Lu-177-PSMA-617 vs Jevtana (cabazitaxel): which should I do next?

We saw recently (see this link) that of chemo and hormonal medicines for metastatic castration-resistant prostate cancer (mCRPC), Jevtana (cabazitaxel) is the preferred third treatment after Taxotere (docetaxel) and Zytiga (abiraterone) or Xtandi (enzalutamide). But when should radiopharmaceuticals, either approved ones like Xofigo (Ra-223), or prospective ones like Lu-177-PSMA-617, be used in the optimal sequencing?

Michael Hofman reported the results of the TheraP randomized clinical trial (RCT). They randomized some well-selected patients to receive either Lu-177-PSMA-617 or Jevtana. Patients were selected according to the following criteria;

• mCRPC (PSA≥20 ng/ml and rising)
• must have had docetaxel
• must have had either Zytiga or Xtandi or both
• healthy, with good liver, kidney, and blood function

In addition, all patients received both an FDG PET scan and a PSMA PET scan. They were excluded from the trial if either:

• Their metastases were insufficiently PSMA-avid - (10% excluded)
• There were many metastases that showed up on FDG but not on PSMA PET scans (as described here) - (18% excluded)
• 85 patients were treated with Jevtana
• 98 patients were treated with Lu-177-PSMA-617

The endpoint used was the percent of patients whose PSA declined by at least 50% (PSA50) from baseline after the treatment. After a median follow-up of 13 months:

• Lu-177-PSMA-617 had a PSA50 of 66% vs 37% for Jevtana
• The percent who had PSA progression was 31% less in those getting Lu-177-PSMA-617 relative to those getting Jevtana
• At 12 months, progression-free survival was 19% for Lu-177-PSMA-617 vs 3% for Jevtana
• Pain improvement was better for Lu-177-PSMA-617 (60%) than Jevtana (43%)
• It is too early for data on overall survival (see below for update)
• Serious/life-threatening adverse events occurred in 33% of those taking Lu-177-PSMA-617 vs. 53% of those taking Jevtana
• The most common adverse events reported by those taking Lu-177-PSMA-617 were fatigue, pain, nausea, dry mouth/eyes, low platelets, and anemia. Only 1 patient discontinued for toxicity.
• The most common adverse events reported by those taking Jevtana were fatigue, pain, diarrhea, nausea, loss of taste, neuropathy, dry mouth, and neutropenia, 3 patients discontinued for toxicity

(update 12/23) With longer term follow-up, it became apparent that although Lu-177-PSMA-617 was quicker to reduce PSA, there was no survival difference. After a follow-up of 36 months:

• Overall survival was 19.1 months for those starting with Jevtana vs 19.6 months for those starting with Lu-177-PSMA-617 (not statistically different)

This study further highlights the importance of getting both an FDG and a PSMA  PET scan at about the same time. (update 10/17/22) SUVmean>10 was a good biomarker for predicting whether Lu-177-PSMA-617 will succeed. High FDG PET predicted poor treatment response.

PSMA expression is highly variable. It is not expressed in low-grade cancer in the prostate. Expression increases as metastases develop, reach a peak, and then decreases. PSMA expression also increases when second-line hormonals are first used, but then decreases with continued use. Given this variation over time and treatment, several questions about PSMA-targeted therapy remain unanswered:

• Should it be used soon after second-line hormonals?
• Should it be used before or soon after docetaxel? (see this link)
• Would the problem of heterogeneity be minimized if Jevtana and Lu-177-PSMA were given simultaneously?
• Should it be used in minimally metastatic patients?
• Should it be used in newly diagnosed metastatic patients?
• Should it be used with immunotherapies (e.g., Provenge, Checkpoint inhibitors)?
• Will PARP inhibitors enhance the cell-kill rate?
• Is PSA the best biomarker of effectiveness?
• What are the best radionuclides to use (e.g., Ac-225, Th-227)?
• What are the best/most specific ligands to use? (e.g., PSMA-617, PSMA-I&T)
• Are there better surface proteins to target, perhaps simultaneously (e.g., FAPI)
• How do they compare to PSMA BiTE therapies?
• How does it compare to Xofigo for bone metastases?

Why Lutetium-177-PSMA treatment sometimes may not help, and may even harm

(updated)

Lu-177-PSMA usually improves survival

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

Among the tumor samples from the 60 men with mCRPC they found:

• 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

Analysis of DNA-repair defects revealed:

• 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.

(update 2/24/23) Sayar et al. report the results of a PSMA autopsy study.

• 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
  

HDAC inhibitors are available off-label and include: Valproic Acid (Depakote), Zolinza (vorinostat), Beleotaq (belinostat), Faridak (panobinostat), and Buphenyl (phenylbutyrate).

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)

(update 12/2020) Michalski et al. looked at 54 patients. Some had at least one tumor that was positive on FDG, but negative on PSMA (FDG+/ PSMA-). They compared outcomes to patients that had only PSMA+ tumors. They found:

• 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

(update 2/16/22) A secondary analysis of the TheraP trial of Jevtana vs LuPSMA looked at patient response depending on whether their cancer showed up also on FDG PET scans. They looked at the percent of men whose PSA reduced by 50% or more (PSA50) in the cohort that received cabazitaxel vs the cohort that received Lu177PSMA. Each cohort was analyzed according to whether they were highly avid on a PSMA PET scan (SUVmean≥10) "high PSMA" and whether their metabolic tumor volume on an FDG scan was greater than 200ml (MTV≥200) "high FDG". They required high PSMA (SUVmax≥20), and excluded men who were FDG+ and PSMA-.

• 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

It is unknown whether the survival of untreated patients might be longer or shorter had they received treatment. It is possible that discordant patients may benefit from sequenced (before or after) or concomitant treatment with:

• 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: 
1. Los Angeles, Europe & Australia (AMG 160) (early results)
2. AMG 160 + Xtandi/Zytiga + PD1i
3. City of Hope, LA AMG 509
4.  NY (REGN5678) -> trial ended for toxicity
5. Germany AMG 212 (CD3/CC1) (Phase 1 results)
6. various US sites (HPN 424) (early results) -> trial ended
7.  various sites in N. America (JNJ 63898081)
8. TNB-585 (5 US sites)
9. CB-307 (UK)
10. LAVA1207 (4 US sites)
11. 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

It is possible that such adjuvant treatment may decrease the population of discordant sites, and minimize repopulation effects.

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.

I-131-MIP-1095 has entered a phase 2 randomized clinical trial

As I reported last year, a new radiopharmaceutical has entered the pack. I-131-MIP-1095, a powerful beta-particle emitter attached to a PSMA-targeted ligand, will enter a multicenter phase 2 randomized clinical trial. Progenics®, the manufacturer, put out a press release, which can be read here. (Update 4/2020) The clinical trial has begun recruiting in 17 locations in the US and Canada.

They will be testing a combination of I-131-MIP-1095 with enzalutamide (Xtandi) in patients who are metastatic, castration resistant, have not yet had chemotherapy, and who have become resistant to Zytiga. It is hoped that Xtandi will radiosensitize the cancer to the radiopharmaceutical with a resultant PSA decrease.

175 evaluable patients will be recruited; half will get the radiopharmaceutical + Xtandi, half will get Xtandi alone. All patients will be screened using DCFPyL PET/CT to assure that their metastases are PSMA-avid. The primary endpoint - the percent who have greater than 50% PSA reduction - will be collected for a year. Secondary endpoints - radiographic response, progression-free survival, and overall survival - will be reported at the end of two years.

Another radiopharmaceutical in clinical trials is Lu-177-PSMA-617 .  There are various phase 1 and 2 clinical trials in the US and internationally (see list at the end of this link).

I recently reported about the very promising outcomes of Ac-225-PSMA-617 in Germany. Patients report that they are combining Ac-225-PSMA-617 and Lu-177-PSMA-617 to get the advantages of each. Weill Cornell in NYC is investigating Ac-225-J591 in a phase 1 trial.

For information on the trial of Th-227-PSMA, see this link.

Does Lu-177-PSMA-617 increase survival?

We have enthusiastically reported the encouraging outcomes of the early clinical trials of the radiopharmaceutical Lu-177-PSMA, most recently at this link. Based on reduction in PSA, it performs well. But medicines have no real benefit if all they do is treat PSA. We want medicines that 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)

The authors conclude:

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

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. There have been a couple of small trials of "third-line" medicines after docetaxel and abiraterone were used.

In a non-randomized trial among 24 mCRPC patients after treatment with docetaxel and abiraterone, overall survival was:

• 9 months with cabazitaxel

In a Danish study among 24 mCRPC patients after treatment with docetaxel and abiraterone, overall survival was:

• 5 months with enzalutamide

So these data suggest that Lu-177-PSMA-617 may have prolonged life more than third-line treatment with another taxane or another hormonal agent. However, we expect much cross-resistance between abiraterone and enzalutamide, and resistance building up with prolonged use of taxanes. It is always hazardous to compare patient outcomes or declare success when they have not been randomized. Certainly there is enough suggestive data to warrant a Phase 3 randomized clinical trial.

A new Lu-177-PSMA ligand has good results in a new study

Targeted nuclear medicine has shown some impressive outcomes in several small studies, mostly conducted in Germany. Most of the studies have used a radioactive beta-particle emitter, Lutetium 177, attached to a ligand that has high and specific affinity for prostate cancer cells. Most medicines developed for this purpose have a ligand that attaches to Prostate-Specific Membrane Antigen (PSMA), a protein found on 90% of all prostate cancer cells. The ligand for Lu-177-PSMA has to have a "grappling hook" on one end (called a chelator) that holds onto the Lu-177. On the other end is a "magnet" of sorts that binds tightly to the PSMA. The beta particles then kill the cell that the ligand attaches to and some nearby cells as well.

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)

(Update 11/2018) Heck et al. updated the above with information on 100 patients. They were heavily pre-treated with a median of 3 pre-treatments. In fact, they were required to have had Zytiga or Xtandi, and at least one cycle of taxane chemo. They were all mCRPC and 35% had visceral metastases. They may have had up to 6 cycles of Lu-177-PSMA-617 (average was 3.2 cycles).

• 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%)

A meta-analysis looked at the PSMA-I&T and PSMA-617 ligands in relation to the PSMA-J591 ligand. With a combined sample size of 369 patients across 10 studies, Calopedos et al. reported that:

• 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

Lu-177-PSMA-617: Another update

Because there is great interest in systemic therapies for metastatic prostate cancer, I want to provide readers with the latest news about the Lu-177-PSMA-617 trials in Germany.

I recently reported (see this link) on 74 patients – 31% had PSA declines greater than 50%. A new report by Rahbar et al. expands the patient base to include PSA data on 99 patients and toxicity data on 121 patients treated at 12 therapy centers.  After median follow-up of 16 weeks, and up to 4 therapy cycles:

·      45% had a PSA decline greater than 50%

o   40% after a single cycle

·      18/121 patients (15%) had serious or life-threatening hematotoxicity, affecting red blood cells (10%), platelets (4%), and white blood cells (3%)

·      Xerostomia (loss of saliva) occurred in 8%

This is a very encouraging PSA response. For comparison, only 13% had a PSA reduction greater than 50% in the Xofigo clinical trial. However in that trial, 66% had a 50%+ decline in bone alkaline phosphatase, which may be a better biomarker for bone metastases. The hematotoxicity was identical.

What we really want to know is whether the treatment increases survival, and whether it is any better than Xofigo in doing so. The potential benefit of Lu-177-PSMA-617 is that it can treat non-osseous metastases too. We await future clinical trials to prove its benefit.

Lu-177-PSMA Update

One of the more important emerging radiotherapies for metastatic castrate-resistant prostate cancer is Lu-177 that is chemically bonded to a ligand -- an antibody or a small molecule that attaches to the prostate-specific membrane antigen (PSMA). We’ll call this class of medications Lu-177-PSMA. PSMA is expressed on the surface of 95% of all metastatic prostate cancer cells. See this link for a fuller explanation. Many of the studies on Lu-177-PSMA have been conducted in Germany. Recently, there was a report on a small study from Bad Berka, Germany with some early encouraging results. There have been a few more trial reports since then.

All of the more recently published studies used a ligand called PSMA-617, a small molecule that attaches to PSMA, rather than a PSMA antibody. It was hoped that this ligand would be more specific to prostate cancer cells, with less affinity for salivary glands and kidneys where it can cause side effects and false positives.

Kratchowil et al. at the University of Heidelberg reported on 30 patients treated with one to three cycles of Lu-177-PSMA-617.

• ·      PSA decreased in 21/30 patients (70 percent).

o   PSA decreased by > 50% in 13/30 (43 percent)

o   Among 11 patients who had 3 cycles of therapy, 8 (73%) had PSA declines >50% that were sustained for over 24 weeks. Number and size of metastases decreased as well.

• ·      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.

Rahbar et al. at the University Hospital Münster reported on 74 patients treated with a single dose of Lu-177-PSMA-617.

• ·      PSA decreased in 47/74 patients (64 percent).

o   PSA decreased by > 50% in 23/74 patients (31%)

• ·      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

Rahbar et al. also report outcomes on 28 patients after one vs. two treatments.

• ·      PSA decreased in 59% of patients after 1 treatment and in 75 percent after 2 treatments.

o   PSA decreased by > 50% in 32 percent of patients after 1 treatment and in 50% after 2 treatments.

• ·      Median survival was 29 weeks, compared to 20 weeks based on historical expectations.
• ·      No clinically significant or lasting toxicity occurred.

Radiotherapy with Lu-177, though encouraging, is still in its early days. There is much work to be done in identifying the optimal ligand, optimal dose, optimal number of treatments, optimal patient/disease characteristics, and adjuvant therapies. I encourage participation in clinical trials in the US (NCT00859781) and in Germany.

Will Lu-177-anti-PSMA be the next Xofigo?

Xofigo 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%. Unlike external beam radiation, it can be used when there are many widely distributed metastases.

Several new studies looked at a potentially important new radiotherapy. Lutetium 177 is a low-energy beta particle emitter. In this case, low energy is a good thing because it limits the distance the beta particles (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 (radium 223 chloride) is an alpha particle emitter (a helium nucleus consisting of 2 protons and 2 neutrons). Alpha particles 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 beta particles are thousands of times smaller than alpha 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 mostly on the surface prostate cancer cells, at least 95% of them, 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 ability to potentially kill many more cells because of the increased range of the beta 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 gamma rays. The gamma rays are not powerful enough to kill tissue, but they can be detected by a 2D gamma 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.

	Xofigo (Ra-223 Chloride)	Lu-177-anti-PSMA
Emits:	Alpha particles (95%)	Beta particles, gamma rays
Half-life:	11.4 days	6.7 days
Attaches to:	Tissues that uptake calcium	Prostate cancer expressing the prostate specific membrane antigen (PSMA)
Destroys metastases in:	Bone only (areas of active calcium uptake)	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

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% having a reduction in PSA of over 30%, 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% 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%, a partial response in 48%, and a minimal response in 25%.

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 with biochemical progression after primary RP or RT and castrate-resistance, but who have no detectable distant metastases.

First in-human trial of Actinium-225-PSMA-617

Among the more interesting developments in radiation oncology/nuclear medicine in recent years are novel therapies created by attaching radioactive isotopes to molecules (called ligands) that attach to the prostate-specific membrane antigen (PSMA) that is found on the surface of most metastatic prostate cancer cells.

We have seen several small studies conducted throughout Germany using Lu-177-PSMA (see this link for latest update).  Lu-177 is a beta (β) particle emitter – its radioactivity is produced when a neutron decays into a proton and an energetic electron – a beta particle. Xofigo is an alpha (α) particle emitter – its radioactivity occurs when the radium 223 nucleus releases 2 protons and 2 neutrons – an alpha particle or helium nucleus. There are advantages and disadvantages to each (see table in this link).

Lu-177-PSMA was developed at the University of Heidelberg. Those researchers have developed a targeted therapy using an alpha emitter called actinium 225. Ac-225-PSMA-617 can potentially be used in some situations where Xofigo or Lu-177-PSMA cannot. Xofigo only treats bone metastases because radium is biologically similar to calcium and replaces it in areas of active bone growth, like metastases. Ac-225-PSMA-617 has several theoretical advantages:

• ·      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.

Kratochwil et al. report a proof-of-concept in two patients treated with Ac-225-PSMA-617. They used Ga-68-PSMA-11, which shows up on a PET scan, to detect metastases that were positive for PSMA and to detect response to the alpha- emitter. The two patients selected had progressed under other treatments and were in “highly challenging clinical situations,” which included tumor infiltration into the red bone marrow. After bi-monthly treatments, both patients:

• ·      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)

This is a first-in-human trial, and larger trials will be needed to prove efficacy and safety. However, it is an early encouraging development worth taking note of.