Radium-223 May Enhance Immune Response With Sipuleucel-T in mCRPC

Jong Chul Park, MD

Metastatic castration-resistant prostate cancer (mCRPC) is a challenging disease with limited treatment options to improve survival outcomes for patients, says Jong Chul Park, MD, an oncologist at John Hopkins Medicine.

“Despite the approval of multiple agents, mCRPC still remains a lethal disease,” says Park. “New combinations—with new compounds and mechanisms of action—are warranted, without a doubt.”

Park is investigating one novel combination that could eventually translate to a survival benefit for patients with mCRPC. He is leading a randomized phase II study comparing sipuleucel-T (Provenge) monotherapy versus sipuleucel-T plus radium-223 (Xofigo) in patients with CRPC who have bone metastases but no visceral involvement.

Patients will be randomly assigned to receive 6 infusions of radium-223 plus 3 infusions of sipuleucel-T starting after the second radium-223 dose or 3 infusions of sipuleucel-T alone.¹

The primary objective of the study is to determine whether the addition of radium-223 to sipuleucel-T enhances immune response, which will be measured by peripheral PA2024-specific T-cell proliferation using a tritiated thymidine incorporation assay 6 weeks after the first sipuleucel-T infusion. Immune response is a surrogate for survival, says Park.

“The hypothesis of this study is that by combining these 2 FDA-approved agents— radium-223 and sipuleucel-T—we can enhance the immune response and that may actually transfer into improved clinical outcomes. We may see some objective responses if we induce a strong enough immune response.”

OncLive: What is the motivation behind studying these 2 agents together?

In an interview with OncLive, Park explains the potential synergy of radium-223 and sipuleucel-T, as well as the clinical trial’s design and the study’s current progress.Park: Sipuleucel-T was approved by the FDA based on the survival benefit shown in the IMPACT study. However, sipuleucel-T has not been significantly utilized in real-world clinics. One of the issues with sipuleucel-T is that it has no impact on PSA. In general, cancer vaccines have failed to demonstrate great antitumor effects. We are interested in improving the efficacy of vaccines.

Radiation has been shown to have various immunomodulatory effects, such as enhanced display of tumor-associated antigens, expression of molecules like MHC-class I, and potentially may have a favorable impact on microenvironments.

There is a lot of preclinical evidence regarding the immunomodulatory effects of external-beam radiation and there are currently multiple clinical trials ongoing to test this hypothesis. Such trials are combining external-beam radiation therapy with various immunotherapy regimens.

However, the issue with external-beam radiation is that it only targets 1 or a few areas, and it can also cause bone marrow suppression, which can potentially decrease the immune response.

In patients with prostate cancers, the majority of whom have multiple bone lesions, it seems to make more sense to use radiopharmaceuticals instead of external-beam radiation.

Are there any potential challenges to this combination?

How is the trial designed?

There is data that suggest that radiopharmaceuticals also have a similar immunomodulatory impact as external-beam radiation. By using alpha particle-emitting radioisotope, radium-223 can also minimize the risk of bone marrow suppression.Safety will be the biggest concern of this combination. However, both radium-223 and sipuleucel-T have fairly favorable safety profiles. Thus far, we have 1 patient who was assigned to the combination arm and is doing well without any significant safety issues. We are quite comfortable with this combination, in terms of safety.Patients are randomized to either sipuleucel-T alone or sipuleucel-T with radium-223. In the combination arm, sipuleucel-T is given after the second dose of radium-223.

The endpoint is interesting. We are looking at immune response as the primary endpoint. More specifically, we are looking at antigen-specific T-cell proliferation. That is based on the immune perimeter analysis, which shows that antigen-specific T-cell proliferation correlates with survival. After the first infusion of the sipuleucel-T, we will obtain blood samples and do an analysis of T-cell proliferation. This is a surrogate for survival.

We also have secondary endpoints including immunologic endpoints, as well as the clinical endpoints of efficacy and safety.

Has this combination been previously investigated?

What is the timeline for this trial?

We are excluding patients who received radiation therapy recently; however, if patients have a remote history of radium-223 that is allowed. Patients who were previously treated with chemotherapy are not allowed; we are also excluding patients who have underlining immune deficiency or require high doses of immunosuppressant, for obvious reasons.As far as I know, this is the first time radium-223 and sipuleucel-T have been investigated together.We wanted to run some trial tests for the first few patients, rather than enrolling a lot of patients. This is because this trial requires patients to frequently visit the doctor and have their blood drawn. There are some logistics involved that can be challenging for patients. We have to collaborate with radiation oncology for radium-223 infusions, so there is a lot of coordination to make the timeline correct.

Where do you see immunotherapy fitting into the treatment paradigm of mCRPC?

We want to make sure that there are no glitches in the process. Now that we have a few patients in each arm, we will try to speed up our enrollment. The goal is to finish enrollment in the next 12 months and then, hopefully, we will have the immune analysis within a few months following accrual.Immunotherapy in prostate cancer has not really been successful so far; however, the sipuleucel-T approval suggests that there may be another role for immunotherapy in this area. We would like to improve the potential of immunotherapy in this specific population by combining it with radium-223.

1. Park J, Sartor AO, Sullivan R, et al. Randomized phase-2 study of sipuleucel-T with or without radium-223 in men with asymptomatic/minimally symptomatic bone-metastatic castrate-resistant prostate cancer (CRPC). J Clin Oncol. 33, 2015 (suppl; abstr TPS5076).