How does prostate cancer spreadthroughout the body? Does it alwaysspread in the same way?Why doesit spread so readily to bone?
Dr. Sartor: Prostate cancer does have relatively predictable patterns of progression. We know that in the advanced stages, about 90% of patients will have bone involvement and a little over 40% will have lymph node involvement. As high as 20% of men have liver involvement in the later stages.
The exact reason for that pattern of spread is not well understood, but there does seem to be a special interaction between prostate cancer cells and bone.
There is some intriguing data that seems to indicate that prostate cancer cells bind to and grow in the same niche that bone marrow stem cells occupy. For some reason, that particular niche is very supportive of prostate cancer growth. That is the leading hypothesis for why prostate cancer patients end up with a preferential growth in bone.
The cells circulate widely. There is an old but good theory that talks about a seed-and-soil hypothesis. The seed is the cancer cell and the soil is where the cancer cells land and grow. The seed- and-soil hypothesis says you need a fertile seed and fertile soil. Unless you have both, it won’t work. The soil of the bone marrow turns out to be particularly fertile for prostate cancer growth. We’re still debating exactly why.
Isbonejustfertilesoilordosomeprostatecancer treatments like hormonal therapymake it more fertile?
Dr. Sartor: There has been a bit of speculation over that. In truth, to me the data is quit speculative regarding treatment induced soilchanges.
Even if you don’t treat the cancer at all, there is still a propensity for bony spread. Does treatment promote that pattern of spread? Overall, I would say that is speculative.
What is a radiopharmaceutical?
Dr. Sartor: Radiopharmaceuticals are simply pharmaceuticals that are radioactive. There is a long history of using radioactivity in cancer treatment that goes back well over a century. Initial treatments were implantable radiation. Today, we call this brachytherapy or see therapy: we actually put radioactive seeds into the tumor. We still do this today with localized prostate cancer.
There is a different class of radioactivity we’ve termed radiopharmaceuticals. We inject or ingest the radiopharmaceutical drug; the activity of the drug is dependent in part on its radioactivity. The concept of bone-targeted therapy with radiopharmaceuticals goes back to the 1950s.
Early data demonstrated that you could have bone pain relief with phosphorus-32. Phosphorus-32 is taken up into the bone. You could then radiate the areas where the phosphorus accumulates, which turns out to be osteoblastic lesions of the bone. Those studies go back to the 1950s.
Fast-forward to the 1990s: an agent called Metastron (strontium-89) was FDA-approved. It was based on the same principal. Strontium is a calcium mimetic, or imitator. Metastron (strontium-89) goes to areas of rapid bone turnover, acting as a calcium mimetic, and then radiates the surrounding area.
The next agent to emerge was Quadramet (samarium-153-EDTMP), another bone radiopharmaceutical approved for the palliation of bone pain. It worked in the same way as Metastron (strontium-89) but the bone-binding agent is EDTMP.
Xofigo (radium-223) is also a calcium mimetic. The calcium mimetic binds the radiopharmaceutical to this bony area of turnover. (In these osteoblastic metastases—or bone metastases—you have higher areas of bone turnover.)
Xofigo (radium-223) is different from the prior therapies. It is an alpha particle, which may not mean very much to most people.
The preceding radiopharmaceuticals phosphorus-32, Metastron (strontium-89), and Quadramet (samarium-153-EDTMP) are all beta emitters.
A beta particle is really like an electron. An alpha particle has two protons and two neutrons. It’s a huge particle relative to the beta and carries much more energy.
These huge particles can do a couple things. Number 1: they’re more destructive. Number 2: they actually don’t go very far into bone, which is surprising. An alpha particle is like a big Mack truck hitting a bunch of debris. You may not be able to hit very far with your Mac truck, but you are going to cause a lot of destruction to what you actually do hit.
A beta particle is more like a speeding bullet. It will go further, but it won’t do as much damage. After some early studies indicating that Xofigo (radium-223) would have a positive effect on bone, they launched a large, over 700-patient comparative Phase III study. It was an interesting trial design, because men could get any type of treatment they wanted except for chemotherapy or experimental treatments (plus or minus radium-223).
Everybody was getting some form of hormone during the trial. This was in an older era, so they weren’t getting Xtandi (enzalutamide) or Zytiga (abiraterone). They were getting agents like Nizoral (ketoconazole), Diethylstilbestrol (DES), (Ozurdex) dexamethasone, prednisone, Nilandron (nilutamide), etc.
The question was: could Xofigo (radium-223) add to the standard of care treatment? The randomization was standard of care treatments plus Xofigo (radium-223). Lo and behold, that did turn out to be a positive study. Xofigo (radium-223) was shown to prolong survival and to reduce the risk of death by about 30%. It was FDA-approved and now Xofigo (radium-223) is in our broad armamentarium. We consider Xofigo (radium-223) for people with bone metastatic prostate cancer. If you don’t have bone metastases, then it is not considered.
What should patients expect when they take Xofigo (radium-223)?
Dr. Sartor: There was a lot of initial fear about giving an alpha particle. This is the first alpha particle ever approved for the treatment of human beings and the first alpha particle radiopharmaceutical.
There was a bit of trepidation and concern over what might happen. But what actually happened was not much. It was kind of interesting. Xofigo (radium-223) is excreted in the bowel, so there is a little excess diarrhea. There is a little excess fatigue. About 3% of patients (over the placebo group) have vomiting. But 3% percent with vomiting and a little bit of diarrhea was not too much. If you compare that to chemotherapy, the side effects are much less. There was a little bit of thrombocytopenia, which is the fancy word for low platelets. That is serious in some; I think it was about 7% of patients. About 1 or 2% of patients might have some white cell suppression.
Overall, Xofigo (radium-223) was extremely well tolerated. Most patients were surprised. They thought they would have some sort of ill effect, but it just didn’t happen.
Why does Xofigo (radium-223) have a survival benefit? Can it just better target bone mets? Or is there something else going on?
Dr. Sartor: That is the obvious answer. There is more speculation. The obvious part is you’re taking people with bone metastatic disease and you kick the cancer where it hurts.
Bone is where the cancer is residing and where the disease burden is located. If you manage to alter that disease burden in a meaningful way, then it is not a surprise to me that you would end up with better survival. That is what we thought. On a more speculative front, there is a hypothesis that if you decrease the burden in the bone, perhaps you decrease the burden elsewhere.
But that is a hypothesis, not a fact.
What kind of combinations with Xofigo (radium-223) do you think look the most promising?
Dr. Sartor: From the very beginning, Xofigo (radium-223) was co-administered with other agents. I mentioned the Phase III trial called ALSYMPCA. ALSYMPCA utilized that standard-of-care I talked about earlier. The older hormones people used [Nizoral (ketoconazole), Diethylstilbestrol (DES), (Ozurdex) dexamethasone, prednisone, Nilandron (nilutamide)], have been largely replaced by newer hormonal therapies like Zytiga (abiraterone) and Xtandi (enzalutamide).
We’ve now shown combinations with those newer hormonal therapies are safe. There have not been a lot of formal trials, but we have an expanded access program in which people co-administered Xofigo (radium-223) along with the newer hormonal therapies. It didn’t seem to have any adverse events.
There is the possibility, which will require proper trials to determine, that it may be a good idea to combine these agents with Xofigo (radium-223). It wouldn’t surprise me if that turned out to be the case. If you go back to some of the initial radiation studies on treating the prostate, they found unequivocally that adding hormonal therapy to radiation led to better survival.
This is conceptually similar in that you’re using a new hormone and a new form of radiation.
There are a couple of hypotheses that seem to have more credibility than others. One of these is that a combination of Zytiga (abiraterone) and Xtandi (enzalutamide) plus Xofigo (radium-223) is better than Zytiga (abiraterone) or Xtandi (enzalutamide) alone. That is being evaluated in a Phase III trial that has fully accrued, so we’ll have some answers on that. That is one set of combinations that look promising. Another area that is a bit provocative, but for which we don’t yet have a proper study to ascertain if it’s true or not, is the combination of Xofigo (radium-223) and Xgeva (denosumab). There does appear to be some data indicating that patients on both Xofigo (radium-223) and Xgeva (denosumab) do a little bit better than those on Xofigo (radium-223) alone. That is speculative at this time. It’s not a properly controlled study. That is a hypothesis, not a fact.
Another approach that has some rationale is the combination of radiopharmaceuticals and immunotherapy. That combination may yield improvements in therapy.
It would be very speculative to say that combination improves survival, because those studies are not yet in place. This is being explored in a trial combining Provenge (sipuleucel-T) with Xofigo (radium-223). The study is too small to give a plus or minus on the favorable clinical outcome and is designed to look at some of the immunologic effects. Dr. Emmanuel S. Antonarakis and colleagues at the Johns Hopkins University head the trial. Tulane University is also working on the project.