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.
, 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.
OncLive: What is the current standard of care for patients with advanced mCRPC?
: 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.
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.
How do you know what the optimal sequence of agents is for a patient?
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.
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.
What promising research in prostate cancer are you excited about?
[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.
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.
What is new in the realm of bone-targeted therapies in prostate cancer?
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.
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