PSMA-Targeting Radionuclides:  Serious Side Effects, and Navigating a Safe Course

This new form of treatment for metastatic prostate cancer is being used in Europe, Australia and elsewhere, and being tested in clinical trials in the U.S.  As part of my series on PSMA-targeting, here’s more of the story:

With the dramatic results in some men, why aren’t radionuclides a done deal here in the U.S?  Because – just like the use of magic in fairy tales – they come with a price.

Neil Bander, M.D., Director of Urological Oncology Research at Weill Cornell and a pioneer in the study of PSMA (prostate-specific membrane antigen), developed an antibody that targets this molecule that sits on the surface of prostate cancer cells.  He later characterized PSMA, and found many reasons why it is an excellent way to target prostate cancer.  The alpha particle radioligands (using the small molecule delivery system) target the salivary glands, where a small amount of PSMA is made.  Beta particles such as Lu177, used in the Novartis compound, generally cause only minor salivary gland toxicity, Bander says.  But “since alpha particles are at least 1,000 times more potent than beta particles, when you put the alpha particle on the ligand, it targets the salivary glands and the tear glands, and they get destroyed.”

Now, you might be thinking, losing my salivary glands is a small price to pay for really knocking back and maybe even curing my prostate cancer.  But Bander would suggest that you think very carefully about this.  “When you destroy the salivary glands, the result is absence of saliva, inability to taste, difficulty swallowing, and tooth decay and loss.  Affected patients report that it’s a pretty miserable existence.  So that has proven to be a major impediment to using the small ligands to target the alpha particles.  Despite some amazing responses with the alpha particle, “it can be intolerable for the patient.”

So:  Is there any way to protect the salivary gland?  As it turns out, there is.  “While the small molecule ligand targets the salivary glands and lachrymal glands, antibodies do not,” says Bander.  “Antibodies are much larger molecules than the ligands.”  With the small ligands, the radioisotope “can easily pass through normal tissue barriers.  But when we deliver the radioisotope by use of the antibody, we see no targeting of the salivary or lachrymal glands.”

In fact, “we recently completed a trial at Weill Cornell using our J591 antibody to target the alpha particle, Ac225.  Based on an interim analysis, we have seen minor salivary gland toxicity in six of 27 patients, five of whom previously had been treated with the small ligand.  We found that the antibody-targeted alpha particle was well tolerated and very effective against the prostate cancer, even in patients who previously had progressed after treatment with the ligand Lu177.”  This Phase 1 trial was funded by the Prostate Cancer Foundation.

Another key difference between the antibody and ligand: “The ligand is excreted from the body through the kidney and bladder,” says Bander, and there is a risk of kidney toxicity.  “It has not yet been a significant problem, although there have been a few reports of kidney toxicity from the ligand with an alpha particle on it, and it may take a while to develop.  With the antibody, the path of excretion is through the liver, so the kidney is less likely to be subject to damage from the alpha particle.  The liver is pretty resistant to radiation.”

So… no to the ligands, then?  Not so fast, says Bander.  “Here at Cornell, we have data that suggests the best way to target prostate cancer is actually using a dual-targeted combination of the antibody and the ligand.  Our data show that with the combination, we can deliver a substantially higher dose to the tumor without increasing side effects.”  That’s because these agents each behave differently in the body.  “Dual targeting also allows us to use both the beta and the alpha emitters simultaneously, and our research shows this combination of alpha and beta isotopes to be very complementary.  Ultimately, the dual-targeting approach, with both antibody and small ligand, provides a substantial increase in the dose to the tumor without additive toxicity.  At Cornell, we are beginning to treat mCRPC patients with the ligand-Lu177 plus the antibody-Ac225.  Our laboratory data and our understanding of the biology of how these agents interact suggest a substantial benefit to this dual targeting/dual isotope approach.  The ability to substantially increase the dose to the tumor offers, I think, significant potential benefit for improved survival.”

This is what Bander envisioned 30 years ago, when he first began investigating PSMA.  And, he says, “it’s going to get a lot better.”   At the 2019 ASCO international oncology meeting, a session on PSMA “filled a 4,000-seat auditorium.  I was joking that a few years ago, we could have had that meeting in my hotel room and there would have been room for housekeeping!  It’s just like somebody flipped a switch.  Leveraging the ability to target PSMA for imaging and treatment is in the process of dramatically changing everything about how we approach prostate cancer – how patients are diagnosed, how they’re monitored, and how they’re treated.  If serial PSMA imaging can be shown to reflect tumor response, it has the potential to be used in the development of all prostate cancer drugs going forward to provide rapid insight into drug efficacy.  That will make new drug development in this disease much more rapid and efficient.  It’s a game-changer.  I’m confident that the best is yet to come.”

Note: If you are seeing this as a solo story, click here for more.

In addition to the book, I have written much more about prostate cancer on the Prostate Cancer Foundation’s website, pcf.org. The stories I’ve written are under the categories, “Understanding Prostate Cancer,” and “For Patients.”  As Patrick Walsh and I have said for years in our books, Knowledge is power: Saving your life may start with you going to the doctor, and knowing the right questions to ask. I hope all men will put prostate cancer on their radar. Get a baseline PSA blood test in your early 40s, and if you are of African descent, or if cancer and/or prostate cancer runs in your family, you need to be screened regularly for the disease. Many doctors don’t do this, so it’s up to you to ask for it.

 ©Janet Farrar Worthington