Bone Targeted Therapies and Radiopharmaceuticals

Bone Targeted Therapies and Radiopharmaceuticals

My task is to talk about bone targeted therapy and as we know, bone is a dynamic organ. It basically exists through being broken down and rebuilt again. Osteoblasts are the cells that will be responsible for bone building. Osteoclasts will be responsible for bone reabsorption and in cancer there is an imbalance between the blastic and the clastic cells. In prostate cancer, this is predominantly osteoblastic. Other tumors, such as breast cancer, is predominantly osteolytic. Of course, that is how we have issues with skeletal-related events and for patients who are castrate-resistant, we usually go forth with a bone targeting agent first, such as zoledronic acid or more recently dated with denosumab.

This is just a brief reminder of Fred Saad study that was published more than 10 years ago now, looking at zoledronic acid and castrate-resistant prostate cancer patients and demonstrating that there was an improvement into the time to the first skeletal-related event which basically is a change in therapy due to pain, pathologic fractures or other issues that may be related to bone health. As we see, the zoledronic acid 4 mg arm was better than the placebo arm. RANK ligand inhibition has also been used as a way of affecting this particular axis. RANK ligand will basically affect osteoclasts and prevent bone breakdown and increases in RANK ligand are found in tumor cells and this will cause a reduction in osteoprotegerin which will cause increased bone reabsorption.

In a study that was run by Karim Fizazi where zoledronic acid was compared to denosumab, which is subcutaneously administered monoclonal antibody, the target’s RANK ligand. Nineteen hundred patients were entered in this randomized trial and a superior median time to first skeletal-related event was also seen with denosumab and that was superior to zoledronic acid. This trial was interesting in that it was both designed as an equivalence as well as a superiority trial and it met the criteria based upon both of those particular statistical designs. Of note, there was no improvement in survival either with this trial or Fred Saad’s trial.

Bone target agents have improved quality of life issues but until recently, we really haven’t seen a survival benefit until the implementation of alpha particles in the treatment of castrate-resistant prostate cancer. There are basically high energy particles; they are helium nuclei that don’t penetrate a sheet of paper. What do I mean by that? If I took a – – counter, took a vial of an alpha particle admitter and then took a piece of paper and put it between them, they don’t penetrate. It is a short duration or short length of action of radioactive isotope. That is not the same for beta admitters, such as strontium and samarium. You can’t halt it by a piece of paper; you need a lead plate. The important biological characteristic is that alpha particles will induce double-stranded DNA breaks. Those are difficult to repair, they are much more difficult to repair than single-stranded breaks, which are predominantly seen with beta particles. This is why we’ve started to look at isotopes in this area.

There are two previously approved FDA isotopes by the FDA. One is samarium that was approved in March of 1997. This was on a palliative endpoint which was a relief of bone pain, not a survival endpoint, and the strontium-89 which also was approved in June of 1993 based upon a palliative endpoint. These particular agents, strontium and samarium have different mechanisms of action. Strontium is a calcium homolog which will attract the deposition of calcium. Samarium also will attract to bone but it requires chelation with EDTMP to the phosphonic acid groups so that it will be moved to newly deposited bone. Radium-223, which we will talk about in a moment, is similar to strontium and is in the same area of the periodic table and will attract calcium. P32 was used a long time ago. It is extremely toxic and it will attract inorganic phosphorus within the body.

This is the concept that we mentioned before, the idea that an alpha-emitting particle has a shorter radius of action than the beta particle and thus may not affect normal bone marrow cells and will actually target the tumor. As we see from this cartoon in the center of the left-hand portion is the radionuclide that will be targeted by the alpha particle and the normal marrow, which is in the second circle outside is not affected by the alpha particle, but if you were to administer a beta particle that would be included. So again, this is one of the reasons why we think that there is less toxicity.

A randomized phase two trial surprisingly demonstrated survival benefit for radium-223 compared to placebo. So the ALSYMPCA trial was an extension of that original observation and this trial took patients with castrate-resistant prostate cancer. They had to have symptomatic disease more than two bone metastases. They could not have visceral metastases or bulky lymphadenopathy and they were also characterized as being either fit or unfit for docetaxel therapy. This accepted patients both pre- and post-chemotherapy but for pre-chemotherapy patients, they had to be unfit. Patients were stratified based upon alkaline phosphatase, bisphosphonate use, and prior docetaxel use, and they were randomized to receive radium-223, otherwise known as Alpharadin 50 kBq/kg, given monthly for a total of six injections versus a placebo. These are the endpoints of the study. The primary endpoint was overall survival. Secondary endpoints were timed at occurrence of first skeletal-related event, timed at total alkaline phosphatase progression, total alkaline phosphatase response, alkaline phosphatase normalization, time to PSA progression, safety as well as quality of life. These are some of the criteria I mentioned before. I think the important exclusion criteria were prior use of systemic radiopharmaceuticals and also failure to recover from adverse events from chemotherapy or other treatments.

This is the patient distribution. Remember it was a 2:1 randomization, median agents were similar; ethnic distribution was similar as well. Predominantly these were – – performance status of one or better; that is 87% in both arms and the extent of the disease varied from about 40% of patients having more than 20 metastases or super scan to less than six metastases in 16% of patients. The pain index of greater than two by the World Health Organization was seen in about 60% of patients overall in both arms. Hemoglobin, albumin, total alkaline phosphatase, LDH, PSA, all of these were similar in both arms. About 40% of patients in both arms had bisphosphonate use, and about 40% of patients had prior docetaxel use.

This is the survival curve from the ALSYMPCA trial. Overall when you take both groups of patients, there was a 3.6 month improvement and overall survival. The experimental arm was about 15 months, 11.3 months for the placebo arm. The hazard ratio was 0.695. As one would expect, there was a better survival or longer survival in those patients who were pre-docetaxel compared to the post-docetaxel patients. The median survival was 4.6 months versus 3.1 months and as we see if radium-223 administrated in the post-docetaxel setting, that is a similar magnitude to what you see with cabazitaxel or enzalutamide, which is four months or – – so they all fit in the same ballpark.

If you start looking at the forest plot for different subgroups, we see that there tends to be a more favorable response or survival in those patients who have a higher alkaline phosphatase of 220 or greater. It doesn’t really seem to make a difference where the patients have had bisphosphonates or prior use of chemotherapy.

Looking at one of the secondary endpoints, time to first skeletal-related event, radium-223, the median time was about 12 months, placebo arm was 6.7 months. Remember that about 40% of patients were treated with bisphosphonates so I think this raises a very, very interesting question in terms of economic use of drugs. Are we going to start using drugs that have overlapping effects? The question is are these effects additive, synergistic, or you really don’t see that much of an incremental gain by giving bisphosphonates with radioisotopes. I think that is going to be a very, very important question for us to answer.

If we start looking at some of the different components of a skeletal-related event endpoint, external being radiation therapy, spinal cord compression, pathologic fractures, surgical intervention for bones issues, all of these are in favor of radium-223. The only one that was not significant was the surgical intervention and that is probably because of the low numbers. This is a safe treatment to administer. If we look at the adverse event rates in both arms, they are very, very similar. Grade III or IV adverse events, again, are very similar and discontinuation due to adverse events are actually a little bit lower than the radium-223. Median number of injections administered was six in both arms and 63% of patients received all six treatments of radium-223 in experimental – -.

This table summarizes the adverse events seen in the ALSYMPCA trial. As we see, when we start looking at anemia, all grades are very, very similar in both arms. This is the same thing with grade III or IV. If we start looking at thrombocytopenia maybe a little bit more in the radium-223 arm as opposed to the placebo arm, interestingly bone pain is lower and that is what you would expect if you were giving an isotope that may target bone and improve bone pain, diarrhea, nausea, vomiting, and constipation. This was all very similar in both arms.

In terms of sequencing, I think there are some important questions that need to be asked. I think one of which is can we safely give chemotherapy after radium-223. This is a retrospective analysis from the ALSYMPCA data looking at the administration of different forms of chemotherapy. Overall, the proportion of patients receiving chemotherapy in each of the arms is about 15% in the radium-223 group, and 18% in the placebo group. The most common agents, of course, that were administered were docetaxel in 105 patients, and mitoxantrone in 23, and cyclophosphamide in 19. These are the different demographics of those patients receiving chemotherapy. Alkaline phosphatase and bisphosphonate use is very, very similar. Median number of administrations of the study drug were very similar in both arms. The spread was 2 to 6 in the radium-223 and 71% of patients received all six injections of radium-223, 68% had prior docetaxel, 32% had no prior chemotherapy.

If we start looking at hemoglobin and platelet counts, they are very similar in both arms. There does seem to be a trend to a slightly lower level of neutrophils in patients with radium-223 but note it does not reach the area where you would consider that the patients are neutropenic and also there were no increased events of neutropenic fevers in those patients treated with radium-223. This indicates, at least from the ALSYMPCA data, that you can safely give these drugs in sequence. The question of course is can you give these in combination. It certainly would make sense in the future if you have a patient with visceral disease, because as you remember the patients who were treated in the ALSYMPCA trial, if they had visceral disease, they were not permitted to enter the study. I think in the future as we are seeing patients progress, we would like to consider combination therapies. This is some data that Mike Morris has presented at ASCO this past year. What he did was he gave a lower dose of radium-223 every six weeks, 25 kBq plus full dose docetaxel in cohort number one, again a lower dose in radium-223 plus 60 of docetaxel in cohort two, and then the full dose of radium-223 plus 60 in cohort number three. He observed that there was no discontinuation delay of the radium-223 due to adverse events, there was no grade III or grade IV anemia or thrombocytopenia. Ten patients had grade III or IV neutropenia and there were four cases of febrile neutropenia, three in cohort number one and one in cohort number three. So what he decided to do was to select the cohort with the higher dose of radium-223 or full dose 50 kBq, combining that with docetaxel and now that that is out in a randomized phase II trial, we will determine whether this is both safe and effective to use in patients with metastatic disease. He is not specifically limiting this to visceral but I think in the future that is something we are going to need to evaluate, both targeting the bone as well as targeting the soft tissue lesions with chemotherapy.

In conclusion, alpha emitting isotope therapy improved survival in men with castration-resistant prostate cancer. There is minimal toxicity and combination studies are underway with hormonal chemotherapeutic agents. I also wanted to note that we are actually about to start a randomized phase II trial looking at radium-223 plus enzalutamide or abiraterone and comparing that to radium-223 in pre-chemotherapy patients as their first therapeutic manipulation. That trial is now about to open up and we hope to get that accrued rapidly. Thank you for your attention.

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