Xofigo® (radium Ra-223 dichoride) has been a game-changer in the treatment of prostate cancer metastatic to bone. Not only does it provide significant pain palliation and reduce skeletal-related adverse events, but it slows down progression of the disease, increasing median survival by about 30 percent. Furthermore, unlike external beam radiation, it can be used when there are many widely distributed metastases.
Several new studies have looked at a potentially important new form of radiotherapy: lutetium-177 (Lu-177). Lu-177 is a low-energy β-particle emitter. In this case, low energy is a good thing because it limits the distance the β-particles (beta-particles, which are actually electrons) can travel through tissue. Ideally, we want internal radiotherapies to deposit their energy in tumor tissue only; radioemitters that deposit their energy over long distances are too toxic for internal therapeutic applications. Xofigo is an α-particle (alpha-particle) emitter. α-Particles (effectively a helium nucleus, consisting of two protons and two neutrons) are very heavy and can travel only a short distance through tissue; however, they deposit a lot of energy in the tissue they interact with, efficiently killing cancer cells in a small radius. One can safely hold a glass vial of Xofigo in one’s hand because it can’t penetrate beyond the thickness of the glass or penetrate skin. Because β-particles are thousands of times smaller than α-particles, they can travel farther through tissue, but their cell-killing power is less.
Another desirable quality in radiotherapeutics is a half-life long enough to allow for convenient treatment and time in the body to kill off cancer cells, but short enough so that it doesn’t hang around too long, accumulate in the liver and kidneys, and kill healthy tissue. Both Ra-223 and Lu-177 fit that criterion.
Ra-223 is chemically similar to calcium, so tissues that uptake calcium uptake radium as well. That means principally bone, especially in highly metabolically active sites like bone metastases. However, calcium is ubiquitous in the human body, so small amounts of radium may accumulate in other tissues, causing toxicity.
Lu-177 by itself has little therapeutic use; however, scientists have attached it to an antibody found on the surface of at least 95 percent of prostate cancer cells and called prostate surface membrane antigen (PSMA). The radioactive Lu-177 is chemically bonded to a monoclonal PSMA antibody, called J591, which finds its way to prostate cancer cells anywhere in the body. Unlike Xofigo, which only attaches to bone metastases, Lu-177-anti-PSMA attaches to any metastasis — bone, lymph node or visceral. It can potentially treat systemic micrometastases as well. It has the potential ability to kill many more cells because of the increased range of the β-particle. And because it does not attach to non-prostatic tissue, the toxicity is more limited.
Lu-177 has another important benefit that Ra-223 lacks: it emits small amounts of highly penetrating γ-rays (gamma-rays). The γ-rays are not powerful enough to kill tissue, but they can be detected by a 2D γ-ray camera (scintigraphy), or a 3D SPECT scan. This means that we can see even small metastases that the radiotherapy is attacking; it is both therapeutic and diagnostic (sometimes called theranostic).
The table below summarizes some of the key characteristics of Ra-223 and Lu-177:
Tagawa et al. (2013) published the results of a Phase II clinical trial that demonstrated Lu-177-anti-PSMA resulted in declines in PSA among patients with metastatic castrate-resistant prostate cancer. In a follow-up analysis, they reported a better response, including increased survival, but with higher toxicity with increased dose. As with radium-223, PSA response may not be the best measure of its efficacy. They also noted large declines in circulating tumor cells (CTCs). There was better response among patients who had better anti-PSMA uptake. Based on this, they suggested the following additional studies:
- Improved patient selection using PSMA-based imaging and circulating tumor cell (CTC) analysis
- Escalated cumulative doses using dose fractionation
- Concurrent use with docetaxel to radiosensitize tumors
- Earlier use as soon as biochemical recurrence is identified after initial therapy
At the 2015 Genitourinary Conference there were early reports on some of those studies.
- Batra et al. reported on a small Phase II clinical trial of Lu-177-anti-PSMA used with or without docetaxel, and with fractionated dosing. The group that received both docetaxel and the higher cumulative dosing with fractionated dosing had the best response, with 81 percent having a reduction in PSA of over 30 percent, although their overall survival did not seem significantly improved compared to the low dose group. The group that received the highest fractionated dose, but without docetaxel, had an overall survival three times longer (43 months) than the group that received a low dose. Myelosuppression was reversible after treatment.
- Karir et al. reported on CTC counts of patients in the same study. Over 90 percent of those with an unfavorable CTC count (> 5) had a favorable CTC count (< 5) following treatment. Interestingly, they found that anti-PSMA alone, without the added Lu-177, had a favorable effect in a small subset they tested.
Agarwal et al. used Lu-177-EDTMP in 44 patients with metastatic, castrate-resistant prostate cancer or breast cancer with skeletal metastases to see if it provided significant pain palliation. Complete alleviation of pain was observed in 13 percent, a partial response in 48 percent, and a minimal response in 25 percent of patients.
The results so far look promising, and certainly warrant expanded clinical trials.
For those interested, there is an open clinical trial (NCT00859781) at 10 locations around the U.S., testing Lu-177-anti-PSMA plus ketoconazole and hydrocortisone in patients who are castrate resistant after medical or surgical castration, who have had prior primary radical prostatectomy or radiation therapy, but who have no detectable distant metastases.
Editorial note: This commentary was written for The “New” Prostate Cancer InfoLink by Allen Edel.
Filed under: Living with Prostate Cancer, Management, Treatment | Tagged: antigen, J591, Lu-177, lutetium, membrane, PSMA, radiation, surface, systemic |
THE "NEW" PROSTATE CANCER INFOLINK 
I do want to note that J591 has now been in development for many years, and there have to be questions about the remaining patent life associated with this product.
The product and its derivatives, such as Lu-177-anti-PSMA, have been developed primarily by the Weill Cornell College of Medicine and (as far as I am aware) there is no commercial developer involved with the development of this product. This raises serious questions about (a) whether the funds would be available to carry out the necessary, large-scale, Phase III trials that would be needed to seek marketing approval for Lu-177-anti-PSMA; (b) whether there is enough patent life left on the product for anyone to be able to recover that investment.
It may be that another way to look at the development of Lu-177-anti-PSMA is as a “proof of concept”. If it works, the question then would be whether it was possible to develop a similar or better product that used low-energy β-particles for the treatment of metastatic disease, but which also had a significant patent life available.
Congratulations on a very nice write-up. Xofigo provides proof of principle that systemically targeted radiotherapy can prolong survival of patients with castrate-resistant metastatic prostate cancer. Perhaps this should not have come as such a surprise given that radiotherapy has been accepted as a therapeutic modality for this disease for decades.
A critical distinction between 223Ra [Xofigo] and 177Lu-J591, which you allude to, is that 223Ra, as a calcium mimetic, only indirectly targets prostate cancer by virtue of its accumulation in metabolizing bone. On the other hand, the J591 antibody, carrying 177Lu, directly engages the PSMA receptor on the surface of prostate cancer cells and is subsequently internalized into the prostate cancer cell, depositing the radioactive isotope in an ideal location to radiate the tumor cell’s DNA. And as pointed out, this is true regardless of whether the cancer cell is in bone, lymph nodes or elsewhere. The ultra-short range of Xofigo/223Ra has the advantage that it limits “bystander” cell damage, but it also limits the size of tumor that can be radiated. The further the tumor cells are away from the tumor-bone interface, where the 223Ra deposits, those cells won’t get any radiation. Yet, because of the different targeting mechanism, those cells would nevertheless be susceptible to J591-177Lu. This likely explains why the PSA response rate — as an indicator of prostate cancer cell death — is much better with 177Lu-J591 than with 223Ra.
The original J591 antibody was a mouse monoclonal antibody. This was later successfully humanized allowing patients to receive multiple doses. As an inventor on J591 patents, I can tell you there are multiple patents related to the J591 antibody and its use with patent life extending out to 2030.
Regarding a commercial developer: it has been very difficult to get a pharma company interested in developing a radioactive treatment; pharma companies prefer developing pills that can be put on the shelf and used whenever. Radioactive agents have an intrinsic “half-life” decay so they need to be prepared for a scheduled patient. Nevertheless, there is now a commercial developer on board so, I believe, both of your concerns regarding commercial development have been overcome.
My disclosure: as an inventor of J591, I stand to benefit financially if it reaches commercial success.
I asked Scott Tagawa at Weill Cornell about your concern, and also whether he is developing anti-PSMA alpha emitters. Apparently, it is not a problem, and clinical trials are proceeding apace. Here is his verbatim reply:
“Not sure what your editor mentioned. We have plenty of J591 for all of our current studies and will open a couple more this year. He might have been referencing the J591 which has been license to Atlab, a French company who will perform an international randomized trial (in collaboration with us) to make the first major step to approval. Because of the year of production (in the past), the EMA wanted a new batch of the J591 antibody to be produced, which is currently in process. So it’s true that the current batch of J591 that we are using for our clinical trials won’t be used by Atlab, but they are producing more (both for them as well as for us).
“In terms of imaging, we are currently continuing to investigate our two 89Zr PET compounds (full J591 as well as a minibody being developed by Imaginab). We are also about to start a 68Ga-HBED study that will also include 89Ar-J591 imaging. We have also recently enrolled new pts into a study looking at 99Tc-MIP1404 imaging with potent AR-targeted therapy.
“For alpha-emitter therapy, we are hoping to move past the pre-clinical stage into human testing with alpha particles. We have utilized different alpha-emitters in experiments and are still deciding which one to move forward into the clinic.”
Allen,
A few comments on the PSMA radionuclide therapy:
The PSMA receptor is also present in the salivary and lachrymal glands, as one of my GA68-PSMA PET scans shows.
Side effects such as a dry mouth, which can lead to persistent inflammation, may limit the use of PSMA radionuclide therapy!
Heidelberg is currently trying if an alpha emitter (actinium-225) would be more appropriate as PSMA therapy.
Also, please note that there are prostate cancer cells that do not present the PSMA.
Please note that Dr. Neil Bander (see comment above) has been the lead researcher behind the development of J591 and other PSMA-based diagnostic and therapeutic agents relevant to the management of prostate cancer for much of the past 20 years. I am pleased to hear that there is, in fact, a commercial backer for this project again.
Low Road,
Thanks for sharing those scans!
To get around the problem of dose-limiting toxicity, one of Dr. Tagawa’s studies looked at splitting up the doses so healthy tissue (like salivary glands and bone marrow) have a chance to recover. It seems to work better to do it that way.
Interestingly, PSMA is expressed on the surface of many non-prostate cancers, and these radioimmunotherapies are in clinical trials for other cancers.
As Dr. Bander said, the problem with alpha-emitters is their short range, which is less suitable to larger tumors with weak blood supply. I suspect there is a role to be played for both — alpha-emitters for smaller tumors/micrometastases and beta-emitters for larger tumors, with tumors being identified with Ga-68 (or Zr-89, Cu-64, In-111, I-124, F18-DCFBC, F18-DCpyL — lots of choices!) PSMA PET or SPECT scans. PSMA antibodies will find many roles to play.
As you say, about 5% of prostate cancers do not express PSMA. Another antibody, prostate stem cell antigen or PSCA, is highly expressed in prostate cancer, and there have been early studies using antibodies linking it with I-124. Other possibilities include antibodies to surface peptides on the androgen receptor, radioemitters directly linked to small molecules like DHT or those metabolized by the cancer.
Allen,
One additional comment. As you know, an Lu-177-PSMA therapy is commercially available in Germany for everyone, no need to enter a study. I heard from a colleague with bone metastases, that his doctor adds a neoadjuvant medication (ANTABUS®/disulfiram) to enhance the PSMA expression on the cell membrane, but I do not know anything about the theory behind this approach!
Does hormone therapy (antiandrogens) increase PSMA?
SJPAP asks an insightful question. In fact, hormonal therapy does increase PSMA expression. Both PSA and PSMA are androgen regulated, although in opposite directions — i.e., hormonal therapy decreases PSA but increases PSMA. This is pretty well established in the medical literature and presumably is one of the reasons why PSMA expression is generally so high in patients on hormonal therapy.
We also have data, soon to be submitted for publication, that even in “castrate-resistant” patients, changing hormonal agents, while not necessarily having any apparent clinical benefit (the definition of “castrate-resistant”) nevertheless does raise PSMA level. Because of these data, we’ve incorporated the combination of hormonal therapy plus a PSMA-targeted therapeutic, where the timing of the combination is optimized to coincide with peak PSMA level, into some of our clinical trials.
One such clinical trial (NCT00859781) is ongoing in multiple centers around the country in which patients who have a PSA relapse after surgery and/or radiotherapy and after a first-generation LHRH and anti-androgen (e.g., biclutamide/Casodex) but whose bone and CT/MRI are still negative (sometimes called stage M0) may be eligible for such a combination [secondary hormonal agent + 177Lu-J591]. These patients have micro-metastatic disease and are ideal candidates for an effective systemic therapy where the goal is to prevent development of overt metastatic disease and thereby prevent death. One other requirement for this study is that the PSA must be rising somewhat rapidly, with a PSA doubling time of < 8 months.
Most patients in this setting would simply be moved to a second-generation hormonal agent, but we know that hormonal agents don't cure prostate cancer. In this study, by combining hormonal therapy, which will increase PSMA expression, and then delivering a 'second hit' with a targeted agent that can kill the cancer cells (i.e., 177Lu-J591), we hypothesize will improve results and hopefully prevent metastases/death in some patients.
Just one anecdotal observation about Xofigo, that could also be a concern with an alpha-emitter.
While acknowledging the palliative benefit of radium-223, many men also complain of significant fatigue. A close friend who was on the recent concurrent docetaxel/radium-223 trial is now suffering from significant blood count side effects and has received multiple units of blood.
Most recently his platelet count was too low for chemotherapy — a harder problem to resolve than low red, white, or HMG counts. His UCSF genitourinary medical oncologist includes Xofigo as a contributing factor.
rd
A Potential Now Being Realized!
Thank you Allen, for this most informative thread, and also thank you Sitemaster and Dr. Bander for your contributions, as well as thanks to others who have participated.
On February 11, 2000, more than 15 years ago, I traveled to Johns Hopkins for the first of three sessions involving a monoclonal antibody designed to seek out PSMA protein on prostate cancer cells. Then, as now, the antibody was combined with a radioactive emitter, at that time the emitter was indium-111. However, the radiation was not therapeutic, it was for imaging, known as ProstaScint, which was state-of-the-art for advanced imaging of soft tissue metastasis at the time. I remember speculating with the imaging staff and my doctors whether that kind of technology would ever be refined for therapeutic use.
I feel a sense of awe at realizing that this potential is now taking real form with the Lu-177 β-particle emitter or similar candidate.
How wonderful!
A very exciting comparison to Ra-223, which I had previously been worried by its prohibitive barrier against those who have slight visceral tumors, with size limitations that made no sense.
The remaining concern I have with this agent — as with Ra-223 — is the fact that since I have metastatic, hormone-sensistive prostate cancer my clinic still recommends that my stage is not designated for mCRPC therapies …
Dear Dyke:
The use of Ra-223 (or similar products) in men with metastatic, hormone-sensitive disease and no associated bone pain is not, as far as I am aware, recommended by anyone at the present time — unless it is in the context of a clinical trial. However, at this time I cannot find a single trial of radium-223 in men with hormone-sensitive prostate cancer (metastatic or otherwise). The potential use of a product like Lu-177-anti-PSMA in such a setting has rather more potential … but only if we get positive data out of appropriate trials.
I am 85, and have had prostate cancer for 10 years, managed first with proton radiation, and then, after recurrence, with hormone therapy (Casodex/Proscar, then Xtandi) for another 5 years. I am now hormone resistant, with a rising PSA (metastasis to bones and to some lymph nodes).
Now we are planning for treatment with radium-223 for 6 months in tandem with abiraterone. I wonder if Lu-177 PSMA would have been a better choice?
Dear Hanns:
Lu-177 PSMA is not an approved drug (in Germany or anywhere else that I am aware of, yet). Also, I am not aware of any current, open clinical trials of Lu-177 PSMA in the treatment of metastatic, castration-resistant disease.
Thus, while it is certainly possible that Lu-177 PSMA may turn out to be a more useful drug than Ra-223 at some point in the future, I don’t believe it is available at present and so your proposed strategy of using Ra-223 (with or without abiraterone) is probably one of the best options currently available.
Why is Ra-223 ineffective in destroying micro-metastasis?
Austin,
Ra-223 only accumulates where calcium accumulates in the body — mainly areas of active bone growth that are caused by prostate cancer metastases. So, it cannot kill metastatic cancer of any size in soft tissue, lymph, or blood.
Ambivalent about Xofigo as game changer as it it may have ravaged my bone marrow. I am not alone in that regard. If LU-177 PSMA can provide palliative relief and attack bone and soft tissue without infiltrating a patient’s bone marrow then it would be great.
While the radioactive destruction of bone marrow may be less intense with Lu-177 vs. Ra-223, it is nonetheless a risk any time radiation is placed near bone marrow. They are testing to see if it can be minimized by using smaller repeated doses (dose fractionation) rather than a single large dose.