Metastasis is responsible for most cancer deaths, but the organs to which specific types of cancers migrate differ. Prostate cancers tend to metastasize to bone tissue, causing bone-related complications. The symptoms of bone metastases can be very painful and disruptive. Fortunately, some patients can benefit from therapies developed specifically to treat these complications.
Cancer that has nested in the bone can be symptomatic or asymptomatic. Patients may experience pain, nerve compression, spinal cord compression, and bone fractures. The U.S. Food and Drug Administration (FDA) has defined these symptoms as “skeletal related events” or SREs, and has designated the occurrence of SREs as a measurable clinical trial endpoint, enabling researchers to systematically evaluate SRE treatments. In addition to the symptoms listed above, SREs include radiotherapy and surgery of the bone.
Researchers have developed several treatments to target SREs that arise from prostate cancer. Zoledronic acid, a type of bisphosphate therapy that inhibits the resorption of bone tissue, is FDA-approved to reduce SREs. Denosumab, a monoclonal antibody that targets a protein on certain bone cells, is also approved for preventing SREs in patients with bone metastases that arise from solid tumors, including prostate cancer. Strontium-89 (an injectable radionucleotide) is used as a palliative therapy to control pain from bone metastasis and to reduce the need for other bone treatments.
Agents that mitigate SREs are considered to be supportive care, as they do not treat the underlying cancer. They are best used alongside prostate cancer therapies that can improve survival.
In fact, the first and foremost way to prevent SREs, which is often overlooked, is controlling the underlying prostate cancer, according to Matthew R. Smith, MD, a professor of medicine who specializes in prostate cancer treatment at Harvard Medical School. He studies skeletal complications that arise in patients with metastatic prostate cancer at the Massachusetts General Hospital Cancer Center in Boston.
One therapy that prevents SREs by treating the underlying prostate cancer is radium-223 (Xofigo), an α-emitting radiopharmaceutical. Radium-223 was approved by the FDA in May for men with metastatic castration-resistant prostate cancer (mCRPC) that has spread to the bone. The therapy hones in on the bone, binding to certain bone cells and delivering radiation to kill tumor cells. The therapy was well-tolerated by patients in clinical trials and was shown to improve survival by 3.6 months compared to the best standard of care.
“This is important,” Smith says. “No other radiopharmaceutical or bone-specific therapy is known to increase survival.” Radium-223 also specifically delayed SREs that cause pain and other symptoms for patients. While some SREs are symptomatic, others, such as certain fractures detected only by imaging, do not necessarily cause symptoms. “The improvement in symptomatic skeletal events, in my view, is additional evidence that radium-223 provides clinical benefit,” Smith says.
Another agent, called cabozantinib, “has had a spectacular result” in a phase II randomized trial of advanced prostate cancer patients, says Smith, who took part in the study. The phase III COMET-1 is currently testing the oral targeted agent in men with CRPC who have already been treated with the FDA-approved androgen-receptor pathway agents abiraterone acetate and enzalutamide.
Cabozantinib inhibits the MET tyrosine kinase as well as vascular endothelial growth factor receptor 2 (VEGFR2). Seventy-two percent of the 171 men in the phase II trial had tumor shrinkage in areas excluding the bone and 68% had improvements in bone metastases. The striking improvements in patients’ bone scans haven’t been seen before, Smith says. Patients also had relief from the pain associated with these metastases—67% showed improvement in pain.
“The bone metastases improvement was unexpected, but it is explainable,” Smith says. VEGFR is involved in bone remodeling, prostate tumor growth, and tumor-bone interaction.
The FDA-approved, SRE-preventing drug denosumab was shown to significantly delay the development of bone metastases in a large, international phase III trial. But the difference in bone metastasis-free survival when compared to placebo (a 15% reduction in risk) was not enough for the drug to be approved by the FDA as a treatment for prostate cancer. Still, the result shows that targeting the bone microenvironment can delay and prevent prostate cancer colonization of the bone, says Smith who was involved in the trial.
The SREs that occur in parallel with bone metastases shouldn’t be confused with the bone issues that can arise in early-stage prostate cancer, before the cancer has had a chance to spread, Smith says. Men with early-stage disease are often treated with androgen deprivation therapy, which has the unintended affect of boosting the rate of bone loss and increasing risk of fractures. “There is a continuum of bone complications, but the interventions at each stage are different.”