Radium-223 May Reduce Immune Activity in Prostate Cancer Bone Metastases

A new prospective clinical study suggests that radium-223 may change the immune environment of prostate cancer bone metastases in a way that makes subsequent immunotherapy less effective.

The study included 28 men with metastatic castration-resistant prostate cancer (mCRPC) and predominantly bone metastases. Patients received radium-223, with six injections planned at four-week intervals. Researchers wanted to determine whether radiation from radium-223 could make bone metastases more immunogenic and potentially more sensitive to PD-1/PD-L1 checkpoint inhibitors.

Instead, they found the opposite. Using a special PET scan with 89Zr-labelled atezolizumab to visualise PD-L1 throughout the body, researchers found that median PD-L1-related uptake in PSMA-positive bone metastases fell from an SUVmean of 2.5 before treatment to 0.9 after three cycles of radium-223, a reduction of around 64%.

The immune environment also appeared to become less active. Lymphocyte levels decreased both in the blood and within tumour tissue, while PD-L1 expression in bone biopsies was already low before treatment and declined further during radium-223 therapy.

These findings challenge the idea that radium-223 could prepare prostate cancer bone metastases for checkpoint immunotherapy. Laboratory and animal studies had suggested that radiation might make tumours more visible to the immune system, potentially improving the effect of drugs targeting PD-1 or PD-L1. This human study found no evidence of that effect.

The results do not mean that radium-223 makes prostate cancer more aggressive or that lowering PD-L1 is necessarily harmful. Radium-223 is designed to kill cancer cells in bone, and part of the reduced PD-L1 signal could simply reflect the destruction of cells expressing the protein. However, the study found no indication that treatment created the immune activation researchers had hoped for.

The study was small. Although 28 patients were enrolled, only nine had paired PD-L1 PET scans suitable for the main longitudinal analysis, and paired bone biopsies were available from only two patients. The findings therefore cannot establish whether immunotherapy should or should not be given before, during or after radium-223.

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