Osteomimicry May Contribute to Uptake of Radium-223 Within Bone Metastases for Patients With mCRPC

Osteomimicry may contribute to the uptake of radium-223 within bone metastases and may subsequently enhance the therapeutic benefit of radium-223 for patients with metastatic castrate-resistant prostate cancer (mCRPC), according to an abstract presented by Andrew Armstrong, MD, associate professor of medicine, Duke University School of Medicine, at the 2018 Genitourinary Cancers Symposium.

“Circulating tumor cells [CTCs] are spreading into the bone and the bone microenvironment, they’re surviving, and they’re becoming genetic alterations that employ an osteoplastic program,” said Armstrong. “They’re able to stay alive in the microenvironment and behave much like osteoblasts.”

Radium-223 is calcium mimetic and an alpha-emitting bone targeting therapy, and past studies have yielded promising results for the treatment, said Armstrong. The ALSYMPCA trial among men with symptomatic bone metastatic castration-resistant prostate cancer demonstrated greater survival benefit over supportive care. Additionally, a greater benefit for radium-223 was observed in men with elevated serum alkaline phosphatase, a known prognostic biomarker in mCRPC.

Armstrong and his team conducted an investigator-initiated pharmacodynamics study of radium-233 delivered on-label to men with bone predominant mCRPC and disease progression to investigate genomic and phenotypic alterations in CTCs, circulating tumor DNA (ctDNA), and metastases.

Prior to radium and 3 and 6 months after radium treatment, liquid and metastatic biopsies were collected, including CTCs for phenotypic characterization and CTC/ctDNA genomic analysis. The primary objective of the study was to determine the changes and prevalence of CTC bone alkaline phosphate (BAP) over time. The authors measured radium-223 decay products in tumor and surrounding normal bone during treatment.

The study included 20 men with heavily pre-treated symptomatic bone predominant mCRPC. Each participant was treated with 55 kBq/kg of radium-223 over a median of 6 doses every 4 weeks.

“The patients we enrolled in the study were representative of the typical patients in the United States treated today with radium,” said Armstrong. “The majority of men had high volume of bone metastases, were all castrate resistant, had good performance status, but high-grade tumors.”

Results showed that the majority (18) of the participants had a decline in total bone specific alkaline phosphatase. The BAP decline (52%) was more prominent than the decline in total alkaline phosphate (25%). Nine of the 16 participants with evaluable CTCs had CTC expression at baseline; of the 9, 4 had elevated serum BAP levels. After 6 months, 7 of the 16 had detectable CTC expression.

“This may indicate that decline in serum BAP is bone derived, while tumor CTC BAP persists over time,” said Armstrong.

Based on the study, the researchers found genomic and phenotypic evidence of osteomimicry in CTCs and CTC cultures from men with mCRPC, along with persistent CTCs and genomic alterations associated with aggressive disease. According to Armstrong, they have established CTC cultures and CTC derived in vivo models of mCRPC for future characterization.

Looking forward, Armstrong indicated that functional studies of osteomimicry alterations are needed to understand the implications for progressive bone metastases and radium-223 uptake in men with mCRPC. In addition, radium-223 uptake in prostate cancer bone metastases has direct implications for possible combination therapy.