Over the past three years, diverse new therapies have been approved to treat advanced prostate cancer, including agents that have shown some promise in delaying its progression to the bone.
Andrew Armstrong, MD, ScM
Over the past three years, diverse new therapies have been approved to treat advanced prostate cancer, including agents that have shown some promise in delaying its progression to the bone. At the same time, new research is focused on the disease’s spread through the mechanism of bone-mimicking metastases, among other areas, with the goal of identifying additional pathways that may prove targetable.
"Over 95% of men who die of prostate cancer have bone metastases, and there is a strong tie of prostate cancer lethality to bone metastases," said Andrew Armstrong, MD, ScM, an associate professor of Medicine and Surgery at the Duke Cancer Institute in Durham, North Carolina, and a member of the NCCN guidelines panel for prostate cancer. Armstrong studies how prostate cancer cells metastasize, and is developing blood tests and treatments to reduce or prevent the ability of prostate cancer cells to spread.
One of the processes under study includes a concept calledepithelial plasticity, which describes the ability of cancer cells to convert to other types of cells with different functions. This plasticity may allow prostate cancer cells to become bone-forming cells and spread to the bone, a concept known asosteomimicry(bone mimicry). This adaptive process allows prostate cancer cells to invade the bone space, survive and grow there, and resist therapies. Many drugs currently in development are targeting this process.
Current therapies, including the most recently approved agents, are focused on maintaining bone health and delaying the spread of cancer, while new approaches toward protecting bone in nonmetastatic cancer are being evaluated in clinical trials.
While undergoing treatment, patients with prostate cancer can minimize bone loss, including osteoporosis and fractures, by increasing exercise and exposure to sunlight, screening for and treating vitamin D deficiency, and keeping tabs on reversible causes such as alcohol consumption and thyroid disease.
Antiresorptive agents, including bisphosphonates and the RANK ligand antagonist denosumab, help prevent bone loss in men undergoing hormonal therapy and improve bone mineral density in men with osteoporosis or osteopenia.
“Screening for loss of bone density is thus reasonable as we now have agents that are able to minimize the risk of complications such as fracture,” said Armstrong. “We can also reduce the impact to the bone by minimizing exposure to hormonal therapies by using androgen deprivation therapy selectively and intermittently, particularly in men without metastatic disease.”
The FDA approved denosumab in 2010 to prevent skeletal-related events (fracture, need for surgery or radiation to bone, spinal cord compression) in patients with castration-resistant bone metastases, and in 2011 as a treatment to increase bone mass in early-stage patients at risk of fractures from hormone therapy. Although denosumab was shown in a randomized study to modestly delay the onset of bone metastases, it did not improve survival and the delay in onset of bone metastases was not sufficiently robust to lead to FDA approval for that indication.
Current NCCN guidelines indicate that the preferred use of denosumab and zoledronic acid is in men who have progressive disease despite low levels of testosterone, and who are thus at higher risk for bone complications. The benefit of these therapies in men with hormone-sensitive metastatic disease has not been established, noted Armstrong.
Newer agents, including the hormonal therapies abiraterone and enzalutamide, are able to delay further spread of cancer, including progression in the bone, but do not prevent it entirely. To date, these new therapies are approved only for men with castration-resistant metastatic disease. Phase III trials of abiraterone, enzalutamide, TAK-700, and ARN-509 are ongoing or planned in earlier stages of prostate cancer, which could lead to their use prior to the onset of bone metastases if proven successful at delaying death and metastatic progression.
“But again, these trials are focused on delaying the spread of disease and reducing risk, rather than preventing it entirely,” Armstrong said. “Trials in the adjuvant setting after surgery or radiation are planned to address whether these novel systemic hormonal agents may improve cure rates in men with high-risk localized disease, and thus prevent bone metastases."
Drug sequencing is another area of active research, as there have been few studies to date that evaluate these new agents in the context of other therapies.
“We don't know, for example, how docetaxel works after any of [the new therapies], or whether giving abiraterone or enzalutamide first is preferred. These trials, driven ideally by predictive biomarkers and risk stratification, should help guide treatment selection,” he said, adding, "There are some hints that Provenge may be beneficial earlier in the process, as well as some thought that enzalutamide and abiraterone may be active early, before chemotherapy. The PREVAIL trial (NCT01212991) is looking at enzalutamide pre-chemotherapy.
“Radiation given after chemotherapy has active properties in the bone. Radium-223, an alpha emitter, also improves new bone formation and should be evaluated in earlier disease settings,” Armstrong said.
Agents in the pipeline focused on delaying metastases include an ongoing phase III trial evaluating the combination of OGX-011 (custirsen) with docetaxel. OGX-011 has demonstrated “a dramatic response in the bone,” Armstrong said. Three other therapies targeting the immune systemthe immunotherapy vaccine PROSTVAC and ipilimumab, and the immune modulatory oral agent tasquinimod—are also in phase III trials. Drug combinations, including abiraterone and enzalutamide, are also being studied.
"I study circulating tumor cells (CTCs), which look almost like bone cells, in order to identify targets in the cell. There are many oncogenic pathways we are not currently targeting. I'm also looking at biomarkers in CTCs in patients with progressive metastases and developing assays to better detect them, based on their ability to change into bone forming cells, home to the bone marrow, and spread,” he said. “If we can identify the seeds of metastases and the drivers of these seeds, then we can develop better systemic agents to address this major public health problem.”
The hope, researchers and clinicians say, is for the discovery of new therapies that will turn prostate cancer into a chronic, manageable disease. In the meantime, however, they stress the importance of effective clinical practice in its prompt identification and treatment.