Robert B. Den, MD, discusses bone-targeting agents in prostate cancer and the potential future of combinations.
Robert B. Den, MD
About 90% of patients with prostate cancer who develop metastases will develop growths in the bone, says Robert B. Den, MD. These bone metastases can severely impact a patient’s quality of life, so finding the right bone-targeting agents is imperative, he adds.
Commonly used bone-targeted agents for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) include zoledronic acid (Zometa), denosumab (Xgeva), and radium-223 dichloride (Xofigo).
During a presentation at the 2018 OncLive® State of the Science Summit™ on Prostate Cancer, Den, an associate professor of radiation oncology at Thomas Jefferson University Hospital, discussed bone-targeting agents in prostate cancer. In an interview during the meeting, Den explained where the landscape currently stands with bone-targeting agents, and the potential future of combinations and novel strategies.Den: Prostate cancer is a unique malignancy in that it tends to have a preponderance of metastases to the bone. Bone metastases can impact a patient’s quality of life by causing severe bone pain, so this is an area where we have begun thinking about targeting the bone microenvironment specifically, in a sort of tumor agnostic way.
The focus of my talk was to look at 3 bone-targeting agents: zoledronic acid, denosumab, and radium-223. Most of the agents that target prostate cancer directly have been shown to improve survival, and also have benefit in terms of decreasing the rate of skeletal-related events. However, the 3 agents that I mentioned are designed to target the makeup of the bone.
Bone is generally made up of 2 components, calcium and phosphatase. Zoledronic acid works through the phosphatase side, radium-223 works through the calcium side, and denosumab works by decreasing a specific ligand called RANKL and decreases the osteoclastic activity of the bone.
The bone is on a constant “balance beam” that is both building and destroying bone all the time in every person. This balance is based on the production of bone by the osteoblasts and the reduction of bone by the osteoclasts, and denosumab decreases the osteoclastic activity. In contrast, radium-223 works as a calcium mimetic , so it works in place of calcium. It is incorporated naturally by the body into the bone, to cause uptake of the radium-223 specifically into the bone.
We know that this specifically targets the areas where there is increased bone formation, and prostate cancer tends to be a “blastic” disease, meaning that it is an area where the cancer cells cause the increase in bone formation. Thus, radium-223 gets targeted specifically to areas of increased prostate cancer. In the phase III randomized ALSYMPCA trial, we saw an overall survival (OS) benefit with the use of radium-223. This was quite remarkable because it was the first radiopharmaceutical to show an improvement in OS in men with prostate cancer.
The take-home message of my talk was that these agents are specifically designed for patients who have mCRPC. While denosumab and zoledronic acid have not shown improvements in survival, they have shown improvements in palliation of patients. Radium-223 has shown both OS and palliative effects for patients. These are good components for the armamentarium in the management of men with mCRPC. There have been studies looking at the addition of zoledronic acid to docetaxel in men with mCRPC. Those studies failed to show a benefit of adding zoledronic acid. I don't really view the agents as competitive; I view them as being supplementary. In general, we use zoledronic acid and denosumab for overall bone health and to prevent osteoporosis, and then we use radium-223 in men with mCRPC for its survival benefit. Yes. Generally, we will start with one of the bisphosphonates like zoledronic acid, add on denosumab, and then if the patient progresses to castration-resistant disease, that is when we would utilize radium-223. Of course, all of these agents have potential adverse events, so we sometimes decrease the dose or stop agents and add agents on as needed. You want to take a holistic approach to a patient with prostate cancer, think about the plethora of agents that can be used, and how to best sequence or put them into combinations to maximize quality of life and OS. I would say that the combination of radium-223 and other agents, whether it is an androgen receptor (AR)-targeted agent or a chemotherapy agent, is really in its nascent state. There are a number of phase III trials that we are waiting to report. While the expanded access program showed a benefit of the combination of radium-223 with denosumab or with abiraterone acetate (Zytiga) or enzalutamide (Xtandi), there is a phase III trial that has only reported out initial results showing a detriment in survival and an increased risk of fractures using the combination of abiraterone and radium-223.
The phase III trial with enzalutamide has not reported out yet, so we have to wait and see whether this is a general finding for AR-targeted agents combined with radium-223, or whether it was specific to that clinical trial. I can say that people who have used it in combination in practice prior to this trial being reported have not reported the findings of increased fracture risk or decreased survival in their patients.
However, a phase III trial is the gold standard by which we judge combinations of treatments or a novel treatment. It is worth taking a pause and considering the importance of combination therapy. It is peculiar because from looking at the toxicity profile of both agents, we would not have suspected or predicted to see combined toxicities or worsened outcomes. However, until the trial is accrued and completed, one never really knows the results. This, perhaps, shows the true power of a phase III clinical trial. There are more bone-targeting agents that are currently under investigation. Over and above the bone-targeting agents, people have seen the power of using an alpha emitter like radium-223 and are now asking, “Can these alpha emitters actually be linked to other targets?”
An example that has generated a lot of buzz recently has been using actinium-225 to kill cells expressing prostate-specific membrane antigen (PSMA) to target the cancers not only in the bone, but also in the soft tissue and visceral organs, which a bone-targeting agent will avoid. The initial results that have been published by German investigators have shown some remarkable responses. However, like radium-223, denosumab, and zoledronic acid, the PSMA-labeled alpha particles need to go through vigorous clinical testing to show their overall benefit.The field of prostate cancer has gone through an explosion within the last 5 to 10 years with the FDA approvals of multiple agents. These agents have shown activity in late-stage disease, and subsequent trials have begun to show activity in earlier-stage disease. This brings a lot of hope and excitement for our patients, as we can use these agents that are active earlier in the disease state and actually increase survival to a greater extent.
This has also led more and more people to be actively involved in prostate cancer research. Our group has looked at the use of DNA-damaging agents, such as PARP inhibitors and DNA-PK inhibitors, and phase II trials have shown that by selecting patients with particular mutations, you can actually get great responses. This is a whole new area of prostate cancer research, which, over the next 5 years, will be seen manifested in clinical benefit for patients.