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PSMA-Targeting Radionuclides:  Dramatic Success

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:

As we have discussed here, 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.  Results from work by Bander and others generated worldwide interest – particularly in Germany.

Bander made an antibody that targets PSMA, and linked it to a radioisotope called lutetium 177 (Lu 177), a beta emitter.  With colleagues at Weill Cornell and “with a nod from the FDA,” in 2000, Bander began a series of prospectively designed clinical trials that showed “excellent targeting of metastatic prostate cancers wherever the disease was located in the body.  These treatments resulted in PSA d eclines and improvement of pain.”  At the time, however, he notes, the pharmaceutical industry was not interested in radioactive drugs, and the prostate cancer field was more focused on the development of Taxotere chemotherapy.

In Germany around 2013, physicians began using different agents that bind to PSMA: small molecules, called ligands, instead of antibodies.  Some of these had been developed in the U.S. by John Babich, Ph.D., (now at Weill-Cornell), and Martin Pomper, M.D., Ph.D., of Johns Hopkins.  The Germans tested Lu177 as well as a different radioisotope, actinium 225 (Ac225), “which is an alpha emitter,” says Bander.  “Ac225 is several thousand times more potent than Lu 177,” which, again, is a beta-emitting particle.  (I have to be honest here, I don’t fully understand alpha vs. beta particles, but this article might help those who are motivated understand more.)

In Germany, a “compassionate use” program is often used to allow the use of new, previously untested therapies in patients who don’t have much other hope.  This means that, for a patient with a serious illness who has no other medical options and who agrees to take the risk, doctors can try promising – but unproven – treatments outside of a formally designed clinical trial.  “So in Germany, they were able to give these radiolabeled ligands (small-molecule radionuclides) to patients on an ad hoc basis, not as part of a formally designed and specified treatment protocol.  A number of centers in Germany started to make their own radiolabeled ligands.  They started treating patients and started publishing the results, sometimes on just one or two patients, sometimes on small groups, sometimes on large retrospective series of patients,” in various nuclear medicine journals.

“The other thing they did,” Bander continues, “was, they would only treat patients whose cancers showed up well on PSMA-PET scans.  They selected their patients, which helped them achieve high response rates.”  Notably, a report of two patients treated with a PSMA-Ac225 ligand showed spectacular results.  “To say they were dramatic would be an understatement.  These two patients had already had their cancer progress despite treatment of every kind of therapy then available for prostate cancer.   Everyone was blown away by those two cases.”  The “before and after” images showed that widely metastatic cancer had melted away from the pelvis, ribs, spine, liver and brain.  PSAs that were in the hundreds in one man, and thousands in the other, became undetectable.

Those ligands became readily available in Germany, Austria, Australia, India, South Africa, and “other countries that have more liberal regulatory policies than the U.S.,” Bander says.  “It was just an onslaught of publications, all showing excellent results.  That’s what really flipped the switch and got Big Pharma interested; among them, Novartis and Bayer.”

At the June 2021 meeting of the American Society of Clinical Oncology (ASCO), results from the Phase 3 trial of LuPSMA (Lu177), run by Novartis, confirmed a significant delay in tumor progression and improved survival in men with metastatic castrate-resistant prostate cancer.

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

 

 

 

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Backstory: The Road to PSMA-Targeting Radionuclides

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:

Neil Bander, M.D., Director of Urological Oncology Research at Weill Cornell and a pioneer in the study of PSMA, saw the potential of targeting PSMA, a molecule that sits on the surface of prostate cancer cells, soon after it was discovered more than 30 years ago.  His research shed light on why PSMA was such a promising target, and in 2000 his team began clinical trials with J591, a PSMA-targeting antibody he made.

“We were interested in two different approaches,” Bander says.  “One was putting a radioactive isotope on the antibody” – a molecular grenade of cancer-killing radiation – “and the other was putting a drug on the antibody.”  This “antibody-drug conjugate” approach was very new; fewer than a handful of drugs were available to attach to antibodies, “and all of them were owned by drug companies.  We didn’t have ready access to those,” so instead, Bander’s team focused on linking a “radioactive payload” to the antibody.

 The other benefit of using a radioactive isotope as a weapon:  it could be seen on imaging!  “Because of the radioactivity, we could see where this antibody-isotope was actually going,” says Bander.

Think of an old movie, where as a B-52 plane travels, it’s superimposed on a map, and an arrow connects Point A – California, let’s say – to Point B – Guam on our plane’s journey – and all points in between.  Bander didn’t have an arrow, but he could plot the progress of the radioactive isotope just the same.  “We could see immediately that the antibody was going right to the tumor cells.  Wherever we saw tumor sites – on the patient’s bone scan, CT scan, or MRI – we could see those sites lighting up after we gave the radioactive antibody.  So right from day one, we knew we were hitting the target!  We knew we were actually delivering the radioactivity to the tumor sites.”

But Bander and colleagues noticed something odd:  the radioactive isotope was also going to other sites where there was no apparent cancer.  They soon realized what was happening:  the PSMA-targeting isotope was finding cancer that was too small to show up on conventional imaging!  “We knew very early on that this could potentially be a very potent imaging modality.”

The Phase One trials were for men with metastatic castrate-resistant prostate cancer (CRPC).  These were men whose cancer had progressed despite all the standard treatments of the day.  In about 10 to 20 percent of participants, “we did not see their tumors light up.”  Is this because their tumors somehow don’t make PSMA?  Bander doesn’t think so.  (Note: Martin Pomper of Johns Hopkins does, and is working on ways to target those non-PSMA-making cells.)  “If you remove prostate cancer, say in surgery or biopsy, and do a test to see if there’s PSMA – and this has been done in many thousands of patients – almost 95 percent are PSMA-positive.”  Nonetheless, in some men, the PSMA-targeting agent does not show up much on imaging.  “In our studies, we found about 15 percent did not image, and another 5 to 10 percent imaged weakly, but we treated all those patients anyway.  We found that if you are PSMA-negative or PSMA-weak, you are significantly less likely to have a good response to the treatment.”  However:  “If your imaging study lit up like a neon sign, you had a very high likelihood of responding.  It was a pretty clear distinction.”

Bander’s group tested two different isotopes and found that lutetium 177 (Lu 177) was the most effective.  “Responses varied, from no response to PSA stabilization to 95-percent decreases in PSA levels that could last many months,” says Bander.  “We also saw that as we increased the dose, the responses got better.”  Other centers reported success in some animal tumor models with breaking up the dose of radiation.  “Instead of giving just one big dose, if you split it up into two or more smaller doses, you could deliver an even higher cumulative dose.  So we did a phase 1 study of fractionated J591-Lu 177, gave higher doses and got better and more durable responses.”

This was 2007.  Why hasn’t this become mainstream therapy?  One big reason:  the pharmaceutical industry is like a freight train.  Once it gets going on a particular track, it picks up steam and generates huge momentum.  Until that happens, however, momentum can be very slow.  Twenty years ago, Bander says, “pharmaceutical companies had no interest in radiopharmaceuticals.”  Instead, their model was for literal shelf life: drugs put into a tablet or capsule and shipped to sit either at a pharmacy or in a patient’s medicine cabinet.  “Making drugs from living cells was a whole new area,” but the industry has evolved to “this greater willingness to make very complicated products.”

PSMA-targeting radioisotopes have reached a crucial tipping point, says Bander.  “When we characterized PSMA – its specificity for prostate cancer, the fact that 95 percent of prostate cancers were PSMA-positive, that cancer internalizes the PSMA-targeting antibody, that it’s upregulated by hormonal therapy, and that it’s a potential target in other types of tumors – interest started to build.  Then when we showed that if we administered a PSMA-targeting agent, we could actually validate in a patient that it was reaching the cancer, it increased even more.”

A big kick in the pants to the world of PSMA-targeting treatment came from striking results achieved overseas, discussed here.

Note: This is one of a series of stories I’ve just written on PSMA-targeting.  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

 

 

 

 

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Killing Metastatic Prostate Cancer with PSMA-Targeting Radionuclides

There’s some bright hope on the horizon for men with metastatic prostate cancer:  it’s PSMA-targeting therapy. This is different from PSMA-targeted imaging, which shows where small bits of prostate cancer are hiding in the body.  But it uses the very same building blocks.  Think of molecular LEGOS:  Instead of attaching the tracer molecule that can “see” prostate cancer, a different isotope (chemical brick), called a radionuclide, can be attached: one that can kill cancer.

PSMA stands for prostate-specific membrane antigen (PSMA), a protein that sits on the surface of 95 percent of prostate cancer cells.  Briefly, to recap the PSMA story so far, we have talked about how PSMA-targeting came to be, covered the first PSMA-imaging agent to get limited FDA approval, and the second imaging agent, which will be used more widely.  Now it’s time to talk about radionuclides.

“With the same chemical scaffold serving as both a diagnostic and therapeutic agent, the field of ‘theranostics’ has recently gained traction,” Martin G. Pomper, M.D, Ph.D., Director of Nuclear Medicine and Molecular Imaging at Johns Hopkins, told me in a recent interview.  Pomper’s team developed the small molecule PSMA tracer that is now the FDA-approved agent, PYLARIFY.  “Recent advances have really lit this form of treatment on fire.”

In Europe and Australia, and in international clinical trials, PSMA-targeting radionuclides such as 177Lu-PSMA-617 (called lutetium-177-PSMA-617, or LuPSMA), are being used to kill metastatic prostate cancer.  “In Australia, 177Lu-PSMA-617  proved superior to cabazitaxel in terms of PSA response and lack of significant adverse effects when compared head-to-head in the TheraP trial,” says Pomper.  “We are working with Novartis on a similar agent, called 177Lu-PSMA-R2, which has even fewer side effects, including lack of uptake in salivary and lachrymal glands.  We are hoping that agents using this molecular scaffold will be able to be outfitted with a variety of even more potent radionuclides than 177Lu.  It is anticipated that 177Lu-PSMA-617 will be FDA-approved at the end of this calendar year.”

In the international Phase 3 VISION trial, reported in June 2021, 831 men with PSMA-positive cancer (cancer that shows up on PSMA-PET) were randomly assigned either to receive LuPSMA plus standard of care, or standard of care alone.  Men who received LuPSMA were about 40 percent less likely to die and 60 percent less likely to have disease progression on scans, compared to the men who received standard of care alone.  After 21 months, cancer progression was delayed for longer: 8.7 months vs. 3.4 months among controls, and men in the LuPSMA group had better median overall survival: 15.3 months compared to 11.3 months in the control group.  Side effects of LuPSMA included fatigue, bone marrow suppression, dry mouth, and nausea/vomiting.

Note:  The TheraP trial compared LuPSMA to chemotherapy (cabazitaxel), but the VISION study did not include chemotherapy, immunotherapy, or other therapies that oncologists would otherwise try.  Oncologists will tell you that  any one therapy may not ever become the magic weapon for beating metastatic prostate cancer – but along with other weapons, PSMA-targeting radionuclides will be part of a pretty impressive arsenal.  Also, as LuPSMA and similar agents get FDA approval, you can bet that doctors will start giving them to patients at earlier stages, when cancer is more vulnerable and easier to kill, and that’s going to boost survival, too.

You might also be wondering about the cancer cells that don’t make PSMA.  New methods of treating them are on the horizon, too.  Pomper is developing new molecules and therapies to target “PSMA-invisible” forms of prostate cancer.  “We are working on agents that work through different mechanisms and can complement the PSMA-targeted agents,” he says.  “I believe that combining theranostics with immunotherapy, PARP inhibitors and other emerging agents – in addition to further optimization of dosage, dose rate and type of isotope of the PSMA-targeting agents – will be able to stave off progression of the disease for years, and that these patients will eventually succumb to ailments other than their prostate cancer.”  In other words, that one day, maybe not too far away, these new forms of therapy will allow men to die with, and not of, prostate cancer.

There are even wider implications, too:  “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.”

We’re not done here.  I’ve got a lot more on PSMA-targeting therapy.  I want to put it in context, and also break it up into reasonably-sized chunks.  So bear with me: I’m doing this as a series, but to get it to you ASAP, I will post it all at once. 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

 

 

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Matters of Prostate Cancer Survivorship

Who’s a survivor?  You are, if you are trying to get your life back after a diagnosis of prostate cancer.

 

            Survivor.  What does that word bring to mind?  (Besides, of course, the name of the rock band whose song, “Eye of the Tiger,” went double-platinum in 1982 and was the theme of “Rocky III.”)

            There are more prostate cancer survivors now than ever before.  More men are being cured of localized disease, and more men are living longer with advanced cancer than ever before.  This is great news!  It also means that, as men live longer after treatment for prostate cancer, they have new things to deal with – which brings us to the evolving area of cancer survivorship.

             Survivorship is basically the day-to-day effort to live your best life during or after treatment for localized cancer, or between and in the midst of treatments for more complicated disease.  It’s such a big part of cancer treatment now, in fact, that medical centers are devoting significant resources to it.  One of them is Dana Farber, where medical oncologist Alicia Morgans, M.D., will soon become the new Medical Director of Cancer Survivorship.

The criteria for survivorship used to be a lot more strict, she notes.  “The old-fashioned definition would say that patients living with cancer are not survivors” – that a true survivor could only be someone whose cancer has been cured.  That has changed.  “Now, anybody living after a diagnosis of cancer is a survivor and deserves to have the best quality of life possible.”

Good news: for many men recovering from treatment or living with prostate cancer, help is available.  But it may be up to you to ask for it, if your doctor doesn’t address it specifically.

Note:  Here is where your spouse, partner, family or friends can help.  Those who love you may be aware of some things that you might not have noticed, and their insights can help your doctor take better care of you – if you say it’s okay for them to talk about it.

“Men are stoic, and may not feel comfortable admitting a weakness or vulnerability, or they may not have the words to describe what they’re going through,” says Morgans.  “Or, they may not perceive a problem, but their caregivers or loved ones may.  Raising their concerns – with the permission of the patient – to the doctor can be very helpful.”  This is especially true, she adds, in cases where the patient is experiencing “psychological distress, depression, anxiety, and may not recognize it.  Sometimes the caregiver can say, ‘You don’t realize it, but you’ve had a really short temper.’ Or, ‘You may not recognize it, but you’re sleeping all day, and you’re not eating.’Or, ‘Your cancer is controlled, but your behavior is very different, and you seem really down.’  We may not perceive these changes as being different or outside our norm, but if they’re empowered to speak (with your permission!), your caregiver or family members can really help reflect back to us more accurately what’s happening with you.”

While visiting the doctor, phone a friend!  If it’s not possible for a family member to be there at the appointment, no problem!  “We can often call or conference a loved one in,” with Zoom, FaceTime, or through the medical center.  There are also “electronic ways,” Morgans adds, for loved ones to communicate with the doctor.  You can write an email to the doctor, using the patient’s portal – or even your own.  “In many systems, caregivers can have an account that’s connected to the patient.  I have many patients whose spouse has an adjacent account.  Others just use the patient’s account.”

Be sure to identify yourself, that this is the patient’s daughter, spouse, or friend.  “Don’t represent yourself as the patient if you’re not the patient.”  This does happen, Morgans says.  “Sometimes wives will get on there as the patient, and you know it’s the wife: women tend to talk a lot more than men!  I’ll see a long description, and write back, ‘Is this John’s wife?’”  The information is still appreciated, she adds.

“If there’s something they think the doctor needs to know, and if they’re empowered by the patient to speak to us, the caregiver or spouse can intervene in a meaningful way.”

Sexual Health

Sexual health is “one of the most underrecognized issues” for prostate cancer patients and their partners.  One big reason why is that men just don’t want to talk about it, either because they keep hoping it will get better, or they just decide to be stoic and carry on.  “Even though we have a roadmap for how to address these issues after surgery or radiation, we often lack the support system,” says Morgans.  “There are way too few sexual health counselors specifically dedicated to helping men recovering from prostate cancer.”  And yet: “This is an area of high interest to many patients.  Sexual health affects their personal experience, their mood, energy, everything they do.”  It also affects the health of their partners.

Although this is the issue many men wish would just go away, what they need to do is just the opposite of hoping for the best:  be proactive.  If you had surgery and you haven’t already had this discussion with your urologist, find out what you can do for penile rehabilitation.  This may include pills such as Viagra, Cialis, or other PDE5 inhibitors; vacuum devices for stretching the penis to protect against scar tissue formation; in-office or at-home treatment with a small TENS unit to stimulate nerve regeneration and help with return of urinary control; penile injection; or a penile implant.

Don’t suffer in silence!  Don’t listen to anyone, yourself included, who thinks, “Your cancer has been cured. Just be happy with that.”  There are many steps you can take to recover your sexual health – but they won’t happen if you don’t ask for help.

Intimacy: This is not the same as sexual health, but men on ADT and their partners still need intimacy.  If your oncologist or medical center does not provide counseling in this area, ask for a referral to a sexual health counselor, and keep this in mind: you are not alone, whether you’re the patient or his partner.  There are thousands of couples dealing with this issue, as well.  Your doctor also may be able to recommend support groups, online and affiliated with local medical centers.

Fighting Back on ADT

ADT will try to affect your overall health, but here’s the good news:  you can fight back, Morgans.  Arm yourself with what it might do, and you will be better able to protect yourself against its tactics.  So here, in no particular order, are some of the things ADT might affect, and countermeasures you can take:

Bone health:  Prostate cancer can affect your bones, and so can ADT, in different ways.  Treating prostate cancer in the bones not only protects them, it can improve survival!  ADT raises your risk of osteoporosis – but not only is this treatable, it’s not a “done deal” that every man on ADT will develop it!  “Avoiding fractures is so important,” says Morgans.  “Men who have fragility fractures (due to osteoporosis) can lose their mobility and independence, and can have some major changes in their lives until those fractures are repaired.  If we simply follow the guidelines we already have on how to care for bone and prevent osteoporosis, we can improve those outcomes pretty dramatically.

“A lot of the complications associated with ADT are absolutely things that we can address head on, try to prevent and to reverse; for instance, we have effective therapies to counteract bone thinning and lower the risk of fracture and complications from weak bones.  Many of the known side effects of ADT are not necessarily inevitable.”

Your risk of cardiovascular disease:  Here’s some good news:  A new drug, Orgovyx (relugolix), was approved in December 2020 by the FDA for men with advanced prostate cancer, based on results of the Phase 3 HERO study.  It lowers testosterone, but it works in a different way.  It’s also administered differently – a once-daily pill instead of a shot – and it has a significantly lower risk of major adverse cardiovascular events compared to Lupron (leuprolide).  If you have cardiovascular risk factors, such as high blood pressure, high cholesterol, a family history of cardiovascular disease, diabetes or pre-diabetes, if you’re overweight or if you smoke: heart disease needs to be on your radar, because ADT can make it worse. “Multiple studies have shown that men who have cardiovascular risk factors, particularly if they are not addressed, have higher rates of complications and even death on ADT,” says Morgans.  But treating these risk factors with diet, exercise, and medication if needed, can “improve overall survival and also quality of life.  When your body is healthier, you feel better.”

Note:  For just about every category on this list, exercise is one of the answers.  Men on ADT who exercise lower their risk of having cardiovascular and cognitive effects, developing insulin resistance, diabetes or pre-diabetes, obesity, and high blood pressure.  “All of these are modifiable risk factors,” says Morgans.

Depression:  “Depression is highly treatable,” says Morgans.  “This is important, because evidence suggests that men treated with ADT do have higher rates of depression than men who have prostate cancer but are not receiving ADT.”  But depression is underdiagnosed and undertreated in men on ADT, she adds, “perhaps because of reticence to ask for help, or a perceived stigma with mental illness,” or perhaps because it has crept up, and the patient hasn’t recognized that there’s a problem.  This is where friends, family and caregivers can help.  Depression can affect sleep, appetite, and memory, as well.

Cognitive changes:  ADT can cause cognitive decline and dementia.  However, this is more complicated than it sounds, Morgans notes.  For one thing, symptoms of depression can be mistaken for cognitive decline, and can improve with antidepressants and exercise.  For another, there are multiple forms of dementia, including vascular dementia.  “If that risk is increased because of ADT, then a medicine that reduces the risk of major adverse vascular events could feasibly lower the risk of dementia, as well,” although this remains to be proven in large-scale studies. In general, “what’s good for the heart is good for the brain,” and taking steps to improve your cardiovascular health will help protect your cognitive function, too.  “We also have strategies and mental tricks to help improve memory, and even medicines that may slow the progress of Alzheimer’s.”  The key is to tell your doctor, and get further evaluation and help if needed.  “The choice of therapies may help, as well,” Morgans notes. “In multiple ongoing studies, some really interesting MRI data suggests that there may be differences in some distribution of blood flow in the brain” between androgen-targeted medicines, “including one study with darolutamide that has just launched.”

Hot flashes:  “At its basic level, ADT is lowering testosterone, which keeps men’s bodies functioning in a way they’re used to,” says Morgans.  “Just as we see when women go through menopause, there are widespread changes.  The constellation of symptoms is much broader than just the effects of ADT on the prostate cancer cells themselves.”

Among the most annoying and persistent – and undertreated – are hot flashes, which “can affect mood, sleep, and cognition,” says Morgans.  A novel approach on the horizon is a “wearable,” she adds.  It’s like an Apple watch, and can be linked to your phone.  The basic idea is to stimulate the autonomic nerves on the wrist, with a cool sensation.  “PCF is actively engaged in supporting work that can potentially improve quality of life and reduce hot flashes in men on ADT.  This is an area with much room for improvement, where attention is needed, and pharmacologic therapies aren’t as effective as we wish.”

For now, treatment with antidepressants may help; so can exercise.  Many men seek relief of symptoms with holistic treatments, including relaxation therapy, hypnosis, cognitive-behavioral therapy, and acupuncture.

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

 

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Envisioning What PSMA-Targeting Can Do

Imagine looking at a very young Ian McKellen, the knighted British actor, and thinking, “Half a century from now, if they ever film the Lord of the Rings trilogy, he could be the best Gandalf ever!”

That kind of vision is rare – but scientist Neil Bander, M.D., has it.  Nearly three decades ago, Bander, now Director of Urological Oncology Research at Weill Cornell, saw the potential of a newly discovered molecule called PSMA to be used in two ways:  for imaging and also for precisely targeted treatment of prostate cancer.  Over the last few years, both aspects of his vision have been coming true – in clinical trials and newly in practice in the U.S., and in practice in Europe, Australia, South Africa and elsewhere – for a growing number of men with prostate cancer.

You’re going to be hearing a lot more about PSMA, a protein that sits on the surface of 95 percent of prostate cancer cells, and about strategies for targeting it.  One of the most promising tactics involves an antibody developed by Bander and colleagues, and it is no exaggeration to say that without funding from the Prostate Cancer Foundation (PCF, which has invested $28 million into PSMA-targeting research over the last nearly 30 years), the antibody wouldn’t be nearly as far along as it is today.   Briefly, here’s how it came to be:

The late 1980s-early 1990s saw the dawn of monoclonal antibodies, lab-developed clones of B cells that make antibodies designed to zero in on one specific target, like molecular homing pigeons.  Scientists studying cancer were using this technology like gangbusters, “trying to find tumor-specific antigens on cancer cells that could be a way to distinguish cancer cells from normal cells at the molecular level,” says Bander.  (An antigen is a foreign substance, like a toxin, bacteria, or cancer; when the body detects it, the immune system makes a very specific antibody to identify and kill this intruder.)  The hope, if they could find a way to target just cancer, and not normal cells, was to develop more precise treatment – unlike systemic chemotherapy, which takes a toll on the rest of the body.

In 1987, a urologist named Gerald Murphy, who directed the Roswell Park Memorial Institute for cancer research and treatment – and who developed the original PSA test –made a monoclonal antibody, called 7E-11. “Not much happened with that antibody until 1993, when a group at Memorial Sloan Kettering Cancer Center, headed by Skip Heston, used Murphy’s antibody as a way to clone the gene for the antigen that was detected by the antibody,” says Bander.  “When they cloned the gene, their analysis indicated that it was very specific for prostate cancer.  They also found it was actually present in the cell membrane of prostate cancer cells,” and called it PSMA, for prostate-specific membrane antigen.

Soon afterward, Bander received PCF funding to develop antibodies that were specific to prostate cancer cells.  He studied 7E-11, and realized that “if you were looking to target PSMA, this antibody had a significant flaw:  it binds to a part of the PSMA protein that is inside the cell membrane, a site that antibodies can’t readily reach.  In fact, the 7E-11 antibody could only bind to dead prostate cancer cells.   But fortunately, PSMA spans the cell membrane; a short region of it is inside the cell, another region traverses the membrane, and the largest part of the molecule is outside the cell.  Because the antibody is administered through the bloodstream, he notes, “the only thing it sees is what’s on the outside of the cell.  We set out to make a series of antibodies to the part of the molecule that’s on the outside.  A few other groups, including Skip Heston’s group, also set out to do the same thing.  We happened to get there first.”

In 1997, Bander and colleagues published in Cancer Research their development of four antibodies, the first antibodies that could stick to the part of PSMA on the outside of the cell, and the first antibodies that could attach to living prostate cancer cells.  Their most promising antibody was called J591.  Over the next few years, “we did a pretty thorough analysis of these antibodies – where they bound on PSMA and how specific they were for prostate cancer cells vs. normal tissues.”  Then, “because our goal from the outset was to develop this into a therapeutic,” they “humanized” it, genetically re-engineering it from a mouse-derived antibody into a sequence that the human body would not see as a foreign protein.

Bander and colleagues also spent years “really trying to understand more about PSMA, how good a target it was.  They learned that PSMA was very highly overexpressed in cancer; that although normal prostate cells are PSMA-positive, prostate cancer cells are PSMA-loaded.  “We also found that as prostate cancer cells get more aggressive and are more likely to kill a patient, they have more and more PSMA on them.  The more dangerous the prostate cancer is, generally speaking, the more PSMA there is.”

And, they found, the amount of PSMA on the cell surface is affected by male hormones (androgens).  In fact, “when you put a patient on hormonal therapy (androgen deprivation therapy, ADT) you actually upregulate the amount of PSMA on the cell surface by five- to ten-fold.”  The result is “enormous amounts of PSMA sitting on the surface of prostate cancer cells.”  So in effect, ADT, the mainstay of treatment for advanced prostate cancer, makes the bullseye on the cancer cell bigger:  on a tiny scale, from the size of a golf ball to that of a three-foot-wide crater!

But wait!  There’s more!  Bander’s team looked at other types of cancers, and found that the blood supply in almost every other type of solid tumor was PSMA-positive!   For example, a kidney tumor itself does not make PSMA – but its blood supply sure does.  In fact, “the blood supply is pretty strongly PSMA-positive.  We were surprised by this,” but the finding was independently noted by the Heston group.  “We did not and still do not understand why that is the case, but this means a PSMA-targeted drug is potentially useful not just in prostate cancer, but in other types of cancer, where the approach could be to basically eliminate the blood supply to the tumor.  We’ve done some clinical trials to show that this is a real possibility.”

One more early finding, something “we didn’t anticipate,” says Bander:  “When you bind the antibody to PSMA on a living prostate cancer cell, that cell swallows the PSMA and whatever’s attached to it!”  Like a fish gulping a fat worm with a hook, the cancer cell takes in the PSMA antibody and the cancer-killing payload.  This discovery, he continues, “opened up the door to develop antibody drug conjugates: you put a very potent drug on the antibody, direct it specifically to the prostate cancer cells, and the prostate cancer cell swallows up the drug, whereas PSMA-negative cells don’t.  This was, in effect, a door opening to developing chemotherapeutic agents that are only taken up by the cancer cells.”

The door keeps opening wider.  “If you look at PubMed today,” says medical oncologist and molecular biologist Jonathan Simons, M.D., CEO of PCF, “there are now 3,707 research papers on PSMA discoveries.  That’s a paradigm-changing impact.”

Coming up soon: we’ve talked all around the subject of killing prostate cancer by targeting PSMA.  Now how, exactly, does that work?

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

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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

 

 

 

 

 

 

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High-Risk Localized Prostate Cancer:  Changing the Rules

A full-on assault of high-risk prostate cancer with intensive neoadjuvant hormonal therapy before surgery marks a huge shift in medical thinking.  Instead of doing things in a well-ordered sequence, oncologists like UCSD’s Rana McKay are launching many weapons earlier than ever, when cancer is less prepared for battle, and they’re going for a cure.

Why the No-Holds-Barred Approach Now?

Which scenario would you prefer:  “I’ve got high-risk prostate cancer.  I sure hope it doesn’t come back after surgery or radiation!  Fingers crossed!  My doctor and I are really hoping for the best!” or,

“I’ve got high-risk prostate cancer that has a chance of coming back after initial treatment.  So, my doctor is going after it relentlessly, like Inspector Javert hunting Jean Valjean in Les Mis.”

High-risk prostate cancer is formidable: it will spread if not treated and is more likely to recur after initial treatment.  That’s why doctors like Rana McKay, M.D., medical oncologist and PCF-funded Young Investigator at the University of California San Diego (UCSD) are now throwing the proverbial kitchen sink at high-risk prostate cancer as soon as it is diagnosed.

This marks a huge shift in medical thinking.  Advanced prostate cancer treatment in the past has been like a methodical series of “if: then” statements in math, like, “If A, then B,” or “C if and only if B.”  If cancer spreads beyond the prostate, then the traditional next step has been androgen deprivation therapy (ADT), shutting down testosterone and other male hormones that drive prostate cancer’s growth.  If the cancer becomes resistant to ADT, then other medications are added: chemotherapy and/or androgen receptor (AR)-targeting drugs (also called androgen-directed therapies, or AR-signaling inhibitors).

Over the last few years, doctors have been compressing this time frame, giving these AR-targeting drugs at the time that ADT is initiated – based on studies such as STAMPEDE, LATITUDE, suggesting that the cancer, which evolves and mutates as it spreads, is more vulnerable to treatment sooner rather than later.   Although these treatments can extend survival, they are not a cure.

What’s different about this new, full-on, kitchen-sink approach?  First, a high-intensity burst of hormonal suppression (ADT plus an androgen-directed drug, such as enzalutamide or abiraterone) is finite, given as neoadjuvant therapy for a few months before surgery and for up to a year afterward.  Then it’s over, and within a year, testosterone comes back.

Second:  “We are going for a cure,” says McKay.  This is worth repeating:  Going for a cure!

Early results of exciting clinical trials, with more on the way, are highly encouraging.  One Phase II trial still in progress, led at UCSD by McKay in collaboration with Mary-Ellen Taplin, M.D., of the Dana-Farber Cancer Institute, grew out of a 2014 PCF Challenge Award study, led by Taplin.  The investigators tested two combinations of drugs given for six months before surgery:  abiraterone and prednisone plus leuprolide (Lupron), vs. abiraterone and prednisone, Lupron, and apalutamide.  After surgery, “men were randomized to continue therapy for one year, or simply to be monitored.”  The initial results of this trial were presented at the American Society of Clinical Oncology meeting in 2020.

“We showed that about one out of five men who received intensive hormonal therapy up front demonstrated very residual amounts of tumor, or no tumor at all, in their prostatectomy specimen” when the surgically-removed tumor was thoroughly examined by a pathologist under the microscope.   This “pathologic response,” seen in the surgically removed tissue, “hasn’t yet been proven in prostate cancer to be associated with long-term outcome,” notes McKay.  “But in several other tumor types – breast, bladder, rectal cancer, and others – evidence demonstrates that the pathologic response is associated with overall survival.”  In follow-up data from this and two other neoadjuvant studies, recently published in the Journal of Urology, McKay and colleagues showed that “of those patients who had no tumor or very little tumor left behind in their prostate, the rate of recurrence (the average follow-up time so far is 3.6 years)  was significantly lower.  In our cohort of 117 patients, only two patients who had a pathologic response and minimally residual disease had a recurrence, and no man died of prostate cancer.  Our hope is that we will develop data to prove that a pathologic response is associated with long-term outcomes in prostate cancer.”

 In Some Responders at Prostatectomy, Cancer’s Already Dead!

Over time, prostate cancer acquires genomic alterations that help it to be more aggressive.  Each tiny mutation gives the cancer extra protection, maybe starting out with the genetic equivalent of a bullet-proof vest or stronger helmet, then becoming much more sophisticated – imagine a fighter jet deploying decoy flares or chaff as missile countermeasures.

Is it more vulnerable, and easier to kill, early on?  McKay and colleagues believe the answer is yes, and they’re testing this idea in several clinical trials.  One phase II study at UCSD still in progress, in collaboration with Taplin, involved 119 men with “unfavorable intermediate or high-risk disease.  “More than 90 percent of the patients had high-risk disease, and all of them, from the get-go, had very aggressive tumors,” says McKay.  “Over one-third of patients had Gleason 9 or 10 disease, and about 60 percent of patients had stage 3 cancer,” that had spread slightly beyond the prostate but with no evidence of distant metastases.  Men in the trial received either neoadjuvant abiraterone and prednisone plus leuprolide (Lupron), vs. abiraterone and prednisone, Lupron, and apalutamide.

One major reason why McKay and colleagues are testing this approach with surgery rather than radiation is to study the pathologic response: looking at how much residual tumor is present in the surgical specimen that has been removed after treatment.  Have they seen any changes?  Not in all men, but in about 20 percent, there’s a remarkable change:  “The primary tumor was dead and necrotic.”  The pathologists “looked at every little sliver of the prostate,” and found that these exceptional responders had either “less than 5 mm of tumor left behind, or no tumor left behind.”

Just think about that for a minute:  the surgeon removes the prostate, gives the tissue to the pathologist, who starts looking at it under the microscope and sees only corpses of cancer cells!

One patient who participated in this study is Pat Sheffler, who was diagnosed at age 53 with stage 3 prostate cancer and a PSA of 37.  He received abiraterone and prednisone, Lupron, and apalutamide for six months before prostatectomy, and started to see results right away.  In monthly blood tests before his surgery, his PSA levels dropped:  “34, 27, 21, 10, 4, 2, and 0.2.”  At surgery, he had “very minimal remaining tumor,” says McKay.  Then he underwent one more year of hormone therapy after surgery.  Two months after he stopped taking the trial medications, not only was his PSA undetectable, but his testosterone levels were coming back to normal.  “My hope for Pat is that he’s cured, that he can go on just being an amazing dad, husband, and advocate for prostate cancer awareness.”

In another phase II study led by Taplin, published in the Journal of Clinical Oncology, McKay and colleagues at UCSD, Dana-Farber, Beth Israel Deaconess Medical Center, Johns Hopkins, and the University of Washington reported a complete pathologic response (no remaining live cancer cells in the prostate) or minimal residual disease in 30 percent of patients treated with neoadjuvant enzalutamide, Lupron, abiraterone and prednisone before prostatectomy.

But what about the men who were not exceptional responders to big-gun hormone therapy?  The scientists have identified some key genetic changes in men who were non-responders, and they have some ideas about how to help these men, as well.

In several clinical trials, including this one, an intense blast of neoadjuvant androgen deprivation therapy (ADT) and androgen-directed treatment (drugs such as abiraterone and enzalutamide) has shown promising results in some men – but not all men.  Why is this?

McKay, Taplin, and colleagues have found an explanation:  Men who have not responded (who had a significant amount of tumor remaining after neoaduvant treatment) in these clinical trials have certain genetic differences in their prostate cancer – loss of PTEN (a tumor suppressor gene, which is knocked out in as many as 70 percent of men with prostate cancer) or alterations in ERG (an oncogene that fuses with another gene, called TMPRSS2, in as many as half of all men with prostate cancer).

“Very few of the men who responded had PTEN loss,” says McKay, “and ERG positivity was also associated with lack of response.”  But these men also seem to have something else that might render AR-blocking drugs unhelpful: lower AR expression, compared to other men.  Basically, if a tumor does not seem to have a lot of androgen receptor activity, then a medicine that targets these receptors won’t have much to work with.

This information is not discouraging, McKay hastens to add:  it’s helpful!  It has taught the scientists that “the responders have a certain tumor profile, and non-responders have a certain profile.  Similarly, responders had mutations in a gene called SPOP” (which is mutated in about 10 percent of primary prostate tumors).

Knowing this, McKay adds, could be an opportunity:  a springboard for additional or different therapy – perhaps neoadjuvant chemotherapy, for example.  Remember:  you’re still ahead of the game here.  You don’t have metastatic cancer, and many scientists believe that high-risk cancer, when it’s localized, is still vulnerable enough to be cured, if it’s hit hard with multiple weapons.

“This is an opportunity for us to develop and design a personalized treatment strategy for these men,” says McKay.  “It would be awesome if we could use somebody’s own genomics to help design the best treatment for him – similar to what’s being done in the breast cancer I-SPY trials, neoadjuvant studies with multiple treatment arms, some determined by biomarkers (specific genetic alterations that show up in a blood or tissue test).

Some men with high-risk prostate cancer might respond better to a PARP-inhibiting drug, such as olaparib and rucaparib.  This is the focus of another study that will be starting soon, McKay says.  “In men who have germline (inherited) alterations, such as a BRCA1 or BRCA2 mutation, we hypothesize that giving a PARP inhibitor in a neoadjvant setting before prostatectomy might significantly improve pathologic response.  We are finalizing the protocol for NEPTUNE, a biomarker-focused neoadjuvant trial testing PARP inhibitors in localized prostate cancer.”

“It is really exciting to be part of this paradigm shift,” says McKay.  “We have the opportunity to improve outcomes for men with high-risk localized disease, and we’re in the midst of trying to prove that through well-organized, thoughtful clinical trials.

“At the end of the day, the question is, how can we help our patients live longer and live better?  That’s really the big driver.  The good thing about localized disease is that we can try to cure more men of prostate cancer – not just extend life for metastatic disease, but can we develop a pathway so they don’t ever develop metastatic disease, and so they can be cured?  That’s what we’re aiming to do.”  And, bonus:  after the big blast of intense hormonal treatment, most men get their testosterone back.  “Most patients actually recovered their testosterone fully within the first year of discontinuation of treatment.”

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

 

 

 

 

 

 

 

 

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