Understanding the Rationale for Bone-Targeted Therapy in mCRPC

Conor Lynch, PhD

As practitioners gain deeper insight on bone metastases in patients with metastatic castration-resistant prostate cancer (mCRPC), evidence seems to suggest that bone-targeted therapy not only benefits patients from a palliative perspective, but from a survival aspect, as well.

Most recently, this has been evident in studies examining the radiopharmaceutical radium-223 dichloride (Xofigo) in patients with mCRPC. The ALSYMPCA trial, which was the basis for the 2013 FDA approval of radium-223, showed a median overall survival (OS) of 14 months with radium-223 versus 11.2 months with placebo (HR, 0.70; P = .00185) in patients. Now, the agent is being explored in combination with numerous other therapies to see if its efficacy can be strengthened.

“There are several new drugs and discoveries coming down the pipeline that actually focus more on the microenvironment than on the cancer cells themselves,” explains Conor Lynch, PhD. “The dual approach of targeting the microenvironment, such as immunotherapies, focusing on stromal cells in the bone microenvironment, and that other arm of androgen-deprivation therapies (ADT)—or improved chemotherapies—will end up caging those metastases in the bone microenvironment.”

Lynch discussed bone-targeted therapies for patients with prostate cancer in his lecture at the 2016 OncLive State of the Science Summit on Genitourinary Cancers.

OncLive: Can you discuss the biology of bone metastases? What is the reason for having such a deep understanding of them?

In an interview with OncLive during the meeting, Lynch, an associate professor of Tumor Biology at Moffitt Cancer Center, sheds light on the biology of bone metastases as well as the mechanism of action for bone-directed therapies.Lynch: When prostate cancer metastasizes, it typically metastasizes to the bone. Approximately 90% of the men who succumb to the disease will have evidence of metastasis in their skeleton. What we are trying to understand at Moffitt Cancer Center, and in my lab in particular, is first how the actual cancer cells metastasize to the bone. What is it about the bone that actually attracts them?

Secondly, once the cancer cells are there, how do they interact with the bone environment in order to establish and grow? It is that aspect—that communication between the prostate cancer cells and the bone environment—where we think that there’s a lot of molecular targets that could actually be druggable and treatable.

For example, we know that when these cancer cells are in the bone microenvironment, they promote extensive bone destruction—known as osteolysis or bone degradation. At the same time, they also cause extensive bone formation, which are osteosclerotic types of lesions. That is a hallmark of these metastases—they cause extensive bone formation. The lesions often occur in areas of the patients who are weight-bearing, so they can be extremely painful and greatly affect their quality of life.

Anecdotally, how have you seen these bone metastases impact patients and their quality of life?

Because they are harbored in the bone, they then become even more difficult to treat because they can be systemic. They can be in different parts of the skeleton, and some of them are more difficult to reach than others. What we are really trying to do is understand the biology of how these cancers are able to speak to the bone cells, so that we can come up with drugs that can stop that interaction and stop them from growing and metastasizing throughout the skeleton.If a patient has a lesion in the hip or at the base of the spine, there can be a pathological fracture. Even though these are forming extensive bone formation, one would think it would be strong bone—but it’s actually cancerous bone. Therefore, it is not very well organized and it can often crack or fracture. With the spine, for example, one could have a compression fracture.

What is bone-directed therapy, and how does it work?

You can imagine these lesions then impacting the patient’s quality of life and greatly contributing to the morbidity that’s associated with the disease. It can be particularly painful as well for the patient, because there is a lot of bone destruction going on. There are a lot of nerves being aggravated by these cancer cells, as well. That pain can, as I said, greatly decrease the quality of life of the patient and contribute to the morbidity associated with the disease.A lot of therapy at the moment focuses on the cancer cells themselves for a lot of patients, and physicians are using hormone-based therapies, antiandrogen or ADT. We would propose that if these are used in combination [with bone-targeted therapy], if we target the microenvironment or the bone cells that are surrounding the cancers, there could be a greater effect.

Compounds called bisphosphonates are used in the clinic now. These have a bisphosphonic moiety, which allows them to stick to calcium. Of course, bone has lots of calcium in it. These bisphosphonates actually choke the cells that are responsible for bone degradation, called osteoclasts. These are giant, multinucleated cells that are stimulated to fuse by the cancer cells.

By using these bisphosphonates, you can actually get them to stick to areas that are undergoing bone turnover. As the osteoclast is degrading the bone, it essentially can choke on these bisphosphonates and stop that lytic part or the destructive part of the disease.

Now, bisphosphonates on their own do not extend OS for patients—but they greatly improve that kind of quality of care. They prevent, for example, time to pathological fracture. There are other therapies that also target the osteoclast formation part of it.

Prostate cancer metastases in the bone are bone forming—that’s a hallmark of their disease—but they clearly have extensive areas of bone destruction, as well. There are [targeted therapies] such as denosumab, which is a monoclonal antibody directed against a cytokine called RANK ligand (RANK-L). We know that RANK-L is extremely important for the fusion and maturation of these osteoclasts. Therefore, by using this monoclonal antibody, we essentially stop these osteoclasts from forming and destroy the bone.

One of the most exciting things that has happened in the last couple years is radium-223. This is a calcium-binding radioactive molecule as well as an alpha-emitter, so it has a very short range of emission. It can be given to the patient and it sticks to areas that are undergoing bone turnover.

It seems that these therapies are not just being administered as palliative or supportive care; they are targeting cancer cells, correct?

Because the cancer cells and bone marrow stromal cells are interacting with each other, cancer cells die because of this radioactive molecule sticking to the area of bone that is undergoing destruction. Since it also has such a short half-life, it’s fairly safe in terms of giving it to the patient. It has actually been very beneficial for the treatment of patients.In the case of radium-223, it not only targets stromal cells, but also the cancer cells that are feeding off of that stromal response. One of the important things that the cancer gets from this bone turnover process is a lot of growth factors and cytokines. Bone is not just a static tissue; it is also rich in different types of growth factors and cytokines.

When they are released by the osteoclast, it can feed back on the tumor cell and promote their survival and growth. One would argue that things such as bisphosphonates and denosumab could actually prevent the tumor cells from growing. Even though they don’t extend the OS of patients, they are robbing them of some of the growth factors and cytokines that can come from the bone and feed those cancer cells, as well.