Lutetium-177 linked to PSMA: an update


One of the more important emerging forms of radiotherapy for metastatic castrate-resistant prostate cancer (mCRPC) is the radioactive element lutetium-177 (177Lu) 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 [177Lu]PSMA.

PSMA is expressed on the surface of 95 percent of all metastatic prostate cancer cells; see this link for a fuller explanation. Many of the studies on [177Lu]PSMA have been conducted in Germany. Recently, we reported 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 [177Lu]PSMA-617.

  • PSA decreased in 21/30 patients (70 percent).
    • PSA decreased by > 50 percent in 13/30 patients (43 percent)
    • 8/11 patients (73 percent) who had three cycles of therapy had PSA declines >50 percent that were sustained for over 24 weeks; the number and size of their 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 (again in Germany) reported on 74 patients treated with a single dose of [177Lu]PSMA-617.

  • PSA decreased in 47/74 patients (64 percent).
    • PSA decreased by > 50 percent in 23/74 patients (31 percent)
  • PSA was stable (−50 percent to +25 percent) in 35/74 patients (47 percent)
  • PSA increased by > 25 percent in 17/74 patients (23 percent)
  • 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 percent of patients after one treatment and in 75 percent after two treatments.
    • PSA decreased by > 50 percent in 32 percent of patients after one treatment and in 50 percent after two treatments.
  • Median survival was 29 weeks, compared to 20 weeks based on historical expectations.
  • No clinically significant or lasting toxicity occurred.

Radiotherapy with 177Lu, 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. We encourage participation in clinical trials in the US (see NCT00859781) and in Germany.

Editorial note: This commentary was written for The “New” Prostate Cancer InfoLink by Allen Edel.

10 Responses

  1. And in Australia at Peter MacCallum Cancer Centre, Melbourne (click here).

  2. Paul beat me to it … there is at least one active study recruiting in Australia as he mentions; we have a couple of guys who attend The Reluctant Brotherhood advanced support group who are enrolled. PSMA is also being tested as a marker for recurrence.

    Albert Chang at UCSF is very eager to put a US trial together. One study evaluating the combination of gallium and PSMA for identifying high-risk prostate cancer and recurrence is already recruiting.

    The issue I have with the studies above is that Alan only reports PSA was used as a benchmark for success or failure. I am wondering if bone scans were also observed, since PSA may not be the best marker in advanced prostate cancer.

  3. Paul,

    Thanks for the link. I noticed that they are only including patients refractory to both hormones and chemo, but I’m glad they are investigating it.

    Rick,

    To be clear, Lu-177-PSMA is “theranostic;” that is, it is mainly used as a therapeutic agent but also for diagnosis. For diagnostic purposes, it emits gamma-rays that can be detected. Sometimes they combine it with an indicator like Ga-68-PSMA, a positron emitter, to get a stronger reading on a PET scan. PSMA is a cancer cell surface protein, and researchers are looking for various ways to use it diagnostically and therapeutically. There are many diagnostic trials of Ga-68 and other positron-emitters attached to entities that attach to PSMA (and other cancer proteins) for PET detection, but those trials are not looking at therapeutic entities. Some labs have designed viruses or toxic nanoparticles that can attach to it. In addition to Lu-177, Ac-225 (an alpha-emitter) is also being explored therapeutically, but only in Germany, as far as I’m aware.

    These are small studies with limited follow-up. I think PSA declines are a very good surrogate endpoint in such patients, which is why it is often used in pilot tests like this — PSA never declines by over 50% on its own in mCRPC patients. I’m sure they all had imaging as well. As mentioned above, the Heidelberg study reported that the number and size of metastases were reduced. The second of the two studies from University Hospital Münster reported survival data, which is probably the best endpoint.

  4. A promising therapy. Hope to see it fast-tracked here in the U.S.

  5. Iodine-131 is used to mop up residual cells following thyroidectomy for papillary cancer of the thyroid. Are there any trials on the use of lutetium PSMA for high-risk prostate cancer following robotic prostatectomy?

  6. Not that I am aware of — yet!

  7. I am from Germany. A friend of mine was diagnosed with a PSA value over 100 ng/ml and I recommended him to have a PSMA PET/CT done. It turned out that he had metastases in pelvic lymph nodes, lymph nodes outside the pelvic area, and a few bone metastases. Let alone the prostate.

    He started with ADT but nobody offered a therapy beyond that which could convince him. He is a maverick and learned about the Lu-177 PSMA treatment and asked the team that did his PSMA PET/CT if they could do that for him. They offered a special price and he got two injections so far –- as the primary treatment!

    The Lu-177 PSMA treatment reduced his metastases in size and some vanished from the next PSMA PET/CT completely. However, it becomes obvious that this will not cure him of his cancer completely. It cannot remove the prostate cancer from the prostate and does not work all that well for bone metastases. Also he has problems to find doctors to discuss the next steps in his treatment since this is a situation they are completely unfamiliar with.

    I recommend to treat his prostate now one way or another and then destroy the remaining metastases with SBRT. Repeating SBRT if needed as done in the Decaestecker/Berkovic studies.

    He will end up with no visible prostate cancer and as a result of that with a very low PSA value. So he will be completely restaged and I think he will have a very low risk to die from prostate cancer then.

    Maybe this is the future treatment for high-risk prostate cancer.

  8. Dear Georg:

    The treatment you are suggesting for your friend might be able to place him in long-term, remission, but I feel the need to tell you that it is highly unlikely to cure his cancer.

    If I was your friend I would be asking the doctors about something like the following:

    (a) Androgen deprivation therapy
    (b) Radiation therapy of the primary tumor in the prostate (perhaps using just SBRT, but perhaps using a combination of IMRT + brachytherapy)
    (c) Additional radiation of any known metastases to bone and the lymph nodes
    (d) Additional docetaxel-based chemotherapy

    If he is to have any serious hope of 10-year progression-free survival, he is going to need some type of very aggressive treatment above and beyond the Lu-177.

  9. Dear Sitemaster,

    I just recommended to make a scan with a Ga68 PSMA PET/CT. He came up with the Lu-177 therapy. He had been seeing famous doctors in Germany before that. They told him there were no data on using the Lu-177 therapy that early so they could not recommend that. On the other hand they could not tell him why he should not use it and added: “It should work“.

    Let me comment on the steps you outlined:

    (a) He is currently having ADT and is adding Lu-177 to it. This will end in a few weeks time after his third shot. If I look at the NCCN guidelines they specify “Any M1“ should be treated with ADT only. He will continue with ADT during the following steps too.

    (b) Planning a prostate treatment requires to know the outcome of the Lu-177 treatment; e.g., having surgery, including extended LND, is not required if the affected lymph nodes are already destroyed by the Lu-177 therapy. Whether you can use SBRT depends on how much prostate cancer remains in the prostate after the Lu-177 therapy.

    (c) Once the prostate is treated it is planned to treat the remaining metastases with SBRT.

    (d) Docetaxel may be used depending on the resulting PSA level after having done steps (a) to (c). Yes, there are studies now which recommend to use it early on. But maybe you can use Lu-177 instead to improve the prognosis.

    The PSMA therapy does work well, the first cycle is usually the most effective one. Here are some images cited from Prof. Haberkorn of the Heidelberg cancer center (using iodine-131):

    Lymph nodes treated
    Bone metastases nodes treated

    Georg

  10. Dear Georg:

    No one is arguing about the potential value of Lu-177. The problem, as your friend was advised, is that we have no idea how effective Lu-177 will be in a situation like his, and the only way to find out will be to give him no further treatment other than the ADT and the targeted SBRT. If I was wearing your friend’s shoes, I would want to take additional action. Exactly what would need to be carefully explored.

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: