Charles Ryan, MD, discusses the evolution of zoledronic acid and denosumab, and the future role of radium-223 as it begins to be studied in combination regimens in prostate cancer.
Charles J. Ryan, MD
Prostate cancer researchers are continuing to explore strategies to optimally integrate bone-targeted agents into patient care.
For example, an ongoing trial is assessing the combination of a radiopharmaceutical, radium-223 dichloride (Xofigo), with an androgen receptor-directed therapy, either abiraterone acetate (Zytiga) or enzalutamide (Xtandi). The open-label, phase IIa study is accruing patients with metastatic castration-resistant prostate cancer (mCRPC). The primary endpoint of the trial, which hopes to enroll 68 patients, is patient bone scan response rate (NCT02034552).
Another trial expected to launch within the next year is investigating the combination of abiraterone plus radium-223 in patients with hormone-sensitive metastatic prostate cancer.
“That’s really the goal for practicing physicians as we talk through prostate cancer today, which is that we have this long menu of various therapies but we are trying to find the right treatment for the right patient at the right time,” explained Charles Ryan, MD.
Ryan, professor of medicine and urology, Thomas Perkins Distinguished Professor in Cancer Research, Helen Diller Family Comprehensive Cancer Center, and chair of the 2017 OncLive® State of the Science SummitTM on Genitourinary Cancers, lectured on the impact of bone-targeting agents in patients with mCRPC. In an interview during the event, he shed light on the evolution of zoledronic acid and denosumab (Xgeva), and the future role of radium-223 as it begins to be studied in combination regimens.Ryan: Bone-targeting agents are critically important, and that’s because 90% of men who die from prostate cancer die with boney metastases, and often they die because of the complications of boney metastases. While we continue our research and clinical development of new therapies that target the tumor directly, it’s also critically important to think about the bones and how we can protect them from tumor invasion, and, in fact, reduce the likelihood of the disease killing patients.
Therefore, I think of bone-targeting agents in 2 arenas. One are the bisphosphonates and the RANK-ligand targeted therapies. These have been in clinical use in prostate cancer for many years. They have a definitive role in conjunction with antitumor therapy; they prevent skeletal-related events or complications in the bone from tumor invasion. The 2 most widely utilized ones are zoledronic acid and denosumab. I highlighted those a little bit in terms of where they are in our clinical use. There are some questions still on when to optimally use them, when to not use them, how long to use them, and what to do about preventing the complications, the most serious of which is osteonecrosis of the jaw.
Then, I transitioned to the development of radioisotopes, in particular radium-223. I spoke about samarium, which is more of historical interest than anything else. Samarium was developed as a palliative treatment for people with boney metastases. It did demonstrate reductions in opiate use and improvements in pain control, but it never demonstrated a survival benefit. Therefore, the development of radium-223 over the last few years has represented a major step forward in that it is a bone-targeted agent that also has antitumor properties and a survival benefit.
It is approved in multiple countries; it has widespread use in prostate cancer. I reviewed the science of the use of radium-223, the studies moving forward in which it will be combined with abiraterone in various contexts, and I talked about the potential complications of it, when to use it, as I emphasized the [the need to find the] right therapy for the right patient at the right time.With regard to the bisphosphates or RANK-ligand targeted therapies, I typically initiate them, hopefully, before the patient is at significant risk for boney complications—but is at risk for a boney complication. In other words, I don’t give it to prevent bone metastases; I give it only in patients who have bone metastases. I like to give it before I see things like pain developing or alkaline phosphatase rising, because I know those are adverse prognostic factors. In many ways, what we are trying to do is prevent complications.
The other thing that’s important is that in a patient who has progressive disease, where I’m going to be thinking about integrating an anticancer therapy, such as abiraterone, enzalutamide, or docetaxel, I may initiate the bone-targeted therapy at the same time I initiate the antitumor therapy. In the setting of abiraterone and enzalutamide therapy, what can happen is many patients will have a good response to those therapies; the prostate-specific antigens (PSAs) may go down by 90%, and, in that setting, I don’t view the risk of boney complications to be quite as high. That is a situation in which I may be treating them monthly, for example, with denosumab, and then I may pull back on that therapy when their disease is under control.
What I don’t want to do is have a patient who is doing great, has a PSA that is down, and their tumor is under control, and then they develop osteonecrosis of the jaw because I have used too much denosumab when it really wasn’t indicated. There is an issue of when you start, when you leverage the greatest benefit from it, and whether you should pull back. Both studies with those 2 agents used it for 2 years maximum, so we don’t have a lot of data about what to do after that time frame. I actually think that we may have maximized our knowledge about those 2 therapies because they have a great role. We’re still deciding, or figuring out, when to use them optimally, but we also have a sense that they have limitations. I don’t think we will ever repeat a study where we look for a survival benefit from 1 of those therapies. Interestingly, we saw that zoledronic acid in the setting of hormone-sensitive metastatic disease did not delay progression; that was a study we did in the United States.
Denosumab, for example, was also given to patients with nonmetastatic CRPC and did not have a significant impact on metastasis-free survival, so we are not using it in that context. Therefore, we are not using these therapies to prevent metastases, and we have adequately answered that. Ongoing research is a bit of an open question at this time. There are a couple of studies that are underway. There is one in CRPC where radium-223 is being combined with abiraterone and testing it against abiraterone alone. That is underway and I don’t know where that is in terms of its accrual.
The second study that will launch within the next year is the combination of abiraterone plus radium-223 in patients with hormone-sensitive metastatic disease. This is, of course, building on the recent developments from the LATITUDE and STAMPEDE studies, both of which have demonstrated a significant improvement in survival for patients receiving abiraterone in conjunction with hormonal therapy. We are hoping to take that to the next level and that, by adding a survival-enhancing, bone-targeted therapy in patients with newly diagnosed, high-volume, metastatic boney disease, that we might be able to delay progression and improve survival even further. The key takeaway from my talk is that bone-targeted therapy should be something we consider in every patient with CRPC, and we can consider both the bisphosphonates, RANK-ligand targeted therapies, and radium-223. They can be given together. But, more to the point is that these need to be considerations in all patients, because they can help prevent complications, preserve quality of life, and prolong life.
My hope is that, from today’s meeting, attendees took away the fact that prostate cancer, kidney cancer, and bladder cancer, which were also covered, are changing very rapidly, as is all of oncology. There are particularly nuanced views that need to be taken to the integration of some of the new therapies. Our team at UCSF is on top of that, because we have a wonderful group of physicians and researchers at our center who provide great care and are also available regionally for physicians throughout Northern California. I certainly hope there is a local benefit and that physicians from around the area learn, get a chance to interact, and can also see that we are bringing experience—and in some cases, our involvement—in the development of new therapies down to the patient level.