|
Xofigo (Ra-223
Chloride)
|
Lu-177-anti-PSMA
|
Emits:
|
Alpha particles (95%)
|
Beta particles, gamma rays
|
Half-life:
|
11.4 days
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6.7 days
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Attaches to:
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Tissues that uptake calcium
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Prostate cancer expressing the prostate specific membrane
antigen (PSMA)
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Destroys metastases in:
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Bone only (areas of active calcium uptake)
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Bone, lymph nodes, viscera, systemic micrometastases
|
Destructive range:
|
Shorter range:<0.1 mm or about 8 cells
|
Longer range: ~0.25 mm or about 125 cells
|
Cancer cell killing power:
|
Higher
|
Lower
|
Imaging:
|
Not detectable
|
Gamma camera (scintigraphy) or SPECT
|
Toxicity
|
Gastrointestinal, edema, myelosuppression
|
Myelosuppression: platelets, neutrophils & leukocytes
|
Friday, August 26, 2016
Will Lu-177-anti-PSMA be the next Xofigo?
Tuesday, September 5, 2017
A new Lu-177-PSMA ligand has good results in a new study
There are also ligands that attach to prostate cancer proteins other than PSMA, and radioactive elements other than Lu-177 that are in clinical trials. This is a rapidly developing field.
The new ligand is called PSMA-I&T (imaging and therapy) or sometimes PSMA-DOTAGA. The ligand used in most of the other studies was PSMA-617 (also known as PSMA-DKFZ) or PSMA-J591. The ideal ligand attaches strongly to PSMA in prostate cancer tumors and to nothing else. Importantly, it should not accumulate in the kidneys to a great extent because it could damage them.
Last year, the Central Clinic of Bad Berka, Germany reported on 56 patients treated with Lu-177-PSMA-I&T (see this link). 80% of treated patients had a PSA response and toxicity was minor. Heck et al. at the Technical University of Munich reported on 19 metastatic castration-resistant patients who were treated with 7.4 GBq per cycle and up to 4 cycles.
- In 56%, PSA decreased by at least 30%
- In 33%, PSA decreased by at least 50%
- In 11%, PSA decreased by at least 90%
- Complete remission of metastases in 5%
- Metastases stayed stable in 63%
- Metastases progressed in 32%
- Performance status was stable or improved in 74%
- In those with bone pain, it was reduced partially or completely in 58%
- Mild (Grade 1 or 2) toxicities included dry mouth (37%), anemia (32%), and platelet loss (25%)
- There were no severe (Grade 3 or 4) toxicities.
- There was no kidney toxicity up to 40 GBq (see this link)
- In 38%, PSA decreased by at least 50%
- Median clinical progression-free survival was 4.1 months
- Median overall survival was 12.9 months
- Treatment-emergent hematologic grade 3/4 toxicities were anemia (9%), thrombocytopenia (4%), and neutropenia (6%)
- 68% of patients had some PSA decline
- 37% of patients had a PSA decline of at least 50%
- More patients had a PSA decline with the PSMA-I&T and PSMA-617 ligands, but there was a wide range of outcomes
These early indicators look good. Even if it just stabilizes performance status and mitigates bone pain in these end-stage patients, there is an important benefit. Of course, what we really want to see is evidence that it increases overall survival
While PSMA-I&T was developed to be a good ligand for imaging purposes as well as therapeutic purposes, a recent study found that, when used with Ga-68 (a positron emitter), PSMA-HBED-CC (also known as PSMA-11) was slightly better at detecting metastases (see this link). Another PSMA ligand, DCFPyL, that incorporates the positron emitter F18 into the ligand more tightly (avoiding chelation, which can easily be reversed), seems to be superior to the Ga-68-PSMA-HBED-CC PET tracer (see this link). Both DCFPyL PET and Ga-68-HBED-CC PET are in numerous clinical trials in the US and Canada. Lu-177 is a gamma emitter that can be seen by a gamma camera or via SPECT. However, it is usually used in conjunction with a positron-emitter in order to obtain a superior image.
Readers may wish to read these other articles on this subject:
Will Lutetium-177-anti-PSMA be the next Xofigo?
Lu-177-PSMA update
Lu-177-PSMA: another update
First in-human trial of Actinium-225-PSMA-617
Ac-225-PSMA-617 extends survival (update)
Ac-225-PSMA-617 (update)
I-131-MIP-135, a new radiopharmaceutical, in clinical trial at Memorial Sloan Kettering
Friday, August 26, 2016
Lu-177-PSMA Update
- · PSA decreased in 21/30 patients (70 percent).
- · Hematotoxicity (from bone marrow suppression) was mild.
- · Xerostomia (dry mouth), nausea and fatigue were transient and occurred in <10 percent.
- · Excess radioactivity was cleared from the kidneys within 48 hours.
- · PSA decreased in 47/74 patients (64 percent).
- · PSA was stable (- 50% to +25%) in 35/74 patients (47%)
- · PSA increased by > 25% in 17/74 patients (23%)
- · No significant loss of red blood cells, white blood cells or kidney function
- · Mild decline in platelets, but within normal range
- · PSA decreased in 59% of patients after 1 treatment and in 75 percent after 2 treatments.
- · Median survival was 29 weeks, compared to 20 weeks based on historical expectations.
- · No clinically significant or lasting toxicity occurred.
Sunday, December 15, 2019
Why Lutetium-177-PSMA treatment sometimes may not help, and may even harm
We've seen in a couple of small trials in Germany and Australia that Lu-177-PSMA seemed to provide better than expected survival. In Germany, median overall survival was 12.9 months across 104 patients. In Australia, median overall survival was 13.3 months across 50 treated patients. In both trials, all or almost all patients had already received taxane chemotherapy and either enzalutamide or abiraterone. There was no control group in either trial, so we can only guess at what overall survival would have been without the therapy.
In the "ALSYMPCA" trial of Xofigo, among the subgroup of patients who had received docetaxel for their painful mCRPC (see this link), median overall survival was 14.4 months with Xofigo vs. 11.3 months with placebo. The ALSYMPCA trial was conducted before abiraterone and enzalutamide were approved, so it is impossible to know how prior treatment with one of those might have changed survival.
In a recent trial of Jevtana as a third-line therapy, after docetaxel and either abiraterone or enzalutamide, median overall survival was 13.6 months for Jevtana vs. 11.6 months for the other second-line hormonal.
So, in heavily pre-treated patients, Lu-177-PSMA seems to improve survival about as well as Xofigo or Jevtana when used as a third-line therapy. The VISION trial found that LuPSMA treatment increases survival by 5 months in heavily treated patients (similar to Xofigo).
PSA is not always a good indicator of effectiveness, as has been found for Xofigo and Provenge. Lu-177-PSMA reduced PSA in about 2/3 of treated patients in most studies. That leaves about 1/3 of patients who derived no benefit (even though they had PSMA-avid tumors), and waterfall plots showed that a few patients had large increases in PSA following PSMA-targeted therapy.
It is worth noting that the PSMA protein contributes to the survival of the cancer, and just the PSMA ligand that attaches to it has some activity in delaying progression, even without a radioactive component (similar to the way an anti-androgen attaches to the androgen receptor, delaying progression). It is also worth noting that ADT initially increases PSMA expression, but decreases its expression with continued use.
The opportunities are:
- to select patients who are likely to benefit
- give alternative therapies (like Jevtana) to patients who are unlikely to benefit
- provide adjuvant therapies that may increase survival
PSMA avidity - optimal point in time
It has long been known that PSMA is a moving target. The advent of PSMA PET scans has enabled us to track PSMA expression. Cancers that express a lot of PSMA (called PSMA-avid tumors) can be distinguished from cancers that express very little. Radiologists determine avidity by comparing the uptake of the tracer in cells that express PSMA to the uptake of the tracer in cells known to not express PSMA. Early low-grade prostate cancer does not express PSMA at all. Higher grade prostate cancer may express some PSMA. PSMA expression really starts to take off when the cancer metastasizes, although it is highly variable between patients. About 90-95% of metastatic men express at least some PSMA on their prostate cancer cells. At some point, however, as genomic breakdown continues, PSMA is no longer expressed by metastases. Treating when PSMA is not adequately expressed can cause a lot of toxicity to healthy tissues (especially kidneys and salivary glands) and little therapy (see this link and this one). Thus, there is an optimal point for treating each patient with PSMA-targeted therapy. Treatment too early or too late, may exert selective pressure on the predominant non-PSMA-types, allowing them to take over.
Michael Hofman and others at the Peter MacCallum Cancer Center in Melbourne (see this presentation and this link) have initiated several clinical trials using Lu-177-PSMA at earlier stages of disease progression:
- #lutectomy trial (Declan Murphy, PI) is treating PSMA-avid high-risk patients with Lu-177-PSMA, followed by prostatectomy and pelvic lymph node dissection
- #upfrontPSMA (Arun Asad, PI) is treating patients first diagnosed with high volume metastases with Lu-177-PSMA + ADT + docetaxel vs ADT + docetaxel.
Other opportunities for early use include Lu-177-PSMA treatment for those in the following settings:
- active surveillance
- persistent PSA after prostatectomy
- salvage treatment after first recurrence
- salvage treatment after second recurrence
- metastatic CRPC before docetaxel or advanced hormonal therapies
- non-metastastic (on bone scan/CT) CRPC before docetaxel or advanced hormonal therapies
Centers in Germany may be willing to treat patients per protocol (i.e., outside of a clinical trial) in some of those situations.
Repopulation
In radiobiology, one of the ways in which radiation can fail to destroy cancer is called repopulation. It means that when radiation kills some cancer cells but leaves many behind, the remaining ones now have access to space in which to expand and access to nutrients and oxygen that the other cancer cells had deprived them of. Paradoxically, the tumor can then grow faster than it ever would have before the treatment. This is sometimes seen with rapidly growing tumors, as some head and neck cancers. They sometimes irradiate those cancers multiple times a day to prevent repopulation.
Repopulation is never seen with X-ray (or proton) treatment of relatively slow-growing prostate cancers. X-rays penetrate throughout the prostate and kill all the cancer there. If there is any survival of an oxygen-deprived tumor core, it will be killed by the next fraction of X-rays in a day or two. However, Lu-177 emits beta rays that may only penetrate to about 125 cells around each target. Ac-225 (also sometimes used in PSMA therapy) only kills about 8 cells around each target. With such short-range killing, there is a real danger of repopulation if there are insufficient PSMA targets within the tumor. Multiple treatments are usually not given for several weeks, and the tumors may have changed by then.
PSMA heterogeneity
What we have learned recently is that not only does PSMA expression change over time, but in a given patient, some tumors may express PSMA and some may not. Moreover, even within a single tumor, some cells may express PSMA and some may not.
Paschalis et al. looked at the degree of PSMA expression of 60 patients with metastatic castration-resistant prostate cancer (mCRPC). They also looked at tissue samples of 38 of them taken when they were diagnosed with hormone-sensitive prostate cancer (HSPC). To detect the amount of PSMA expressed, they used an antibody stain that attaches to the part of the PSMA protein that lies above the cellular membrane. They rated the tumors "0" if there was no PSMA up to "300" if all cells expressed PSMA. They also performed a genomic analysis, looking for mutations in over 100 genes associated with DNA-repair defects.
Among the tumor samples from men with HSPC they found:
- 42% of the 38 men with HSPC had no PSMA at diagnosis - it only emerged later
- 5 of the 6 HSPC men diagnosed with Gleason score 6 or 7 had little or no PSMA expression at that time
- About half of 30 HSPC men diagnosed with Gleason score 8-10 had little or no PSMA expression at that time
- Those who expressed PSMA had a worse prognosis
- Expression of PSMA varied greatly (heterogeneous) between patients
- Expression of PSMA varied greatly between biopsy samples from the same patient
- The higher the PSMA expression in a patient, the greater the amount of PSMA heterogeneity
- PSMA expression had increased from when they were diagnosed with HSPC
- Half of the tumors with no PSMA at HSPC diagnosis continued to have no PSMA
- 73% expressed PSMA; 27% did not - only 1 of whom had neuroendocrine prostate cancer
- 84% of those expressing PSMA exhibited marked PSMA heterogeneity
- Heterogeneous patterns were identified:
- PSMA positive and negative cells interspersed in a single area
- PSMA-positive islands in a sea of PSMA-negative cells
- PSMA-positive regions separated by >2 mm from PSMA-negative regions
- Some metastases wholly PSMA-positive, some wholly PSMA-negative in the same patient
- Bone and lymph node metastases had similar PSMA expression; liver metastases (none neuroendocrine) had lower PSMA expression
- mCRPC patients with DNA-repair defects had higher PSMA expression
- HSPC patients without DNA-repair defects were less likely to become PSMA-positive
- Patients treated with PARP inhibitors were more likely to respond if they were PSMA-positive
- For validation, in a separate sample of tumors, those with DNA-repair defects were found to have much higher PSMA expression than those without such defects. This was especially true for somatic mutations in BRCA2, ATM, and dMMR.
- PSMA was downregulated in androgen-independent basal cancer cells (resistant to advanced anti-androgens) and neuroendocrine cells.
The significance of this study is that it may explain why about a third of PSMA-avid patients do not respond to Lu-177-PSMA therapy. The emitted beta particles may kill cells within about 125 cells from where they are attached at the PSMA site. Thus cells that do not express PSMA that are more than 2 mm from a PSMA-avid site will not be killed (see "Repopulation" above).
The authors hypothesize that DNA-damage repair defects cause PSMA to proliferate. If they are right, a PARP inhibitor (like olaparib), which has also been found to be effective when there are DNA-repair defects (see this link), may be able to increase the efficacy of PSMA treatment. This is the subject of an ongoing clinical trial.
- 25% had no detectable PSMA
- 44% had heterogeneous PSMA expression in multiple metastases
- 63% had at least one PSMA-negative metastasis
- Loss of PSMA expression was linked to epigenetic changes on the FOLH1 gene
- Treatment of cells (in vivo and in vitro) with HDAC inhibitors restored PSMA expression
Practical detection of heterogeneity/ clinical trials
Now that we know that heterogeneity can impact Lu-177-PSMA effectiveness, it behooves us to find a way of determining the degree of heterogeneity without doing a biopsy of every single metastatic site. One way is to give each patient two PET scans, so they could see the sites that exhibited PSMA expression as well as the sites that exhibited high uptake on an FDG PET scan.
It is futile to offer PSMA-targeted therapy if there are many sites that show up only on an FDG PET scan but few sites that display uptake of PSMA. It also may be futile to treat patients that show some sites where PSMA and FDG sites do not overlap - "discordant." On the other hand, where there is a high degree of overlap between FDG and PSMA - "concordant" - the PSMA radiotherapy will kill both cancers simultaneously. Of course, the ideal candidate would display only highly PSMA-avid sites. Thang et al. reported on the survival of 30 patients who were treated with Lu-177-PSMA (who were either high PSMA/low FDG or concordant, compared to 16 patients who were excluded based on lack of PSMA (8 patients) or a high degree of discordant sites (8 patients). All patients were heavily pretreated.
- Treated patients survived 13.3 months (median)
- Untreated patients survived 2.5 months (median)
- A third of patients had at least one FDG+/PSMA- tumor
- Overall survival was FDG+/PSMA- patients was 6 months
- Overall survival for PSMA+only patients was 16 months
- In men with high PSMA, the PSA50 was 91% for Lu177PSMA vs 47% for cabazitaxel
- Among men with high PSMA, the odds ratio of responding to Lu177PSMA was 12.2 vs 2.2 for cabazitaxel
- In men with low PSMA, the PSA50 was 52% for Lu177PSMA vs 32% for cabazitaxel
- In men with high FDG, the PSA50 was 57% for Lu177PSMA vs 20% for cabazitaxel
- Among men with a high FDG, the odds ratio of any response to either treatment was 0.44
- In men with low FDG, the PSA50 was 70% for Lu177PSMA vs 44% for cabazitaxel
- chemotherapy-
- for non-discordant, newly diagnosed, with high-volume metastases in Australia
- for patients who have progressed after an advanced hormonal and docetaxel, this Australian trial combines it with cabazitaxel.
- immunotherapy:
- trials of adjuvant Keytruda in UCSF and Melbourne
- trial of combo with Keytruda and Yervoy in Australia
- trials of a bispecific PSMA/ T cell-recruiting antibody (BiTE) in:
- Los Angeles, Europe & Australia (AMG 160) (early results)
- AMG 160 + Xtandi/Zytiga + PD1i
- City of Hope, LA AMG 509
-
NY (REGN5678)-> trial ended for toxicity - Germany AMG 212 (CD3/CC1) (Phase 1 results)
various US sites (HPN 424) (early results)-> trial ended- various sites in N. America (JNJ 63898081)
- TNB-585 (5 US sites)
- CB-307 (UK)
- LAVA1207 (4 US sites)
- JNJ-80038114 (Nashville, France, Germany, UK)
- trial of a CAR-T/PSMA therapy at UOP, Thomas Jefferson U & Columbia and Shanghai and City of Hope
- Phase 2 trial (completed) of Progenics' antibody-drug conjugate (PSMA ADC 2301)
- Xofigo for bone metastases - trial of a therapy that may include both
- With EBRT to oligomets in recurrent patients in Australia
- PARP inhibition - trial in Melbourne
- Enzalutamide (Xtandi) randomized trial in Australia
- Adding a systemic radiosensitizer: Veyonda (idronoxil) suppository. A phase I/II trial found it was safe, with only anal inflammation attributable to the suppository. Results were no better than trials without the radiosensitizer; however, unlike those other trials, almost all (91%) patients had already received Jevtana.
- other novel non-PSMA targeted treatments
Based on this new knowledge, it is recommended that patients who are good candidates for Lu-177-PSMA therapy have both a PSMA PET/CT scan and an FDG PET/CT at around the same time. FDG PET scans are generally covered by insurance; PSMA PET scans are not covered by insurance yet.
Friday, January 27, 2017
I-131-MIP-1095, a new radiopharmaceutical, in clinical trials at Memorial Sloan Kettering
Like Lutetium 177, Iodine 131 is a beta particle emitter (see this link). It's beta particle energy is somewhat higher, so that it can penetrate greater distances through tissue - up to 3.6 mm, compared to 1.9 mm for Lu-177. This is an advantage in that it can destroy larger tumors, but it is a disadvantage in that it may destroy more healthy tissue, causing hematological and renal side effects. It is also similar to Lu-177 in that its uptake in human tissues can be detected using a gamma ray camera or SPECT detector. Because gamma ray detection does not afford the image quality that PET/CT does, it may be combined with a positron emitter, I-124. Lu-177 is sometimes combined with Ga-68 for the same purpose. This combination of therapeutic and diagnostic (sometimes called theranostic) may be useful in tailoring the dose to the patient based on individual uptake characteristics.
The molecule (or ligand) that the I-131 is attached to is MIP-1095. MIP-1095 is attracted to the PSMA protein on the surface of 95% of prostate cancer cells. Although it is highly specific for prostate cancer, there are other tissues that express PSMA, especially the salivary glands and lacrimal glands. It is excreted by the liver and kidneys, and may show up in the intestines, and the lower urinary tract. The dose to the kidneys may limit the amount of the pharmaceutical that may be given to the patient.
A group from the University Hospital Heidelberg, Zechman et al., treated 28 metastatic castration-resistant patients with I-131-MIP-1095 with the following results:
- In 61%, PSA was reduced by >50%. This is better than the response seen with Lu-177-PSMA-617 in these trials and in this one.
- PSA decreased in 21 of 25 patients, increased in 4.
- 85% had complete or moderate reduction of bone pain.
- 25% had a transient slight to moderate dry mouth, which resolved in 3-4 weeks.
- White blood cell count, red blood cell count and platelets declined during treatment, but there were only 3 cases of grade 3 hematologic toxicity, often in patients with low blood counts at baseline.
- No renal toxicity was observed.
- The effective dose to cancer cells was higher than for Lu-177-PSMA-617, red marrow and kidney doses were similar, and liver dose was lower.
The clinical trial that is now recruiting at Memorial Sloan Kettering, is a Phase 1 trial to find the best dose of I-131-MIP-1095 among patients with metastatic castration-resistant prostate cancer. Doses will be administered 12 weeks apart for up to 5 cycles or until dose-limiting toxicity is observed (monthly assessments). Interested patients in the New York City metropolitan area should call the contacts listed on the bottom of this trial description.
Saturday, January 30, 2021
Avoiding radiation damage to salivary glands with Ac-225-PSMA-617 therapy
As we await the results of the VISION trial of Lu-177-PSMA-617, research continues into improving radiopharmeuticals. Ac-177-PSMA-617, which is more lethal to cancer cells within a more limited distance, is one of several promising alternatives (see this link).
One of the serious side effects of the experimental Ac-225-PSMA-617 therapy is radiation damage to salivary glands. "Xerostomia" (dry mouth) also occurs with Lu-177-PSMA-617 therapy, but it is usually transient and less severe, although it does increase with the number of treatments. Sathkegke et al. reported occurrence in 85% of South African patients treated with Ac-225-PSMA-617, but no one stopped treatment entirely because of it. Kratchowil et al. reported occurrence of xerostomia in Heidelberg, Germany so severe in 4 of 40 treated patients that treatment had to be discontinued. Feuerrecker at al reported that all their treated German patients suffered from xerostomia; it was so severe as to curtail treatment in 6 of 26 patients.
Acute, low-grade xerostomia is caused by the temporary irritative inflammatory effects of the radiopharmaceutical on salivary tissue. Lasting damage may result from radioablation of the saliva-producing cells and the nerves that innervate them, and their replacement with and obstruction of the ducts with mucus and scar tissue. Loss of saliva can make chewing and swallowing almost impossible, leading to choking and vomiting. Digestion is impaired, and the ability to taste food may be lost. Saliva has antimicrobial properties, so its loss can lead to tooth decay, gum disease, and oral thrush. Speaking can become difficult. It can feel like burning, and interfere with sleep. Humans normally produce about a liter of saliva each day.
Some simple therapies (local cooling with ice, Vitamin C, lemon juice, and PMPA) have been found to be ineffective. Taïeb et al. report that treatment with botulinum toxin, Vitamin E and MnBuOE may be more successful, but that regeneration of salivary glands with stem cells or genetic modification may ultimately be necessary. Riley et al. found very low quality of evidence that amifostine, pilocarpine, palifermin, biperidine, Chinese medicines, bethanechol, artificial saliva, selenium, antiseptic mouthrinse, antimicrobial lozenge, polaprezinc, azulene rinse, and Venalot Depot (coumarin plus troxerutin) may be useful. Nail et al. found sublingual atropine reduced salivary uptake in mice. More benefit may be accomplished with some of the following strategies:
Sialendoscopy
Rathke et al. reported the successful use of sialendoscopy in 11 patients. Sialendoscopy is a kind of endoscopic procedure involving the insertion of a thin probe into the salivary glands. It dilates the openings that have closed due to inflammation. They irrigated the glands with saline and prednisolone. It only worked when done immediately.
Pre-treatment with PSMA-11
PSMA-11 is the small molecule ligand used with Ga-68-PSMA-11. Taken without the radiotracer, it attaches to the salivary tissue, where it can block further uptake by the PSMA-617 ligand. Kalidindi et al. found that in mice, pretreatment with 1000 picomoles blocked uptake of Lu-177-PSMA-617 in the salivary glands and kidneys; but uptake, while reduced, was still at therapeutic levels in tumor tissue. This finding would have to be replicated in clinical trials.
Use only when there is significant PSMA-avidity
Damage to normal, healthy tissue increases when there is insufficient PSMA-avid tumor tissue to attach to. Gaertner et al. found that across 135 patients, uptake by normal tissues of the salivary glands, tear ducts, kidneys, and other vital organs was significantly reduced in men with high tumor load. Gafita et al. and Burgard et al. confirmed this "tumor sink" effect. While it is true for many pharmaceuticals that earlier use is more effective and less toxic, there is a balance to be struck between the tumor-killing effect and toxicity for the PSMA-targeted radiopharmaceuticals. We have seen that such treatment can be too late as well, when new metastases lose PSMA-avidity (see this link). It may be a good idea to reduce dose for low tumor volume.
Mix Lu-177-PSMA-617 and Ac-225-PSMA-617
A cocktail of the two may increase the cancer-killing power of Lu-177-PSMA-617 while decreasing the toxicity of Ac-225-PSMA-617. Khreish et al. reported that only 5 of 20 patients given the cocktail reported mild xerostomia.
Use a PSMA antibody
PSMA-617 and PSMA-11 are small molecules that have been found to attach to the PSMA molecule on the surface of prostate cancer cells. They are not as specific as other ligands. Scott Tagawa is exploring the use of a PSMA antibody, called J591 in two clinical trials (this one and this one), that may be more specific than the small molecules. In a previous clinical trial, there were no reports of xerostomia. The clinical trial of Th-227 targeting PSMA uses a highly specific antibody.
Use a non-PSMA-targeted ligand
Another strategy is to forgo the PSMA target entirely. Ac-225 has been attached to an antibody that very specifically targets hK2 (one of the 4 prostate cancer proteins detected by the 4KScore test). It has entered a clinical trial.
Beware of MSG and other supplements
Harsini et al. conducted a small clinical trial where patients were randomized to take tomato juice with and without monosodium glutamate (MSG). Glutamate is a known heavy-metal chelator. Each patient had two double-blinded PSMA PET scans -- one with MSG; the other without MSG. MSG did reduce the uptake of PSMA into the salivary glands and the kidneys. Unfortunately, it also blocked the uptake of PSMA into tumor tissue. Armstrong et al. reported a similar trial where patients could swish MSG in their mouths or ingest it. Each patient had Ga-68-PSMA-11 PET scans with and without MSG. Swishing had no effect. Oral ingestion reduced uptake in salivary glands and in tumors. Patients getting PSMA theranostics should avoid MSG and Chinese food.
Because the PSMA-targeted radiopharmaceuticals are very loosely held together (chelated) by a coordination complex, it is easily reversed by other heavy metals (like iron, cobalt, vanadium, etc. supplements) or other chelates or chelators (like those frequently found in multi-mineral tablets). Curcumin, a popular supplement, has been found to be a chelator. Use of such supplements may increase the toxicity of these radiopharmaceuticals, or render them ineffective. Antioxidants and free radical absorbers may interfere with the DNA damage that radiopharmaceuticals are trying to achieve. To be safe, and to maximize their effectiveness, patients should avoid all supplements during therapy.
Monday, October 16, 2017
Does Lu-177-PSMA-617 increase survival?
Rahbar et al. reported the outcomes of 104 patients treated with Lu-177-PSMA-617 at University Hospital Muenster, Germany. All patients had metastatic castration-resistant prostate cancer (mCRPC) and had already received docetaxel and at least one of abiraterone or enzalutamide. After the first of an average of 3.5 cycles, they had the following outcomes:
- 67% of patients had some PSA decline
- 33% of patients had a PSA decline of at least 50%
- Median overall survival was 56 weeks (13 months)
177Lu-PSMA-617 RLT is a new effective therapeutic and seems to prolong survival in patients with advanced mCRPC pretreated with chemotherapy, abiraterone and/or enzalutamide.But is this conclusion justified? It's hard to know without a prospective clinical trial where patients are randomized to receive the radiopharmaceutical or standard-of-care. The best we can do is look at the overall survival from clinical trials involving patients with symptomatic mCRPC. In the "ALSYMPCA" trial of Xofigo, among the subgroup of patients who had received docetaxel for their painful mCRPC (see this link), overall survival was:
- 14 months with Xofigo
- 11 months with placebo
In a non-randomized trial among 24 mCRPC patients after treatment with docetaxel and abiraterone, overall survival was:
- 9 months with cabazitaxel
- 5 months with enzalutamide
Thursday, August 25, 2016
First in-human trial of Actinium-225-PSMA-617
- · It can target metastases in any tissue or fluid, including undetectable, systemic micrometastases.
- · Because its alpha particles are very short range, it doesn’t destroy very much healthy bone marrow.
- · Because the alpha particles are highly energetic, they destroy nearby cells very effectively.
- · Because it attaches to PSMA instead of calcium-active sites in bone or other tissue, it may be less toxic to other healthy tissue.
- · Exhibited complete PSA response, becoming undetectable
- · Exhibited complete tumor response on PET imaging
- · Exhibited no hematological toxicity; that is, no bone marrow suppression
- · Exhibited dry mouth from decreased saliva (xerostomia)
Friday, April 30, 2021
First clinical trial of Lu-177-PSMA-617 in recurrent, hormone-sensitive men
While we expect only a few months of extra survival from the VISION trial of Lu-177-PSMA-617 in heavily pretreated, metastatic, castration-resistant men (see this link), we hope to get more out of the radiopharmaceutical if used earlier. Privé et al. reported the results of a pilot trial in 10 recurrent men treated with Lu-177-PSMA-617 at Radboud University in Nijmegen, The Netherlands. They were all:
- Recurrent after prostatectomy ± salvage radiation (PSA>0.2 ng/ml)
- Rapid PSA doubling time (< 6 months)
- Between 1-10 metastases detectable on a PSMA PET scan or USPIO MRI
- At least 1 metastasis > 1 cm.
- Unable to receive SBRT to metastases
- No visceral metastases
- Have not begun salvage ADT
- Treated with a low dose (3 GBq) on day 1; second treatment (~6 GBq) after 8 weeks (compared to dose in VISION trial of 7.4 GBq in each of 4-6 cycles)
After 24 weeks of follow-up after Cycle 2:
- 5 patients had PSA reduced by >50% (1 undetectable)
- 2 patients had stable PSA
- 3 patients had PSA progression
- 6 patients had a radiographic response
- 4 patients had radiographic progression
- ADT-deferred survival was 9.5 months (median)
- Those with lymph node only metastases had the best response
- Those with any bone metastases had lesser response
- PSA was continuing to decline in 3 patients
- PSA was rising again in 6 patients
Side effects were mild (no grade 3) and transient:
- fatigue in 7; nausea in 3
- dry mouth (xerostomia) in 2
- Would a higher dose and more treatments be more effective?
- Would a higher dose and more treatments be more toxic?
- Is it like Xofigo in that it's more effective with micrometatases? If so, would a combination with SBRT targeted at the larger metastases be more effective?
- Since it was more effective on lymph nodes, would it make a good combination with Xofigo for patients who have both lymph node and bone metastases? (See also Th-227-PSMA)
- Because there seems to be a continued abscopal effect for some patients, would combining it with Provenge be optimal?
- Would pretreatment with ADT or a new anti-androgen (Xtandi, Erleada or Nubeqa) increase expression of PSMA, and increase radiosensitivity?
- Can we predict who will benefit?
- Use in other patient populations remains to be explored: high-risk, newly diagnosed metastatic, castration-resistant but chemo-naive. Optimal sequencing with other therapies remains to be explored.
Wednesday, October 26, 2016
Lu-177-PSMA-617: Another update
Thursday, February 18, 2021
Xofigo 2.0
(updated)
Xofigo (Radium 223 dichloride) is a systemic radiopharmaceutical. Radium is chemically similar to calcium and is taken up by bones in places where bone is actively growing, as in prostate cancer bone metastases. Radium 223 emits powerful alpha radiation that kills the cancer cells in the bone metastases. It has been found to double 2-year survival (see this link), extending survival time and reduce the skeletal-related events by almost a third. It often will not reduce PSA or show bone metastases shrinking in imaging, which some patients find disappointing.
It is FDA-approved for castration-resistant men with painful bone metastases, who do not show evidence of visceral metastases on a CT or MRI (lymph node metastases are allowed). So far, it is only FDA-approved as a monotherapy, but researchers have wondered whether it may be more effective in combination with other medicines, or used in other situations.
Predicting successful treatment
NaF18 PET predicts Xofigo success (see this link). NaF18 PET is twice as sensitive for finding bone metastases compared to PSMA PET indicators (see this link).
Always use with a bone-preserving agent
Hijab et al. reported the results of the REASSURE trial. They compared the bone fracture rate of 36 mCRPC patients who took Xofigo to a matched reference cohort of 36 mCRPC who didn't take Xofigo. They were all assessed for fracturesat baseline, 3 times during treatment and every 3 months thereafter with whole-body mpMRI. Very few (2-4 in each cohort) took a bone-strengthening agent. After 16 months of follow-up, they found:
- 56% had new fractures
- 3.7 fractures per patient with fractures
- 13.6 months to first new fracture
- ⅔ of new fractures were in the spine
- Only ⅓ were at sites of metastases
- Half the fractures were asymptomatic (no pain)
- No association of Xofigo dose with risk of fracture
- Higher # of bone metastases, high ALP, and previous use of steroids were associated with higher risk of fractures.
In the reference cohort (mostly using Zytiga or Xtandi, no Xofigo), there was still an increased fracture rate, albeit lower. After 24 months of follow-up, they found:
- 33% had new fractures
- 1.3 fractures per patient with fractures
- Only 38% occurred at sites of metastases
This trial shows that all men taking hormone therapy for mCRPC are at high risk for fracture, but particularly if they use Xofigo, and if they previously used corticosteroids (e.g., with chemotherapy). The effect on bone continues after Xofigo is stopped. These are predominantly "fragility" fractures, not metastasis-related, and can be prevented with bone-strengthening agents like Xgeva or Zometa.
Second-line hormonal therapies
It has long been known that androgen deprivation therapy (ADT) sensitizes prostate cancer cells to radiation therapy. Could a more powerful type of hormonal therapy work even better?
The combination of Zytiga and Xofigo was tried in the ERA 223 trial. The trial was stopped early because there were about 3 times more fractures in the group receiving the combination than in the group receiving a placebo and Zytiga. The combination now carries a black-box warning against the combined use.
It appears that the problem may be at least partly resolved by using a bone-strengthening agent (like Xgeva or Zometa). When they looked at the subgroup who had taken bone-strengthening agents, 15% of those taking Xofigo+Zytiga vs 7% of those taking Zytiga-only experienced a fracture. So, even though Zometa or Xgeva reduced the fracture rates by about half in both arms, the fracture rate was still twice as high among those taking the combination.- 46% of men taking Xofigo and Xtandi without a bone-strengthening agent
- 3% of men taking Xofigo and Xtandi with a bone-strengthening agent
- 22% of men taking Xtandi without Xofigo and without a bone-strengthening agent
- 4% of men taking Xtandi without Xofigo and with a bone-strengthening agent
- PSA progression-free survival was 9 months for Xofigo+Xtandi vs 3 months for Xtand-alone (not significantly different on this small sample size)
- Time to PSA progression after the next therapy was 19 months for Xofigo+Xtandi vs 8 months for Xtandi-alone (significantly different)
- Time to next therapy was 16 months for Xofigo+Xtandi vs 3 months .for Xtandi-alone (not significantly different)
- Overall Survival was 31 months for Xofigo+Xtandi vs 21 months for Xtandi-alone (not significantly different)
- There were 3 asymptomatic fractures found in the Xofigo+Xtandi arm.
- Xofigo (55 KBq/kg) every 6 weeks for 5 injections and lower dose docetaxel (60 mg/m2) every 3 weeks for 10 infusions
- Standard dose docetaxel (75 mg/m2) every 3 weeks for up to 10 infusions
- The normal schedule for Xofigo is 55 KBq/kg once every 4 weeks for 6 injections
- The normal schedule for docetaxel is 75 mg/m2 once every 3 weeks for 6 infusions
- The timing adjustments were made for patient convenience
- Almost all had tried a second-line hormonal therapy
- Most were taking a bone-strengthening agent
- Median PSA progression occurred after 6.6 months in the combination arm vs 4.8 months in the docetaxel-only arm
- PSA declined by ≥ 50% in 61% of the combination arm vs 54% of the docetaxel-only arm
- Median radiographic or clinical progression occurred after 12 months for the combination vs 9 months for docetaxel only
- All 10 treatments were given for the combination, whereas there was a median of 9 of 10 treatments in the docetaxel-only arm
- 12% discontinued treatment in the combination arm vs 23% in the docetaxel-only arm
- Serious adverse events were suffered by 48% in the combination arm vs 62% in the docetaxel arm
- Serious blood disorders were noted more often for docetaxel-only
- Median progression-free survival (PFS) was 39 weeks for the combination vs 12 weeks for Provenge alone.
- The % who had a PSA reduction by more than half was 31% for the combination vs 0% for Provenge alone
- Median overall survival was higher with the combination: not reached vs 2.6 years
- The % who had an alkaline phosphatase reduction of more than 30% was 60% for the combination vs 7% for Provenge alone
- There were no increases in side effects for the combination
- 28 had DNA-repair defects (DRD+)
- 65 had no DNA-repair defects (DRD-)
- Twice as high alkaline phosphatase (ALP) response: 80% vs 39%
- Longer time to ALP progression: 6.9 mos vs 5.8 mos. (not statistically significant)
- Longer time to next systemic therapy: 8.9 mos. vs 7.3 mos. (not statistically significant)
- Twice as long overall survival: 36.3 mos. vs 17.0 mos.
- Better Xofigo completion rates: 79% vs 47%
- No difference in PSA response