 ng/mL), alkaline phosphatase (median 92 vs median 89 u/L) and ECOG scores (≥1: 19% vs 31%).

After a median follow up of 5.3 months, the median radiographic/clinical PFS was longer in the combination arm at 10.7 months versus 3.1 months in the single-agent arm (HR, 0.35; 95% CI, 0.15-0.81; P =.02). Outcomes were also better in the combination arm with respect to PSA responses. Specifically, those who received the sip-T/radium-223 experienced a PSA response of at 33% while those who received sip-T alone did not experience any PSA response (0%; P =.04). Outcomes regarding alkaline phosphatase responses also favored the combination, at 60% versus 7% (P =.01). The time to radiographic PFS was a median of 9.3 months versus 3.1 months, with the combination versus the single agent, respectively (HR, 0.26; P =.0011).

“Of course, this is a very small study and it is fraught with all the complications, nuances, and limitations of a randomized phase II study, but the level of activity was encouraging enough for us to begin to design further studies,” said Antonarakis. “We are now contemplating the design of a larger randomized phase II or even phase III study to test the combination of sip-T plus radium-223 compared with sip-T alone in a broader patient population with more follow-up.”

In an interview with OncLive, Antonarakis, professor of oncology at Johns Hopkins Medicine, discussed the efficacy of radium-223 plus sip-T in patients with bone-metastatic CRPC and the next steps for research for this combination.

OncLive: Could you provide an overview of the trial examining sip-T and radium-223?

Antonarakis: At the 2020 Genitourinary Cancers Symposium, we presented a poster on a randomized phase II study of sip-T versus the combination of sip-T plus radium-223. I was delighted to present these data on behalf of the first author, my colleague Catherine H. Marshall, MD, MPH, of Johns Hopkins Medicine. In the study, we looked at a small population of about 30 patients with metastatic CRPC who were asymptomatic or minimally symptomatic were randomized to receive either standard sip-T alone or the combination of sip-T plus radium-223.

The combination group was a bit logistically challenging because they started off with the radium-223, which was given at an interval of once every 4 weeks; this is the FDA-approved dosage schedule. After 2 doses of radium-223, they then received sip-T, which was also given according to the dosage schedule of that drug at 3 doses every 2 weeks. Afterward, the patients received the third, fourth, fifth, and sixth dose of radium-223. The sip-T was essentially sandwiched in between the radium-223 injections.

The interesting thing about this study, which was a bit unanticipated, was that we saw evidence of synergy in the combination arm. The synergy was evidenced by PSA responses. We saw 5 out of 15 unconfirmed PSA responses; we did not see any PSA responses in the control group.

The more provocative part of this research was that we saw a prolongation of radiographic PFS. In the control arm, the radiographic PFS was about 3 months. In the combination arm, the radiographic PFS was over 9 months, and that was a statistical difference.

Will these agents be used in a triplet regimen in the future?

Yes, this brings up the question about whether or not radium-223 should be combined with a PD-1 or PD-L1 inhibitor. The [idea of a] triplet therapy is attractive although it could add logistical complexity. Could you use sip-T plus radium-223 plus pembrolizumab (Keytruda) or nivolumab (Opdivo)? This idea is theoretically attractive, but logistics need to be worked out. It probably would not be so easy to do; it would take some coordination.

Do you see this combination being utilized in other patient populations with prostate cancer?

Radium-223 is a bone-targeting alpha-particle, so this would not be for patients who do not have bone metastases; it would not be appropriate for the patients with nonmetastatic disease or rising PSA. Again, sip-T is also primarily approved for use in patients with metastatic CRPC.

One question is, “Could we give this combination in the nonmetastatic CRPC population to prevent bone metastases from occurring?” That would be a bit of a stretch because those patients do not have bone metastases, so radium-223 might not even [integrate] into the bone. You might be giving a drug, but that does not mean it would reach its intended target.

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. J Clin Oncol. 2020;38(suppl 6; abstr 130). doi: 10.1200/JCO.2020.38.6_suppl.130