Dr. Alan Partin talks about non-genomic biomarkers for prostate cancer.
Prostatepedia spoke with Dr. Oliver Sartor about how and why prostate cancer spreads to bone, how Xofigo (radium-223) works, and promising Xofigo (radium-223) combinations. Read our April 2017 issue on Bone + Prostate Cancer.
How does prostate cancer spread throughout the body? Does it always spread in the same way? Why does it 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.
Is bone just fertile soil or do some prostate cancer treatments like hormonal therapy make 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 soil changes.
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.
Dr. Raoul Concepcion talks about how drugs like Xtandi (enzalutamide) and Zytiga (abiraterone) work for prostate cancer.
Dr. Emmanuel Antonarakis is an Associate Professor of Oncology and Urology at the Johns Hopkins University Sidney Kimmel Comprehensive Cancer Center.
Prostatepedia spoke with him recently about his clinical trial combining Provenge (sipuleucel-T) with Xofigo (radium-223).
What is the thinking behind your clinical trial?
Dr. Emmanuel Antonarakis: There is a lot of interest in combining immune therapies with other drugs to make immunotherapy work better.
The FDA approved Provenge (sipuleucel-T) in 2010. We’ve been using that drug for the last seven years. We’ve seen that patient survival improves by approximately three to four months on Provenge (sipuleucel-T) compared to a placebo.
However, we don’t typically see PSA levels dropping, tumors shrinking, or symptoms improving. While we recognize that Provenge (sipuleucel-T) is an immunotherapy that does have some activity in prostate cancer, the effects are fairly marginal.
We, and others, have been trying to increase its effectiveness by combining it with other medications. In this particular trial, we’re combining Provenge (sipuleucel-T) with a radiopharmaceutical drug called Xofigo (radium-223).
Why? We think radiation therapy can boost immunotherapy for several reasons.
One reason is that in patients who receive external beam radiotherapy, or conventional radiotherapy, healing tumor cells can release proteins called antigens from inside the cancer. Those antigens released into the circulation by radiotherapy can stimulate the immune cells that recognize and fight prostate cancer.
The second reason is that there is some preliminary evidence that these liquid radiotherapies—or radiopharmaceutical drugs that are injected into the veins, bind to the bone and then give off radiation particles at the bone—might also increase the number of antigens.
An antigen is a substance foreign to the body that elicits an immune response. These antigens are released as part of the cancer cell into the circulation and are then recognized by a stimulated immune system.
The hypothesis is that if you combine Xofigo (radium-223) with Provenge (sipuleucel-T), you would see higher immune responses against the tumor than if you used Provenge (sipuleucel-T) by itself.
What should patients expect?
Dr. Antonarakis: We’re selecting hormone-resistant prostate cancer patients with one or more bone metastases. In other words, their cancer has progressed after standard hormone therapy, but they don’t have any bone pain. Bone metastases have to be present, you have to have hormone-resistant disease, but you can’t have bone pain.
Patients will be randomized to one of two groups. Group 1 will receive Provenge (sipuleucel-T) by itself, according to the FDA dose schedule of three doses two weeks apart.
Group 2 will receive a combination of Xofigo (radium-223) plus Provenge (sipuleucel-T). The Xofigo (radium-223) will be given first according to the FDA dose schedule of intravenous injection every four weeks for six doses.
After the second out of six doses of Xofigo (radium-223), they will then receive the Provenge (sipuleucel-T).
After Provenge (sipuleucel-T), they will receive the third through sixth doses of Xofigo (radium-223). In other words, we give Provenge (sipuleucel-T) in between the second and third Xofigo (radium-223) doses.
Why in the middle?
Dr. Antonarakis: We are guessing when the immune system will be most stimulated by the Xofigo (radium-223). We hypothesize—and this is only a guess—that it will take at least two doses of Xofigo (radium-223) to release enough tumor antigens into the circulation to simulate the antitumor immune cells. We wanted to continue to give at least four additional doses of Xofigo (radium-223) after the immune system has been stimulated to see if we can maintain a prolonged immune stimulation period.
In a perfect world, we would have multiple different sequences, but that would require a much larger trial with at least four different study arms. We thought that was too complicated.
You said you were looking for patients with one or two bone metastases. Are you excluding those with more?
Dr. Antonarakis: Patients have to have a minimum of one bone metastasis, but there is no maximum. If a patient has a hundred bone metastases, he is eligible.
Patients cannot have liver or lung metastases larger than one centimeter in diameter.
Xofigo (radium-223) does not get into the liver or the lung. It only targets the bone. And we have never seen liver or lung metastases shrink with Provenge (sipuleucel-T) by itself. We wanted to exclude patients who wouldn’t benefit from Xofigo (radium-223), so we decided to exclude liver or lung metastases more than one centimeter.
We also exclude patients with lymph node metastases more than three centimeters. We allow small liver or lung metastases less than one centimeter and modest lymph node metastases less than three centimeters.
Is the trial being conducted only in Baltimore, Maryland?
Dr. Antonarakis: The trial is being conducted at four sites across the United States: John Hopkins University in Baltimore, Maryland is the lead site. The other sites are Tulane University in Louisiana; Duke University in North Carolina; and Cedars-Sinai Cancer Center in Los Angeles, California.
For more information, contact Dr. Emmanuel Antonarakis by emailing firstname.lastname@example.org or calling 410-955-8964.
Dr. Leonard Gomella talks about what types of imaging techniques for bone metastases men with prostate cancer are likely to encounter.
Dr. Raoul Concepcion is the Director of The Comprehensive Prostate Center in Nashville, Tennessee and the past President of the Large Urology Group Practice Association (LUGPA.)
Prostatepedia spoke with him about approaches to bone metastases within urology groups.
How does a urologist know when a man has developed metastases?
Dr. Raoul Concepcion: Fortunately, the majority of prostate cancer diagnosed today tends to be low-risk and associated with lower Gleason grades. For those men, active surveillance may be an appropriate treatment option. The challenge now is not to just identify prostate cancer, but to identify significant prostate cancer: those at risk for dying of their disease if left untreated. If you have Gleason -3 + 3, what we are now calling Group Pattern 1, or Gleason 3 + 4 (Group Pattern 2), the recommendation is not to do a staging work up. The likelihood of finding metastatic disease is very low. But if you do pick up a higher-grade clone on biopsy in a Gleason 4 or 5 prostate cancer, that man should definitely undergo a staging workup—usually a CT scan and bone scan—to look for metastatic disease.
Bony metastases can be detected in a couple different phases of prostate cancer. Sometimes, bone metastases are found at initial diagnosis during staging work-up. This usually happens with higher-grade tumors. The second phase is when men progress past definitive therapy and adjuvant treatment to we now call metastatic castration resistant prostate cancer (mCRPC). After diagnosis, both low-grade and high-grade patients decide on prostate cancer management.
Lower-grade patients can choose active surveillance, radiation therapy, radical prostatectomy, or even focal therapies like cryotherapy.
Options for higher-grade patients could include multi-modality therapy of surgery, radiation therapy, and hormones. These patients are really the people at risk.
After an individual has been treated definitively for prostate cancer, we measure his PSA after therapy. If his PSA starts to go up again, he is said to have a biochemeical recurrence.
For the most part, these patients do not have symptoms. They’re not in pain. They don’t have significant fatigue. Again, these are patients who have been definitively treated and are currently not on therapy.
Once his PSA starts to go up, we start to look at the rapidity with which it goes up. We call this PSA kinetics, or doubling time. If there is a rapid doubling time in a man who had a higher grade Gleason Pattern at diagnosis, we know he has a higher risk of developing metastatic disease. We usually go ahead and get a scan when his PSA goes above 10. If that scan is still negative in a high-grade patient with a rapid doubling time, most urologists initiate androgen deprivation therapy.
Androgen deprivation therapy, or hormonal therapy, tries to drive down testosterone levels into castration range. If his PSA then starts to go up again, he now has, by definition, mCRPC. Again, these are patients with prostate cancer that has been definitively treated.
They have then gone on androgen deprivation therapy until their testosterone levels got to less than 50, and then their PSAs started to go up again.
What is the trigger for the urologist to start looking again for bone metastases?
That has never been really well defined. I participated in a consortium of academic and community urologists, medical oncologists, and radiation oncologists called the RADAR (Radiographic Assessments for the Diagnosis of Advanced Recurrence) working group chaired by Dr. E. David Crawford to answer just that question.
We recommended that in such patients we should go ahead and look for metastases with a bone scan, a CT scan, or some of the new advanced imaging techniques when the PSA gets to 2.
Why would you hesitate to look for bony metastases earlier?
Dr. Concepcion: I think most urologists, unfortunately, extrapolate what they know about PSA in the early stages when patients aren’t on hormones to the castration resistant prostate cancer space.
If a patient had never been on hormones and his PSA is low, usually it means they don’t have a lot of disease. It’s become a real hurdle, an educational challenge, to get urologists to start thinking about that and not to wait until patients are symptomatic.
Do you think it would make sense for such a patient reading this to ask his urologist to scan him earlier?
Dr. Concepcion: Yes, I think that would be very appropriate. Unless you’re being treated by a urologist with a lot of expertise… A lot of general urologists aren’t going to know about the RADAR recommendations.
Are these scans usually done at the urologist’s office or does the urologist refer the patient to someone else?
Dr. Concepcion: It depends. Most urologists in community practices, especially in bigger groups, have their own CT scans. That part of the workup can be done in the urology office.
Technetium-based bone scans usually require a nuclear medicine department and are done in a hospital.
A lot of times, we’ll get a CT scan in our office and then coordinate with a freestanding imaging center or a hospital-based imaging center to get a nuclear medicine scan.
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Dr. Leonard Gomella talks about treating bone metastases in prostate cancer patients.