ASCO recently endorsed the Cancer Care Ontario (CCO) guideline “Bone Health and Bone-Targeted Therapies for Prostate Cancer,” which was originally approved by CCO in 2017.1 The recommendations were based on a systematic review and meta-analysis of relevant research and clinical trial reports identified in a literature search from inception to January 2016.
“ASCO’s endorsement of this guideline is intended to be a practical, clinically oriented support for clinicians who provide care to men with prostate cancer,” said Guideline Co-Chair Philip J. Saylor, MD, of Harvard Medical School and Massachusetts General Hospital. “The clinical settings that these recommendations address span the entire spectrum of men receiving treatment for prostate cancer.”
Philip J. Saylor, MD
Jeff M. Michalski, MD, MBA, FASTRO
“Recommendations from CCO, as reviewed and now endorsed by ASCO, show that there are very reasonable measures available to practitioners who manage patients with prostate cancer to minimize the risks of injury to a patient’s skeleton from the long-term use of androgen-deprivation therapy,” added Guideline Co-Chair Jeff M. Michalski, MD, MBA, FASTRO, of Washington University School of Medicine, St. Louis.
Reducing the Risk of Fracture
Guideline recommendations outline a range of measures aimed at maintaining and improving bone health in men with prostate cancer and address preventing osteoporotic fractures, reducing the risk of bone metastasis, and managing bone pain in men with metastatic disease.
The first measure suggests the use of denosumab in men with nonmetastatic prostate cancer at high risk of osteoporotic/fragility fracture while receiving androgen-deprivation therapy. In cases where denosumab is contraindicated or unavailable, bisphosphonates are a reasonable alternative.
“Denosumab is essentially the gold standard, because it has been demonstrated in a prospective phase III study to reduce the actual fracture risk,” Dr. Saylor said. “Bisphosphonates are known to improve bone mineral density, which is likely a very good surrogate endpoint for fracture risk.”
However, Dr. Michalski noted that clinicians should not count on bone-targeted drugs to prevent the spread of cancer. “Although they do a good job of strengthening bone, these drugs do not prevent metastases,” he noted. “You can avoid the costs and risks associated with these drugs, unless [patients] have findings of osteopenia or osteoporosis.”
In their discussion points, ASCO expert panel members emphasized that none of the bone-targeted drugs have been approved for the prevention of first bone metastasis in any clinical setting related to prostate cancer.
As additional preventive measures, the guideline encourages baseline bone mineral density testing using conventional dual x-ray absorptiometry as a way of identifying men who are likely to benefit from pharmacotherapy, as well as the use of risk prediction tools, such as the Fracture Risk Assessment Tool (FRAX).
“It is the standard of care to discuss the impact of androgen-deprivation therapy on a patient’s bone health and to assess them for risk of fracture by doing a bone mineral density assessment at baseline,” Dr. Michalski said.
Skeletal-Related Events and Bone Pain
In men with metastatic castration-resistant prostate cancer, the guideline recommends either zoledronic acid or denosumab for preventing or delaying skeletal-related events, such as pathologic fractures and spinal cord compression. However, the ASCO expert panel noted that the optimal safe duration of high-intensity monthly therapy with denosumab or zoledronic acid has not been well established, because this regimen has been studied in clinical trials for a maximum of 2 years.
“In practice, we often have men with bone metastases who live substantially longer than that, but we just do not know very much about the safety of monthly therapy for those durations,” Dr. Saylor said. In clinical trials of zoledronic acid or denosumab, calcium and vitamin D supplementation has been prescribed or strongly recommended to support bone health.
In men with predominantly bony metastases and no evidence of large nodal or visceral metastases, the guideline suggests the use of radium-223 to reduce symptomatic skeletal-related events and improve patients’ overall quality of life. “Patients who have bone pain related to metastases benefit from the use of external-beam radiation therapy, which is a very simple, safe, and cost-effective treatment,” Dr. Michalski said.
Radium-223 Therapy and Overall Survival
The final guideline recommendation suggests radium-223 therapy in men with symptomatic metastatic castration-resistant prostate cancer with predominantly bony metastases as a suitable measure for extending overall survival. “Radium-223 is a very good drug to treat metastatic bone disease, and it has been shown to improve patient survival and reduce the risk of skeletal-related morbidity,” Dr. Michalski said. “It is a safe and effective drug delivered monthly over six cycles.”
In relation to this recommendation, the ASCO expert panel noted that the combination of abiraterone and prednisone with radium-223 should be avoided because it led to an increased risk of fractures in a recent clinical trial.2 Dr. Saylor noted that it is important to highlight these findings, which were not available at the time of the CCO guideline publication.
Dr. Saylor concluded that the guideline encourages clinicians to discuss with their patients the impact of long-term androgen-deprivation therapy on bone health and the importance of early assessment and early intervention with bone-strengthening agents in patients identified to be at risk of adverse outcomes.
DISCLOSURE: For full disclosures of the study authors, visit jco.ascopubs.org.
1. Saylor PJ, Rumble RB, Tagawa S, et al: Bone health and bone-targeted therapies for prostate cancer: ASCO endorsement of a Cancer Care Ontario Guideline. J Clin Oncol. January 28, 2020 (early release online).
2. Smith M, Parker C, Saad F, et al: Addition of radium-223 to abiraterone acetate and prednisone or prednisolone in patients with castration-resistant prostate cancer and bone metastases (ERA 223): A randomised, double-blind, placebo-controlled, phase III trial. Lancet Oncol 20:408-419, 2019.
Originally published in ASCO Daily News. © American Society of Clinical Oncology. ASCO Daily News, January 28, 2020. All rights reserved.