PYLARIFY PSMA-PET Imaging:  Targeting Tiny Bits of Cancer

Maybe you’ve been diagnosed with high-risk prostate cancer.   Maybe you have already been treated for prostate cancer, but your PSA is starting to creep back up, which means that the treatment didn’t get all of the cancer – but maybe it’s just right there in the prostate area, easily targetable with radiation.  Or maybe it’s just in one lymph node, or it’s in a transition state called oligometastasis: not widespread, but in just a few isolated spots outside the prostate.  In other words, maybe the cancer can still be cured – if you can just find it.

This is a problem nobody wants, but the good news is that there’s never been a better time to have it:  because now your doctor has a way to see exactly where the cancer is. 

It’s called PSMA-PET imaging, and it works kind of like a heat-seeking missile.  A radioactive tracer that lights up in a PET scan is molecularly engineered to find one very specific target:  PSMA (prostate-specific membrane antigen), a protein that lives in high concentrations on the surface of most prostate cancer cells.  Because the tracer is injected systemically, it can shine a virtual spotlight on whatever it tags – even tiny bits of prostate cancer as small as a grain of rice – anywhere in the body.  Several of these tracers have been studied, and one, called 68Ga-PSMA-11was recently FDA-approved for limited use at two hospitals in California: USLA and UCSF.  Another agent called ¹⁸F-DCFPyL (PyL, trade name  PYLARIFY®), developed at Johns Hopkins by a team led by Martin G. Pomper, M.D., Ph.D., Director of Nuclear Medicine and Molecular Imaging, is the latest to receive FDA approval and will be more widely available.

Pyl has proven itself in two important clinical trials:  CONDOR, published in Clinical Cancer Research, and OSPREY; published in the Journal of Urology.  In the OSPREY trial, PyL PET/CT was tested in two groups of patients: men just diagnosed with high-risk, locally advanced prostate cancer who were set to undergo radical prostatectomy with pelvic lymphadenectomy, and men with metastatic or recurrent cancer.  In the first group, the ability of PyL to detect metastases in the pelvic lymph nodes or beyond was determined, and in the second group, PyL was used to detect distant metastases.

In the CONDOR study, men with a rising PSA after treatment for prostate cancer with surgery, radiation, or cryotherapy, who had no visible cancer on standard imaging were scanned with PyL PET/CT, which accomplished what researchers hoped it would: “PyL successfully localized sites of disease in 85 percent of men with biochemical recurrence,” says Pomper, “even men with low PSA levels.  It detected disease in most men with biochemical recurrence presenting with negative or equivocal conventional (bone scan plus CT) imaging, and led to changes in management in the majority of patients.”

For many doctors and patients, this new FDA approval of PyL can’t come soon enough, says Pomper.  “I’ve had patients for years asking me when we are going to be able to use this.  It’s proven very difficult, and taken a long time, but we are finally there.”

In 1996, Pomper was the first to figure out how to engineer a small-molecule, harmless radioactive tracer to PSMA, and his team went on to test the first PSMA-targeted PET agent in a clinical trial.  This he refined into PyL, a more sensitive and specific second-generation agent that provides sharper images.  “With standard imaging (bone scans and CT), we may suspect there is cancer outside the prostate area, but we often just can’t see it in its earliest stages.  Standard imaging is not good enough for detecting and characterizing disease in men with biochemically recurrent prostate cancer, particularly in men with a low PSA (less than 2).  But 95 percent of prostate cancer has PSMA.”  And as Johns Hopkins radiation oncologist Phuoc Tran, M.D., Ph.D., and others are showing in clinical trials of oligometastasis, very small, isolated bits of prostate cancer are now being considered treatable – and possibly curable – targets.  

How is PyL different from ⁶⁸Ga-PSMA-11?  Both are very good.  PyL may provide clearer images, but the main difference is that ⁶⁸Ga-PSMA-11 requires special equipment to make, has a short half-life, and must made in small batches on site in the hospital.  ¹⁸F-DCFPyL has a longer half-life, and can be made in a factory and shipped to any medical center able to perform PET imaging, so it will be widely available.  Although this is a radioactive compound, it is well-tolerated, says Pomper.  “It has no pharmacological effect, it’s given in trace doses.  It just binds to PSMA and goes away; it doesn’t do anything else to your body.”

PSMA-Targeting Can Kill Cancer, Too!

But wait!  This is not all that PSMA-targeting can do!  Think of molecular LEGOS:  Instead of attaching the tracer molecule that can “see” prostate cancer, a different chemical brick can be attached that can kill cancer.  In Europe and Australia, and in international clinical trials, PSMA-targeting radionuclides, such as ¹⁷⁷Lu-PSMA-617, are being used to target and kill cancer in just those tiny outposts, leaving nearby cells undamaged.  This is killing prostate cancer cells at the level of hand-to-hand combat, and it is a bright spot on the horizon as a treatment option for men with metastatic prostate cancer. 

What about the cancer cells that don’t make PSMA?  This, too, is on the horizon, but Pomper is developing new molecules and therapies to target “PSMA-invisible” forms of prostate cancer.  “It took a long time, but now we’re seeing many exciting offshoots of our work in other forms of cancer, as well.  Some pretty amazing things are happening.”

In addition to the book, I have written about this story and 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