Phillip Koo: Hello. My name is Phillip Koo from UroToday.com and it's a pleasure to be with you here today to present the final lecture in the SNMMI lecture series on prostate cancer imaging and therapies. Today we have the distinct pleasure of having with us Dr. Hossein Jadvar who's Associate Professor of Radiology and Biomedical Engineering at the University of Southern California and also the past President of the Society of Nuclear Medicine and Molecular Imaging. He's a world's expert on prostate cancer with regards to nuclear medicine and he'll be speaking to us today about radium-223, so welcome Dr. Jadvar.

Hossein Jadvar: Thank you very much Phillip, for that very kind introduction and invitation to speak today on the topic of radium-223 dichloride use in treatment of patients with metastatic castrate-resistant prostate cancer. I thought that we start with a summary slide so that for those people who don't have much time, they get the summary of how radium-223 fits in the treatment of patients with metastatic prostate cancer. And so I show you this slide that basically summarizes the ALSYMPCA clinical trial that was published in 2013 and soon after the radium-223 was approved by the FDA for use in treatment of these patients.

Essentially, this was a randomized clinical trial that compared radium-223 dichloride plus best standard of care versus a placebo, in this case saline and best standard of care. There were nearly 1000 patients involved with a two to one randomization and what the primary outcome in this case was, was overall survival. And as you can see, radium-223 did prolong overall survival and in fact, it improved the overall survival by about four months, 3.6 months to be exact, associated with about 30% reduction in the risk of death in comparison to the placebo arm.

They also look at a number of other secondary outcomes including the time to first skeletal-related events and there was also benefit there. The median time to the first skeletal-related event was prolonged by almost six months. It also turned out that radium-223 was associated with only mild side effects which was quite manageable. In fact for the most part, the frequency of grade three and four adverse events were quite similar between the two arms of the study.

There are a number of clinical trials right now going on with radium-223 including re-treatment with radium and also how it can be combined with other approved treatments or novel treatments as well as what the sequence is would be best in treatment of these patients. It is also of note that soon after its approval, radium-223 was incorporated into the updated NCCN guidelines as you can see in here. So with that kind of summary slide to give you kind of an overall picture of how radium can be useful, I'm going to go into a little bit of more detail.

Starting with what alpha particles are, alpha particles are essentially helium nucleus with two protons and two neutrons and because of the two protons, they have a positive charge of two. They are quite energetic and they move quite fast, as you can see about 5% of the speed of light. There are major differences between alpha particles and beta particles. Beta particles are essentially similar to electrons and you know about them, for example, in other treatments that we have in nuclear medicine including I-131 for thyroid diseases or more recently, Lutetium-177 dotatate for treatment of neuroendocrine tumors.

Those are beta particles. Alpha particles are now coming into play with first one being radium and there are a number of studies going on with use of alpha particle in other diseases and use of different agents. But essentially, alpha particles have very, quite much shorter range in comparison to beta particles, as you can see by 100 times. They are quite energetic, almost 1000 times higher energy than beta particles and in that short range that they move, they can deposit a large amount of energy and therefore this can be associated with deposition of a large amount of energy in a very short distance, which can be beneficial in many cases for treatment of cancer.

This slide shows again, a difference between beta particles and alpha particles as they move through tissue. In the beta particle, again, because of their longer range and lower energy, if they happen to move through the nucleus and happen to meet at the DNA molecule, they may cause mostly single-stranded DNA breaks. Now we are physiologically able to treat, to repair that kind of damage and therefore the cell may survive in fact, if there is such an event. This is as opposed to alpha particles which are again, very short range and very energetic.

If they happen to go to the nucleus and happen to meet DNA, because of their very high energy, they may actually sever both strands of the DNA and physiologically, we are not very much equipped with repairing that kind of a damage if it happens in the cell. And therefore what usually happens if there is a double-strand DNA breaks because of alpha particle travel through it, the cell goes through a program, what we call program cell death or apoptosis and therefore will die and essentially commit suicide in a sense. And that's the basis for cell killing in use of alpha particles.

So with that very short introduction, let's talk about radium-223. On this side, on the right-hand side, you can see the decay scheme of radium-223. Radium-223 is an alkali metal agent or element in the table of elements. And basically it's a calcium mimetic as you can see in here and therefore by its nature, is bone-seeking. Wherever there is a laying down of bone or bony reaction, osteoblastic reaction, radium will be attracted to that target naturally.

As you can also see the half-life of radium is about 11.4 days and the emitted energy distribution as we already mentioned, is essentially alpha particle, almost 94% of what is decayed is alpha particles. Although there is a small amount of beta particles, as you can see almost about 4% and very little, about 1% of gamma radiation that in fact we can image with alpha particle ... with radium-223.

This slide shows how actually radium-223 hones to the areas of osteoblastic reaction which are typically happens in many cancers including prostate cancer kind of containing the marrow tumor. So as you can see here is a bone with marrow space here which is full of tumor cells and then the bone reacts to that tumor environment by activating the osteoblast and laying down bone. And again, because radium-223 is a calcium mimetic, you can see this dotted yellow lines ... yellow dots which are essentially representing radium. They are being attracted to exactly the same site where the calcium is being laid down.

And this other slide shows the cloud of the alpha particles. So basically, since they're being targeted or honed down to that area, this cloud of alpha particles, as you can see, is covering some of the tumor cells and that's where the tumors are affected by the alpha particles and will respond to it usually to cell death.

Now, there have been a good number of different agents that have been studied through clinical trials for their use in treatment of metastatic castrate-resistant prostate cancer which has a median overall survival of about 23 months.

And these are the trials that have been performed in either chemotherapy-naive patients or in patients who have already received chemotherapy. Now the most common agent or we can call it the granddaddy of the agents is docetaxel which was actually approved by the FDA in 2004. So this was a standard of care in patients with metastatic castrate-resistant prostate cancer and the overall survival benefit with docetaxel is 2.4 months.

Now after that, there have been other agents that have been developed and approved including cabazitaxel, which is another chemotherapy agent as well as there is enzalutamide which is an androgen receptor antagonist and also abiraterone, which is an androgen enzyme inhibitor. And you can see the dates that these have been approved by the FDA and the overall survival benefits that are associated with each of these agents. Now the one that we are going to talk about today is radium-223 dichloride and the trial that was associated with that was ALSYMPCA clinical trial.

And as I already mentioned in my summary slide, this was associated with overall survival of 3.6 months. As you can see in this column, actually all these numbers are essentially in the same range, so the range of overall survival benefit with these agents have been in the range of about three to five or six months. And since it turned out that radium-223 was really associated, they're simple to use and associated with very mild and manageable adverse events, that actually became quite successful in penetrating the market and actually being used in the clinic in treatment of patients with metastatic prostate cancer. However as we already mentioned, radium-223 only targets bone and does not target any other tissue or metastatic tissue that may be associated in these patients.

This is the pivotal paper that was published in July of 2013 in The New England Journal of Medicine by Parker and colleagues entitled, Alpha Emitter Radium-223 and Survival in Metastatic Prostate Cancer which basically paved the way for radium-223 to be eventually FDA approved and used in the clinic.

As far as the estimated equivalent dose of radium-223 with the approved dose of 50 kilobecquerel per kilogram, you can see it in this table. As expected of course, most of the radium is going to go to the bone surface, but there is also some amount of activity that will accumulate in the colon as you can see in here. Now in most places, radium-223 that are used in the clinic are individual doses that are delivered to the clinic for that particular patient and that dose is based on the patient's weight.

To get prepared to do this study, of course, the patient should have bone metastases and I'll go a little bit more into detail of how many bone metastases is needed as seen on a bone scan, a recent bone scan. Also, there need to be some labs which basically looks for the bone marrow reserve and you can see the list of them in here. The absolute neutrophil counts should be above a certain threshold. Also the platelet count should be above certain threshold and the patient should not be anemic with a hemoglobin over 10. The physician should be present at the time of the injection and if everything is within the range, then the patient can be injected with radium-223.

This is the summary or the study design for ALSYMPCA clinical trial. Again, this was a randomized clinical trial that basically compared radium-223 at the dose of 50 kilobecquerel per kilogram through six injections each at a four-week interval, almost a month between these six injections, each of these six injections.

And that was compared to placebo, again, in this case was saline plus best standard of care. The randomization was two to one, two to the radium arm or the active arm and one to the placebo arm. The total number of patients in this case was almost 1000, at 921. Now for the inclusion criteria, the patient should have had symptomatic bone pain and then as far as the number of bone metastases that would qualify a patient to be on that trial was only two, so if the bone scan showed greater than two ... two or greater than two bone metastases, the patient was able to enter this study.

Also, the patient should have not had visceral metastases. In other words, there should have not been any metastases to the liver or for example, the lung or brain or other tissues such as that. Lymph node metastases was allowed as long as the lymph node metastases had a short axis of less than 15 millimeter. Again, this was because as you know, radium-223 cannot target the soft tissues or lymph node metastases. It is only targeting the bone metastases. There was a number of certifications that were done including if the patients were used ... were on bisphosphonates for bone health agents. They also stratified based on alkaline phosphatase levels as you can see and whether the patients received docetaxel chemotherapy before or not. The primary outcome, in this case, was overall survival, but there are a number of other secondary outcomes that they looked at including their time to first skeletal-related events, time to alkaline phosphatase progression and time to PSA progression and these are the results.

These Kaplan-Meier curves, you can see here comparing the radium-223 to placebo. The green line is the radium and the red line is the placebo and as you can see very early on, these two curves kind of separate from each other and that continues on throughout the cuvre in this case. The median overall survival for radium-223 was 14.9 months versus placebo, which was 11.3 months. Again, this translated to an overall survival benefit of 3.6 months which was statistically significant as you can see in the P value.

Now with regard to stratification with use of docetaxel chemotherapy, these are the Kaplan-Meier curves and again, you see that whether the patient was on docetaxel before radium treatment or not, it didn't really matter. In both cases, the patients who were on the radium arm did benefit with regard to overall survival in both cases. However, the patients who did not have the docetaxel, they had a little bit higher benefit of 4.6 months versus patients who did have docetaxel and the benefit was there 3.1 months.

Now both of these were statistically significant of course and it's possible that because these patients who had docetaxel, they already failed chemotherapy and they were considered to be sicker in a sense, they did not have as much benefit as those patients who did not have or did not undergo docetaxel previously.

We also talked about the time to first skeletal-related events. Skeletal-related events is actually very important in this clinical scenario. If patients are not treated, these patients will develop skeletal-related events within six months after they develop bone metastases. These include spinal fractures, [inaudible 00:18:34] compressions and of course, they're associated with high morbidity and perhaps even mortality. So having some benefit in this case would be very important. And radium-223 definitely showed again, in this Kaplan-Meier curves that there was major benefit with regard to the time to the first skeletal-related events by about six months over placebo arm.

What about adverse events? This table basically summarizes the adverse events, either in all grades or the more severe grades of three and four. And as you can see, basically for all of these, either hematologic or non-hematologic adverse events, they were very, very similar to each other. The only one that was somewhat different was grade three or four thrombocytopenia, a little bit higher incidents of about 6.5% in the radium arm versus 2% in the placebo arm. But this was completely manageable and the patients did well after receiving platelet replacement.

Again, if you recall, I mentioned that some of the activity does go to colon and the thought was that maybe that was associated with constipation or diarrhea. But as you can see, this table, the incidents especially the ones that were relatively severe, grade three or four, were quite similar between the two arms. So the fact that some of the radium-223 goes to colon does not seem to be really associated with the observation of diarrhea and constipation in some of the patients who received radium-223.

So we go back to the same summary slide that I started at the very beginning. Again, very briefly, 30% reduction in risk of death with radium, about six months prolongation of the median time to first skeletal-related events and very mild and manageable adverse events.

Now at our center at the University of Southern California where soon after its radium approval, we started treating our patients with radium and one year after treatment of these patients, we published our experience in this case. At that time, we had 25 patients who were treated and basically what we observed is that only about a quarter of the patients were able to finish all the six dose regimens. And the reasons for the other 75% that could not finish all the prescribed dose regimen was because that their disease progressed in other tissues, in the soft tissues, which again by definition, is not being targeted by radium-223.

Now this was actually looked at by other groups and I draw your attention to this particular paper that was published in Clinical Genitourinary Cancer very recently in 2019. And basically across all these experiences around the world, it turned out that a greater extent of prior therapies, for example, if the patient was previously treated on chemotherapy or not, also if the patient had the worse ECOG physical status, the patients who had anemia or had higher baseline PSA levels, alkaline phosphatase levels or LDH levels. These were kind of the variables or parameters that tended to be associated with not being able to complete the entire six ... prescribed six-course regimen of injections with radium-223.

This other article was interesting in regard to observation of PSA flare, which was defined by this group as right after the first cycle of treatment with radium-223, followed by decline below the baseline PSA. And in these patients who were receiving radium-223, this PSA flare actually was observed in about 12% of the patients.

However, if the patient did have this PSA flare as defined by this group, they did tend to have a longer median progression-free survival and overall survival which was quite significant as you can see in here. These patients also had greater alkaline phosphatase decline and on imaging with sodium fluoride PET scan, they also did have evidence for a reduction of their tumor burden. So if PSA flare is observed, that tends to be associated with a better response or a favorable response to radium-223 although the authors suggested that this is based on their definition of PSA flare and that can be looked at by other investigators.

With regard to adverse events, this was again, a very recent paper as you can see, that was published in 2019 in the European Journal of Nuclear Medicine and Molecular Imaging, look at more of the long-term experience with the percentage of patients who can complete all six doses of the radium-223 and the incidence of adverse events. And again, as was observed by us and others early on after introduction of the radium-223, now that we have much more longer data, you can see if the patients had prior chemo, they were ... Only half of them, almost half of them were able to finish all the six courses of the radium-223 and two-thirds of them had the adverse events, which is exactly opposite to what was noted with patients who did not have any prior chemo. In this case, two-thirds of them were able to finish all the six courses and only half had adverse events. Again, this is probably reflective of the fact that patients who did receive prior chemo, they may have had less bone marrow reserve or they were sicker and they already failed another treatment.

Now there are a number of interesting clinical trials that are going on and are being reported as we speak. This is a recent paper that was published with regard to possibility of using re-treatment with second course of six injections of radium-223. So the question was, if the patient is able to finish six courses as prescribed, can we re-treat them again with another course? And the answer seems to be that in some patients that actually can be done and there will be additional favorable response to the second course with re-treatment and it is again associated with relatively mild hematological toxicity, which is quite manageable.

This also very recent study as you can see was published in European Journal of Cancer 2019 by Dr. Morris, basically looked at the combination of radium-223 with docetaxel which is one of the oldest treatments that is used in this clinical space. And they did a dose escalation study with finding what the best Phase II dose is. And in this case they used radium-223 at a dose of 55 kilobecquerel per kilogram every six weeks times five doses. So you already noticed this is a little bit different from ALSYMPCA. In ALSYMPCA, the dose was 50, not 55 and the interval was every four weeks, not every six weeks and the doses, again, in ALSYMPCA was six doses, not five doses. The docetaxel was also used at this dose as you can see, 60 milligram per meter squared every three weeks time 10 doses, which is a little bit less than what you would use typically in patients who are treated only with docetaxel.

The reason this was done was to try to adjust for possibility of combined adverse events to the bone marrow so they made the interval in radium treatment a little bit longer, maybe one dose fewer, but each dose was slightly higher in activity. And then they reduce the docetaxel dose a little bit to again, accommodate for a possibility of combined adverse events to the bone marrow. But they found that if they use that combination and compare it to only patients who are receiving docetaxel, in fact, the combination arm was associated with a longer PSA suppression and also a longer alkaline phosphatase suppression as you can see in here. These are Kaplan-Meier curves. Actually, in the other ones they were not significant, statistically significant, but the time to PSA progression was definitely statistically significant, showing that this type of combination of chemotherapy and radium-223 can be beneficial in comparison to only chemotherapy.

And there is also other trials that are going on which are either published or being still studied or recruiting and you can see their names and clinical trials identifiers on this side including a number of different agents that are being combined including abiraterone, enzalutamide as it was discussed, docetaxel, we already discussed, cancer vaccine, Sipuleucel-T, DNA damage inhibitors or the new cancer immunotherapy PD-1 inhibitor pembro.

But the one that I want to draw your attention on is on this one which is a combination of radium-223 and abiraterone. In this trial, it is called eRADicAte. This was a double-blind trial, randomized, Phase III. There were two arms. The radium arm was combination of radium-223 and abiraterone plus prednisone or prednisolone. The placebo arm was just placebo and essentially this was just abiraterone on its own with prednisone.

There was an interesting observation in the interim analysis that actually the median time to a fracture, a bone fracture, was higher in the arm that combined radium and abiraterone as opposed to just abiraterone alone. And later on in looking at the data more carefully and in more detail, it turned out that almost 80% of these patients who had fracture in the combination arm, actually had no bone metastases at the site of fracture. In other words, they were not pathologic fractures which were very interesting combination ... which was a very interesting observation.

Now there was also seen through looking at the data that the patients who did not have bone health agents, for example biphosphonates, they did tend to have higher fractures in that group. In general, osteoporosis at baseline and interestingly lower number of bone metastases, if it was less than six versus more than six or greater ... or equal six was associated with increased fracture risk.

These are very interesting observations which may indicate that bone health agents are important to be used in some of these treatments including combination treatments and perhaps radium-223 is changing the biology or milieu of the normal bone or healthy bone in such a way that they may be more prone to a fracture in combination with other agents like your abiraterone, which is an androgen enzyme inhibitor and it draws the attention to use of bone health agents in this kind of combinations. Despite all of these observations which are morbidity, there was no imbalance in mortality observations in the two arms.

And finally, some of what are the remaining issues. There is a still lot to be done in this clinical space. We need to know what is the best interval for use of a ... between doses of radium-223, how can it be sequenced with other treatments that are available or the novel treatments. For example on the horizon, we are looking at Lutetium-177 or Actinium-225, PSMA agents for radioligand therapy, so these will be very interesting trials that are foreseen in the future. I talked about a little of the combination treatments but more of those are going on.

Also is it does, if a patient is not able to finish all the six treatments or the prescribed six treatments, are they gaining any benefit from whatever they received? We still don't have the answer to that question very well. Can higher doses be used greater than 50 that was used in ALSYMPCA clinical trial? How can it be synergized with other treatments? There is a very recent trial that is going on combining radium-223 with paclitaxel. And basically also some general notions on trying to minimize cross-resistance between these different types of treatments, either in sequence or in combination. What would be the cost-effective care and what would be the best biomarkers of response? I showed you one slide on PSA flare, but we still need better ways of predicting which patient are going to respond best to these type of treatments and what their prognosis is.

Radium-223 is also being used in ... or tried in other bone-dominant diseases, metastatic diseases including breast cancer and also very recently, there was an article on user vetting osteosarcoma as you can see here. And with that, I conclude my talk and thank you again for the opportunity.

Phillip Koo: Great. Thank you so much Dr. Jadvar for that awesome review of radium-223 and that review of a lot of the clinical trials and the latest data. So in your expert opinion, what advice would you give to referring physicians with regards to when radium-223 would be most appropriate?

Hossein Jadvar: Radium-223 is most appropriate when the patient does not have much tumor burden in the soft tissues. So if the patients do have a large amount of nodal disease or you have disease in the liver or lung or other places, those are essentially not going to be good candidates for radium-223. Radium-223 is essentially should be reserved for patients which are bone ... have their metastases dominantly in the bone. As I mentioned, there can be some lymph node metastases in these patients as was also allowed in ALSYMPCA clinical trial.

Now how much exactly of lymph node metastases should be allowed or is okay, that answer is not exactly known, but at least in the ALSYMPCA clinical trial, if their lymph node metastases, but the size ... the short axis of these metastases were less than 15 millimeter, they were allowed into the clinical trial. So again, it should be realized that radium-223 only targets bone. So if the patient is getting some benefit from radium-223 in the bone, they're not going to gain any benefit from their disease elsewhere. And therefore perhaps in those cases, radium-223 can be combined with other treatments which also targets those sites of disease for the best outcome.

Phillip Koo: Thank you. So one final question, there seems to be a lot of misunderstanding of radium-223 in the community in the sense that a lot of people still think of this drug as a drug that is a palliative agent that improves bone pain. Can you speak to as to why you think this might be happening and how we need to look at this drug differently?

Hossein Jadvar: Yes. Well actually, the radium-223 does alleviate pain in some patients, but the clinical trial was not ... It's different from Samarium-153 or the Strontium-89. We tried the other agents that were available before we ... in relation to bone palliation. Those agents as you mentioned where they were just designed and used and approved for bone palliation and they did not show that they actually ... or improve outcome. Radium-223 from the very beginning, in the ALSYMPCA clinical trial was designed to show that it does benefit the patient in a sense of improving a number of very important outcomes including overall survival and the time to a skeletal-related events.

And therefore, I would put it in a different category than just bone palliation where which again, people are familiar with the previous agents. In this case, if you look at the table that I showed, the bone pain that can occur in some patients, it was basically the same between the placebo arm and radium arm. But there is definite observation that in some patients, not only they benefit from the increased overall survival and delay in skeletal ... time to a skeletal-related events, but they also benefit from relief of some bone pain. So in that sense, it can also be useful.

Phillip Koo: Great. Thank you very much Dr. Jadvar, for your time and sharing your expertise and we look forward to having you back sometime in the future.

Hossein Jadvar: Thank you, Phillip.