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.