Promising new data on lutetium-177 PSMA radioligand therapy


According to a presentation given last week in San Francisco, lutetium-177 (177Lu) prostate-specific membrane antigen (PSMA) radioligand therapy has significant clinical activity in men with metastatic prostate cancer (as opposed to just in men with very late stages of prostate cancer).

The presentation was given by a group of German investigators (Kulkarni et al.) at the annual meeting of the Society for Nuclear Medicine and Molecular Imaging (SNMMI): click here to see the abstract and here to see an associated media release.

The data appear to come not from a randomized clinical trial, but rather from a large series of patients with metastatic prostate cancer who were re-staged using gallium-68 (68Ga)-PSMA positron emission tomography/computed tomography (PET/CT) after their initial diagnosis and then treated with 177Lu-PSMA radioligand therapy (PRLT). The basic findings from the study are as follows:

  • The database comprised 214 patients.
  • 70 percent of the patients exhibited a reduction in their PSA level.
  • 54 percent of the patients exhibited a reduction in their PSA level of > 50 percent.
  • Average (median) overall survival in all 214 patients was 27 months.
  • First-line PRLT was associated with the longest survival (with all 18 patients so treated alive at 55 months of follow-up).
  • Patients previously treated with chemotherapy had a median overall survival 19 months.
  • Median overall survival was also shorter (17 months) in patients previously treated with radium-223.
  • Prior surgical or radiation treatment of the primary tumor had no significant effect on overall survival.
  • Patients who had a PSA reduction of > 50 percent after at least two cycles of PRLT had a median overall survival of 38 months.
  • Additional treatment with abiraterone acetate or enzalutamide in combination with 177Lu PRLT also prolonged survival.

While we are still going to need to see data from randomized clinical trials to confirm data from this series of patients, these data do seem to imply the potential of 177Lu PRLT in the treatment of men with:

  • Metastatic, hormone-sensitive prostate cancer (mHSPC) — potentially including micrometastatic HSPC
  • Non-metastatic, castration-resistant prostate cancer (nmCRPC)
  • Metastatic, castration-resistant prostate cancer (mCRPC)

A set of three 68Ga-PSMA PET/CT scans issued in association with the above-mentioned media release show a case of persistent remission in a 62-year-old patient who had no evidence of disease at 8 and 17 months after his initial 177Lu PRLT. Prior to this treatment, the patient had mCRPC with a PSA level of > 350 ng/ml after treatment with LHRH analogs and bicalutamide but was chemotherapy naive. Clearly this is an exceptionally good response and so we should not expect responses like this with all patients.

A so-called “image of the year” — also issued in a media release from the SNMMI — shows 68Ga-PSMA PET/CT scan data before and at 3 months after treatment with 177Lu PSMA617 for a set of eight exceptional responders to this therapy at the Peter MacCallum Cancer Centre in Melbourne, Australia. These eight patients had all “exhausted standard therapeutic options” and had PSA reductions of > 98 percent post-treatment with 177Lu PSMA617. Again, we should not expect responses like this with all patients. (A particularly dramatic 3D version of this image can be seen here on the UroToday web site.)

10 Responses

  1. How much was due to Lu-177 and how much to associated therapies with enza and abi, and other combinations? I understand for men with these conditions using combinations and rapid sequences could accelerate a response without identifying which element was decisive. 206 of the 512 had no previous ADT thus newly diagnosed, I assume. Those men have a panoply of treatments available. It is confusing to me what Lu-177 offers men.

  2. Dear John:

    We won’t really know that until we have data from well-designed clinical trials, but it is clear that Lu-177 can act as a “rescue therapy” for at least some men who have progressed after all sorts of other forms of treatment.

  3. John C:

    Correction: 206 of the 224 treated men had previous ADT — only 18 were previously untreated. The question had been — how early in cancer progression does PSMA appear? So far, it seems that it is a characteristic of prostate cancer metastases. But just how early does it show up in metastases? That’s what this study helps answer. Those who were treated earlier, had a better response.

  4. Hi Alan,

    I think it is the long-term toxicity data which are going to of most value from this cohort that have survived beyond 4-5 years.

    Theoretically there is a small increase in the risk of a secondary cancer from the radiation exposure. The bone marrow effects seem to be confined to patients with bone metastasis or previous chemotherapy. The long-term renal effects will be decisive as all the dose has to pass through the kidney. There is no doubt that the treatment works and, given the short penetration of beta particles, intuitively small volume disease would be the best target group.

    I am hoping that studies combining lutetium PSMA combined with PARP inhibition in early-stage metastatic disease will be conducted. It may be curative for those not suitable for salvage pelvic radiation.

    Cheers,

    John Whittle

  5. Dear Sitemaster,

    Lu-177 is not a “rescue therapy”. There appears to be little comprehension in the prostate cancer community of how this works.

    I had the great fortune to spend time some 18 months ago with one of Peter Mac’s lead researchers. I was micrometastatic with a PSADT of 10 weeks and my question was simply “Could Lu-177 suppress prostate cancer in this state”.

    The response was that the result would be very limited and a poor investment, the phrase “avoid medically induced poverty” was used.

    The whys are interesting and I had an hour’s crash course in nuclear medicine as it applies to prostate cancer. My takeaway as a layman is as follows,

    1. As Lu-177 decays it emits beta energy particles,
    2. These are short range which limits damage to healthy tissue.

    There remains an undetermined risk of radiation-induced issues from multiple doses. Quote: “You may not thank us if you have leukemia in 5 years”. I can only infer that is why ethics approval of most trials at the time only went to use of late stage patients.

    3. To kill a cell you need two distinct energy hits on its DNA strand.
    4. You cannot predict the vector of the emitted beta energy.
    5. So in low-density/volume metastatic scenarios, the cell kill rate is poor as little energy intersects the DNA strands.
    6. In high-density tumors, say with a SUVmax of 200, the results can be outstanding as those Peter Mac images show. More a calculated outcome than exceptional, to my understanding..

    And that takes me to my annoyance with this study. PSA is is only an analogue and not the key to understanding the first-line PRLT results (or any other). One needs data on the SUVmax readings from the scans, that is the 68Ga avidity, stratified by percentage of detected locations.

    If anyone has access to the full paper can you please indicate is this is referenced?

  6. Dear Peter M:

    (1) With respect, I did not state that 177Lu “is” a “rescue therapy”. What I wrote, very carefully, is that ‘Lu-177 can act as a “rescue therapy” for at least some men’. And I am very well aware of how this and similar development-stage agents “work”.

    (2) We do not yet know how this and similar drugs can best be used in clinical practice. That may well depend on the exact form of ligand that is being used to deliver the 177Lu to specific tumor sites, the precise dose of radiation delivered to a tumor at a specific site over a specific time frame; and a whole bunch of other issues (inclusive of the size, density, and site of the tumor, and the aggressiveness of the subtype of prostate cancer being treated).

    (3) There is certainly a risk for secondary cancers with any drug of this type — just as there is from any form of radiation therapy. As yet, however, we don’t know how big that risk is. We just know that there is one.

    (4) None of this will be resolved without well-structured, randomized, controlled trials in well-defined groups of patients.

    (5) There is no “full paper”. These are data presented at a conference a few days ago. It may be a year or so before they are formally published. If you want more information, you could contact the senior author of the paper, Richard Baum, in a week or so, when he will probably be back in Germany. His e-mail address is richard.baum@zentralklinik.de.

    I have no idea why you are “annoyed” by this study. For all we know they tracked all sorts of things that aren’t reported in the abstract or the associated media release, and I have no idea whether this group of German researchers were using the same PSMA ligand as the PSMA617 ligand being used by the team at Peter Mac, which could be critical to how these drugs are used and how effective and safe they may be in particular subsets of patients.

  7. Prostate cancer cells express PSMA even when the cancer is just within the prostate and there are no metastases. You can see the cancer in the prostate using a PSMA PET/CT.

    This trial tries to determine if a bone scan plus a CT scan can be replaced by a PSMA PET/CT scan.

    They have (apparently) already enrolled 200 patients in this study.

    George

  8. George:

    There are certainly metastases that grow within the prostate as the cancer progresses. But to my knowledge, PSMA has never been demonstrated in non-metastatic tissue, such as in men with low-risk or even intermediate-risk, localized prostate cancer. It seems to be characteristic of metastatic progression.

  9. The PSMA PET/CT or /MRI depends on the PSMA expression of prostate cancer cells. These cells express PSMA in the primary tumor, i.e. confined to the gland before surgery, as well as in metastases.

    Here are quotes from studies which tested PSMA PET/CT results for prostate tumor within the gland prior to surgery citing a sentence from each:

    — “Conversely, 68Ga-PSMA PET/CT enabled tumor visualization in the prostate. In 92.9% of patients, the intraprostatic tumor foci were correctly predicted“ (see Budaus et al., 2016).

    — “Conclusion: 68Ga-PSMA PET/CT accurately detected the location and extent of primary prostate cancer“ (see Fendler et al., 2016).

    — “All intraprostatic PCA lesions on PET could be confirmed histopathologically“ (see Woythal et al., 2017).

    — “The GS and PSA level correlated with the intensity of tracer accumulation in the primary tumours of PC patients on 68Ga-PSMA-11 PET/CT“ (see Uprimny et al., 2017).
     
    George

  10. George:

    The Budhaus reference you cited was for high-risk cases only, where there is a high potential for mets to develop in the prostate.

    The Uprimny reference, says,”Tumours with GS of 6, 7a (3 + 4) and 7b (4 + 3) showed significantly lower 68Ga-PSMA-11 uptake … compared to patients with GS >7. PC patients with PSA ≥ 10.0 ng/ml exhibited significantly higher uptake than those with PSA levels < 10.0 ng/ml.” This again indicates that PSMA does not show up on prostate cancer cells until significant progression has occurred.

    Fendler actually makes the case against use of PSMA-PET in cases where there are no metastases because the negative predictive value was only 42%. This means the PSMA PET could not show when there was no PSMA-avid cancer in the prostate, as is the case before metastatic progression has occurred. The Woythal reference only makes the rather obvious case that uptake of the PET indicator is highly correlated to PSMA expression in immunohistochemical staining, and is irrelevant to this discussion.

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out /  Change )

Google+ photo

You are commenting using your Google+ account. Log Out /  Change )

Twitter picture

You are commenting using your Twitter account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

w

Connecting to %s

This site uses Akismet to reduce spam. Learn how your comment data is processed.

%d bloggers like this: