SREs, Risk Stratification, and Agents in Development

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Daniel J. George, MD, remarks that 2 things matter to patients with mCRPC: survival (how long they are going to live) and quality of life. For patients with substantial tumor burden due to bone metastases, skeletal-related events (SREs) have a negative impact on quality of life. SREs may involve spinal cord compression, pathologic fracture, and substantial bone pain; also, treatment with external beam radiation may be required. Thus, it is important to prevent skeletal-related events whenever possible.

Zoledronic acid is indicated for the treatment of patients with documented bone metastases from solid tumors, in conjunction with standard antineoplastic therapy. Denosumab is a RANK ligand (RANKL) inhibitor indicated for the prevention of SREs in patients with bone metastases from solid tumors. Radium-223 is indicated for the treatment of patients with mCRPC, symptomatic bone metastases, and no known visceral metastatic disease. The combination of zoledronic acid and radium-223 was studied in the Alpharadin in Symptomatic Prostate Cancer Patients (ALSYMPCA) trial; however, the combination of denosumab and radium-223 was not studied, as denosumab was not widely available in Europe at the time of the trial.

The results of the ALSYMPCA trial showed that zoledronic acid in combination with radium-223 was well tolerated, and there was a trend toward better clinical outcome in patients who received both agents. George remarks that in his practice, 40 patients have been treated with radium-223. The majority of these patients have been treated with denosumab previously or concurrently. There have been no significant bony complications in patients who received the combination of denosumab and radium-223.

Oncotype DX is a new technology for risk stratification that can help clinicians better understand a patient's risk profile in terms of pathologic stage and risk of progression. Oncotype DX assesses the genes that are expressed in a tumor and tests for a set of genes that have been shown to correlate with increased risk of having an upgrade in Gleason score. This information is critical, as a change in Gleason score from a Gleason 6 to a Gleason 7, for example, changes a clinician's comfort level with active surveillance. For patients with a Gleason score of 7, the results of large randomized studies have shown a survival advantage with radical prostatectomy versus deferred therapy.

Several emerging therapies are currently being evaluated for the treatment of prostate cancer, including cabozantinib, a multi-targeted tyrosine kinase inhibitor that blocks both VEGF and c-MET. The results of phase 1 and phase 2 trials have shown that cabozantinib has broad activity in several solid tumors. In prostate cancer, cabozantinib has demonstrated effects on pain and on bone scan changes. Also, a number of immunotherapies are being investigated, including Prostvac and ipilimumab, a CTLA-4-blocking antibody.