Expert Discusses Bone-Targeted Agents and Other Developments in mCRPC

Przemyslaw W. Twardowski, MD

Key ongoing focal points in the treatment of advanced metastatic castration-resistant prostate cancer (mCRPC) include discovering an optimal sequence for patients, identifying biomarkers, and determining the value of bone-targeted agents, according to Przemyslaw W. Twardowski, MD.

“We should probably follow in the footsteps of other tumor types, such as breast cancer and lung cancer, where you have specific biomarkers that guide us,” said Twardowski. “That should be the goal in prostate cancer. There are some leads in that area.”

Twardowski, director, Genitourinary Program, clinical professor in the Department of Medical Oncology and Therapeutics Research, and a medical oncologist at City of Hope, discussed the treatment of patients with advanced mCRPC during the 2016 OncLive State of the Science Summit on GU Cancer.

OncLive: What is the current standard of care for patients with advanced mCRPC?

In an interview with OncLive, he describes the available therapies for patients with advanced mCRPC, including bone-targeted therapies; the work that still lies ahead with these treatments; and the challenges with finding biomarkers to help develop targeted agents.Twardowski: We have several drugs available for treatment in various categories ranging from immunotherapy, to very potent second-generation hormone agents that suppress testosterone signaling, to chemotherapeutic agents, and also to 1 radioactive isotope treatment. Those are the main categories, and they’re examples of various drugs within groups.

How do you know what the optimal sequence of agents is for a patient?

The treatment, in general, involves sequencing of these agents, starting from immunotherapy through second-generation hormone agents, and then moving to chemotherapy and to radioactive isotopes. Then, there is the whole gambit of clinical trials, of course, that are looking at new drug development in this disease.That is a great question, and there is really no good answer yet in prostate cancer. In other tumor types, there is some advantage because there are specific biomarkers that guide therapy. In a specific biomarker, expression predicts response to one drug and the other biomarker to the other drug. In prostate cancer, there is nothing like that.

What promising research in prostate cancer are you excited about?

I would have to admit that we are relatively primitive in the sequencing decisions. It’s very much based on clinical criteria, on experience. As I mentioned earlier, I typically like to start with immunotherapy first because it tends to lay the foundation for future treatments. Activation of the immune system may help with other therapies down the line. It ranges from less toxic to more toxic regimens as you proceed with sequencing of these agents. Really, there is very little hard evidence in terms of specific sequencing.[A biomarker] that is promising has to do with the specific variance of androgen receptor (AR) expressed in prostate cancer, which may predict responsiveness to various types of agents. That is very promising. Perhaps other subgroups or mutations in AR can also guide us in the future.

There are also some specific genomic alterations that are being found in prostate cancer that have indications for drug development. The 1 specific example that is probably the most promising has to do with the DNA repair genes. The mutations in those genes can predict the responsiveness to a group of agents called PARP inhibitors, and that’s the area of very intense investigation.

What is new in the realm of bone-targeted therapies in prostate cancer?

That is where we are going, of course, and probably in the next few years some of these leads will pay off. It would be a little bit more scientific in our selection of agents and sequencing.My lecture had a specific emphasis on the fact that prostate cancer tends to metastasize to bones—more preferentially as compared to any other organs. It just tends to go to the bone. The metastases to the bone in prostrate cancer results in significant morbidity and mortality, complications, and leads to a major impact on quality of life for patients, and longevity.

Therefore, focusing on drugs that somehow interfere with metastasis to the bones or slow down the growth of them is of particular interest in prostate cancer. There are 3 FDA-approved agents in this setting: zoledronic acid (Zometa), denosumab (Xgeva), and radium-223 dichloride (Xofigo). The first 2 have not shown necessarily prolongation of life, but they have shown a positive favorable impact on bone-related complications, such as fractures, need for surgery, pain, and spinal cord compression.

Radium-223 is uniquely approved only in advanced prostate cancer. It is a radioactive isotope that is injected intravenously and, because it has the structure that is similar to calcium, it tends to migrate to the bones, specifically where there is a high turnover of the bone where the tumor and metastases are located. It delivers a short range of high-density alpha-emitting radiation to those areas. It delivers radiation from within the bone, and that has been associated with survival improvement.

What’s different from radium-223 when you compare it with the other 2 drugs?

However, it only works for bone metastases. It doesn’t have any effect on cancer metastases in other places. However, because of what I mentioned about how prominent bone metastases are in prostate cancer, it’s very valuable.The major difference, the way I think about it, is that the drug has clearly some impact on cancer biology, which results in an improvement in survival. The other agents do not; they don’t prolong life, but they do improve some aspects of quality of life. That is the major difference in the way I think about these drugs. Zoledronic acid and denosumab are not really used alone. They are used in the context of other targeted agents.

Looking ahead, what more do you see happening with bone-targeted agents?

On the other hand, radium-223 can be used as a more specific therapy on its own for advanced prostate cancer with its survival benefit. There are all kinds of other differences in terms of mechanism of action, mode of administration, and adverse events.It’s still a significant problem. I don’t think we are quite sure; frankly, there are some good leads, but we’re not quite sure, even at the basic level, why prostate cancer has such a proclivity for bone metastases. That would be very important to still elucidate the mechanisms of that process, because that would lead to some other potential leads in terms of treatment.

I would have to argue that with all of the progress and usefulness of these compounds, they really have relatively modest effect on outcomes in advanced prostate cancer. We need more potent, better drugs. As always, patient selection is really very important.

Another level we probably also need to know is how much these agents are contributing now in the era of other newer therapies. They were developed in the period of time when some of these newer treatments for prostate cancer were not available. Those new treatments have their own positive impact on bone metastases. How are these agents truly adding to the newer agents? I don’t think we already know. That would be an important area to find out.