ASCO GU 2018: Genomic and Phenotypic Evidence for Prostate Cancer Osteomimicry in Circulating Tumor Cells from Men with Metastatic Castration Resistant Prostate Cancer Treated with Radium-223

San Francisco, CA ( Radium-223 is a commonly used treatment in men with metastatic prostate cancer who have bone lesions.  It is a calcium-mimetic that is taken up by bone and emits alpha particles to target cancer cells.  Data has shown that Radium-223 confers a survival benefit over supportive care in men with symptomatic bone lesions.  Men with an elevated serum alkaline phosphatase often receive a greater benefit from this treatment as compared to men with a normal serum alkaline phosphatase. 

Dr. Andrew Armstrong from the Duke Prostate and Urologic Cancer Center presented translational data from his work on the role of prostate cancer osteomimicry and how it relates to clinical outcomes in men treated with Radium-223 for metastatic prostate cancer.  His group has demonstrated that men with metastatic castrate-resistant prostate cancer (mCRPC) have circulating tumor cells that commonly express bone alkaline phosphatase and exhibit phenotypic plasticity, and they hypothesize that prostate cancer osteomimicry may contribute to the intralesional deposition of radium-223 and irradiation of the tumor micro-environment. 

Dr. Armstrong and colleagues conducted a study in which 20 men with mCRPC with multi-focal symptomatic bone lesions who were undergoing monthly radium-223 dosing. Patients underwent bone biopsy as well as a “liquid biopsy” to evaluate circulating tumor cells (CTC) and circulating tumor DNA (CTDNA).  The primary endpoint of the study was to evaluate the changes in CTC alkaline phosphatase as the patients underwent radium-223 therapy. Secondary endpoints were to evaluate radium-223 decay and bio distribution, CTC genomic changes over time, progression free survival, overall survival, and bone alkaline phosphatase and PSA changes over time. Greater than 50% of the men enrolled in the trial had been previously exposed to docetaxel, enzalutamide, or abiraterone.  The median progression free survival for this cohort was 5.5 months, with a 13.3 month median overall survival. 90% of the men enrolled in the study had a decline in total bone-specific alkaline phosphatase (BAP) while undergoing radium-223 treatment.  BAP declined more prominently than total alkaline phosphatase. 56% of the patients enrolled in the trial had CTC expression of BAP prior to undergoing treatment.  This decreased to 43% after 6 months of treatment. The group believes that this may indicate that the decline in serum BAP is bone-derived while tumor CTC persists over time. They found that there are several copy number alterations in key osteomimicry genes in CTCs that could potentially become targets for the development of future therapies. 

Based on his data, Dr. Armstrong concludes that osteomimicry may contribute to enhanced radium-223 uptake in osteoblastic bone metastases. Future areas of inquiry include functional studies of osteomimicry genetic alterations in order to develop therapeutic strategies that target the altered pathways in hopes of improving response to treatment.

Presented by: Andrew Armstrong, MD, Duke Prostate and Urologic Cancer Center

Written by: Brian Kadow, MD, Fox Chase Cancer Center, Philadelphia, PA at the 2018 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium, February 8-10, 2018 - San Francisco, CA