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Driving Prostate Cancer “BATty”

BAT: The Opposite of Conventional Wisdom

Could the flat-out opposite of conventional wisdom prove to be effective against metastatic prostate cancer?

 Androgen deprivation therapy (ADT) has been the bedrock of treatment for advanced prostate cancer for more than half a century.  But investigators at Johns Hopkins are rethinking it – in a way that sounds counterintuitive – and driving new approaches to tackle treatment resistance.  They’re discovering that shaking up prostate cancer with high-dose testosterone makes it more vulnerable to other treatments. 

ADT slows prostate cancer’s progress by shutting off testosterone.  Eventually, however, cancer adapts to this new environment and PSA levels start to rise; this stage is called castrate-resistant prostate cancer (CRPC).  ADT is not a curative treatment, and long-term ADT causes significant side effects, including fatigue, hot flashes, weight gain, and loss of sexual function.

Several years ago, medical oncologist Samuel Denmeade, M.D., Co-Director of the Johns Hopkins Prostate Cancer Program, and colleagues came up with a remarkable concept for attacking prostate cancer: alternating ADT with high-dose testosterone.  I have interviewed Denmeade several times over the years for Johns Hopkins publications, and recently I was lucky enough to talk to him in-depth for the Prostate Cancer Foundation’s website.

“It had been known for a long time that something weird happens when you give testosterone to prostate cancer cells,” says Denmeade.  “With low doses you can get the cancer cells to grow,” which nobody wants.  “But plenty of reports said that paradoxically, at high doses the cancer cells don’t grow as well, or they die.  Even Charles Huggins, who won the Nobel Prize for discovering hormonal therapy, said in his Nobel acceptance speech (see below) that another way to kill cancer would be to give too much hormone.  I was always interested in that idea.”

About 10 years ago, Denmeade conducted a small study at Hopkins to test the concept of using testosterone against prostate cancer.  “At the time, it seemed like all the data and literature suggested that the dose was really important; it had to be a high dose.”  The hypothesis:  Prostate cancer cells adjust to a very low-testosterone environment (created by ADT) by making very high levels of the androgen receptor (AR).  And here, as he says, “too much of a bad thing can be a good thing.”  These high levels of the AR now make cancer vulnerable to very high levels of testosterone.  Cancer cells that survive this respond to high-dose testosterone by turning the AR back down – and making the cancer once again susceptible to very low testosterone.”

The idea is “to screw up the cancer cell’s ability to adapt.”  Denmeade and colleagues coined the term, Bipolar Androgen Therapy (BAT), “to capture these polar extremes of very high and very low.  Not just making the testosterone high, but cycling between high and low.”  It’s this cycling that seems to be the key to keeping the cancer off-balance, slowing its ability to flourish.  In BAT, men experience high testosterone levels that decrease over a 28-day period, then bounce back up with the next testosterone injection.

In that early study, of just a handful of patients, “we were very cautious, because we didn’t want to make the disease worse.  We built in all these safety parameters.  But we were surprised:  it didn’t seem we made anybody worse.  It seemed very safe.  The patients did very well, and some of them stayed on the testosterone for a year or more.  Most of them felt really good.  A number of them did not want to come off of it when it seemed they were progressing:  they were just so happy to have more energy, and some of them could have sex again.”

Armed with this initial clinical data to show that BAT was safe and to show some response, Denmeade received funding for additional proof-of-concept studies from PCF, among other sources. Larger studies at Johns Hopkins have followed, including RESTORE, TRANSFORMER, and COMBAT.  Other trials testing this concept have been completed or are under way at the University of Washington, University of Colorado, and in Australia, Brazil, and the Netherlands.

Next:  How BAT Works

“Certain cancers are hormone-dependent and these cells die when supporting hormones are eliminated.  Certain cancers succumb when large amounts of hormones are administered.”–Urologist Charles Huggins, M.D., whose discoveries led to hormonal therapy for cancer and earned him the 1966 Nobel Prize for Physiology and Medicine, shared jointly with virologist Peyton Rous.

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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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MRI’s Future Role in Prostate Cancer Treatment

Prostate MRI’s ability to show what’s happening in the prostate is already transforming how prostate biopsies are done.  Will it change treatment for prostate cancer, as well?

Radiologist Peter Choyke, M.D., believes it will.  He is Senior Investigator and Director of the National Cancer Institute’s Molecular Imaging Branch, and I recently interviewed him for the Prostate Cancer Foundation’s website.  He gave me some good examples of what MRI is already doing, and what’s on the horizon:

 Active surveillance:  “You can monitor patients on active surveillance with MRI,” says Choyke, but there’s a caveat:  “What you’ll typically see is not much change over two to three years.  But if you do biopsies over time, it’s not uncommon to see grade migrations, like Gleason 6 to Gleason 7, with no visible change on the MRI.”  Is that a significant change for the patient?  Does that mean that active surveillance has to stop and the man needs treatment right away?  “As far as I can see, there’s no right answer.  A lot of people are trying to substitute MRI for biopsies.  The danger there is that you will miss patients who are converting from Gleason 6 to 7.  Just because the MRI is unchanged doesn’t mean the histology (what’s happening within the cancer) is unchanged; that’s not a good assumption.”  Choyke suspects that MRI changes actually reflect growth of the tumor, “and are related to the number of cancer cells that are present – which is a really good index of how aggressive the tumor is.  If there are more cells, that’s a bad sign.  But if the cells are about the same in number, that’s not such a bad sign.”

One important role for MRI is before a man starts on active surveillance.  “You want an MRI to see what the extent of the disease is, to make sure you get a targeted biopsy of the lesion or lesions, and to make sure that you’re not putting someone on active surveillance who needs treatment instead.  By doing this, you get the patients who really should be on active surveillance, and can stay on it for much longer.”

 On the horizon:  Local treatment for prostate cancer:  MRI-guided treatments are being tested in clinical trials at the NIH and elsewhere.  The idea here is that MRI is getting so good, it may be able to provide a roadmap for treatment within the prostate.  Instead of removing or irradiating the entire gland, “we have a few protocols where we are trying to treat the lesions that we see on MRI.”  One approach is focal therapy, with MR-guided laser ablation “just to the lesion.”  If this works, there are some big advantages:  “We could significantly reduce the side effects from surgery and radiation,” says Choyke.  “We’re also very interested in, and are about to open enrollment for a trial of, local deposition of anti-androgen therapy – essentially putting androgen deprivation therapy (ADT) directly into the spot of cancer seen on the MRI – so the patient doesn’t have to undergo systemic ADT while receiving radiation therapy.”  Unlike, say, taking Bicalutimide by mouth, which affects the entire body, a micro-dose of Bicalutimide within the prostate tumor “only goes a certain distance before it’s washed away, and it’s in such a low concentration that the systemic effect is negligible.”   This will be tested in men with localized, intermediate-grade cancer, “where ADT is useful but not mandatory,” Choyke adds.  “There may come a time when this can be advanced to higher-grade tumors.”

Another trial in the works will test MR-targeted focal radiation.  “We’re very excited about this because with radiation, you can really do dose painting.  With a laser, you either kill or you don’t kill; you either burn it or you don’t burn it.  But with radiation, you can taper the dose around the edges of a tumor, where there’s a large expectation of cancer.  That’s good for the patient, because you’re not giving the same dose throughout and irradiating things that don’t need to be irradiated, like the rectum, urethra, or bladder base.”  This trial is “awaiting good planning software,” to help plot precisely where and how much the dose should be.

But much more testing is needed.  “First, do no harm.”  If it turns out that “we can treat the cancer successfully without a lot of side effects, that’s a good outcome.  All of that is enabled by the MRI providing the spatial information to direct these therapies.”

Artificial intelligence and MRI:  “We have a very good correlation between what’s on the MRI and the actual pathology of the radical prostatectomy specimen,” says Choyke.  “We have thousands of cases where we’ve compared the pathology to the MRI.  So now, with pretty good accuracy, we can predict the pathology from the MRI.”

But sometimes, MRI can’t see every bit of a tumor.  Sometimes normal tissue is interspersed with cancer, “at the resolution that MRI can’t detect; cancer is sort of hidden in all that normal tissue.”  Sometimes, tumors have stroma (noncancerous connective tissue cells), that masks the cancer cells.  And then there are some higher-grade tumors that simply don’t show up on MRI.  “In our studies, it’s 5 percent, but I’ve seen it as high as 15 percent of patients with intermediate or high-grade disease who have negative MRIs.  We’re looking to see whether artificial intelligence (AI) can pull out these lesions that the human eye can’t detect.”  No one knows why this is; under the microscope, “the pathology of those lesions doesn’t look that different.

“You’d think by now we would understand this very well,” but because the vast majority of tumors do show up on MRI, “it’s hard to accumulate enough cases to make bold statements about what’s going on.  We are continuing to look at it – so stand by for more information!”

This is part3 of 3 stories on MRI, MRI’s role in cancer screening, and MRI’s potential use in 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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MRI: No More “Hit-or-Miss” Biopsy!

Can MRI really make a difference in diagnosing prostate cancer?  Just ask Rob Gray.  It took nine years for his cancer to be diagnosed.  He felt like a human pincushion after going through numerous tests, exams, and five prostate biopsies – some of them saturation biopsies (each involving 20 or more needle samples!).  Doctors couldn’t find cancer, but they couldn’t rule it out, either.  The inconclusive “TRUS” (transrectal ultrasound) biopsies took their toll, as well: scar tissue developed in his prostate, making cancer even more difficult to detect with TRUS.   Rob is firmly convinced that, had it not been for an MRI-guided fusion biopsy, his cancer, which turned out to be Gleason 3 + 4, still might not have been found.  Today he is cancer-free.

Out with the “Hit-or-Miss” Biopsy!

With TRUS, unfortunately, Rob’s story is all too common, says radiologist Peter Choyke, M.D., Senior Investigator and Director of the National Cancer Institute’s Molecular Imaging Branch, and a pioneer in the rapidly evolving use of MRI to evaluate prostate cancer.  He is at the top of the MRI-prostate cancer field, and I was privileged to interview him recently for the Prostate Cancer Foundation’s website.

Why have so many men, like Rob, endured multiple inconclusive biopsies?  Choyke explains: “Let’s look at what until very recently was state of the art: 12 biopsies performed by the urologist under TRUS, six on one side and six on the other.  It really wasn’t targeted to anything in particular.”  The basic biopsy sampled the upper, mid and lower part of each side of the prostate (this, by the way, was an improvement over the old biopsies of 20 years ago, which took only six samples!).  Even with 12 samples, “there are a lot of opportunities to miss lesions.  And, because urologists don’t want to injure the urethra, which is in the center of the prostate, they tend to put the needles more towards the back of the gland, so the front part of the gland was relatively unsampled in a traditional TRUS biopsy.”

In other words, the traditional biopsy is largely hit or miss.  “Once we started doing MRIs,” says Choyke, “we realized that a lot of tumors are above where the needles usually went in; in fact, those lesions are more amenable to transperineal biopsy.  That was important in helping us detect the cancers in men who had multiple negative TRUS-guided biopsies.”

A targeted biopsy – done with TRUS, but using the MRI as a roadmap – can direct the needle to specific areas that look suspicious.  “Also, once you have the MRI, you realize how big the lesion is.  With TRUS, you just had a specimen that was positive.  You didn’t know if it came from a 3mm- or a 5 cm-sized lesion!  It was just ‘positive.’  Now with MRI, we have a much better feel: is this a big lesion, has it been there a long time, has it grown outside the prostate, possibly to the lymph nodes?  Are the seminal vesicles involved, is the bladder involved?  There’s a lot of anatomy that you can get from the MRI that you just don’t get from the biopsy information.  Was the needle in the center of the lesion, or the periphery – or did it biopsy something completely different than the main lesion?  Is this cancer caught very early, so it’s hard to see, or is it large and obvious?  That influences the discussion of treatment options, and allows the patient to make a much more informed decision.  With MRI, you’re way far ahead of the game.”

And this is why Choyke believes that “in the best of all possible worlds, every man with suspected prostate cancer would get an MRI.”  MRI is of even more benefit, he adds, as a man’s PSA rises.  “We did a study where we compared men with a PSA less than 5 with men with a PSA greater than 5.”  For men with a lower PSA, “the advantage of MRI was much smaller compared to a traditional TRUS biopsy.  But for those with PSA greater than 5, it was clearly superior to have an MRI.”

That said, there are some qualifiers:  Not every insurance policy pays for MRI, and good-quality MRI is not universally available.  The power of the MRI machine itself used to matter more, with 3 Tesla strength preferred.  But today, the major determinants are, “how old is the MRI unit, and is there a radiologist who is focused on prostate MRI, who has been to courses learning how to interpret it properly?  Or, is the radiologist a generalist without specific expertise?”  If you’re paying for part or all of the cost out-of-pocket, Choyke notes, “these scans are very expensive.  I don’t think it’s unreasonable to ask good questions.”

Another bonus to today’s prostate MRI:  With more sophisticated machines, very few men require the endorectal coil, a latex-covered probe, inserted in the rectum, that helped provide better-quality images of the prostate with earlier-generation equipment.  “We advocated for endorectal coils universally five years ago; but once we bought a new scanner, we now reserve coils for cases in which the patient’s already been treated and we’re looking for recurrent disease in the pelvis, which can be very subtle.”  With the recent approval of 18F DCFPyl PSMA-PET, which uses a highly specific molecular tracer to find prostate cancer cells anywhere in the body, “we’re using the coil less and less.  That’s associated with lower cost, better patient appreciation, and faster scans.  Nobody regrets to see the passing of the endorectal coil.”

This is part 1 of 3 stories on MRI, precision cancer screening, and MRI’s potential use in 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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Do You Need Prostate MRI?

Prostate MRI is on the upswing in cancer diagnosis.  Should it play a role in screening, too?  

Many men with suspected prostate cancer are getting MRI, because the information it provides is so good:  MRI can show the size and location of tumors and guide a personalized, targeted biopsy aimed at suspicious areas – instead of a best-guess biopsy that tries to sample tissue from each part of the prostate.

Traditionally, if a man’s doctor suspects he has prostate cancer, the next step has been a biopsy.  But that’s changing:  Today, ideally, the next step should be an MRI, says radiologist Peter Choyke, M.D., Senior Investigator and Director of the National Cancer Institute’s Molecular Imaging Branch.  And even more ideally, maybe MRI should be part of regular screening.  I recently interviewed Choyke for the Prostate Cancer Foundation’s website.

“Prostate cancer is not one disease: it’s a broad spectrum ranging from cancer that is slow-growing, indolent and probably will never bother the man, to cancer that is very aggressive, as bad as pancreatic cancer in its severity,” Choyke explains. “It’s important to pick out who has that really aggressive type, and who has the indolent type.”  In large, multicenter studies in the United Kingdom, prostate MRI is part of regular screening.  If the MRI is negative, “men go back in the screening pool and are monitored with regular PSA tests.  If the PSA goes up, they repeat the MRI,” and undergo biopsy only if anything suspicious shows up on the MRI.  “The virtue of this approach is that in the UK, almost one-third of men avoid biopsy, which is very significant.  If you don’t do the biopsy, you don’t detect incidental Gleason 6 disease,” which does not always require treatment. “But in the U.S., biopsies continue to be done even when the MRI is normal or equivocal.”

Do higher-risk men need MRI sooner than others?  Choyke is investigating this question in studies of targeted populations, including men with a family history of prostate cancer, men of African descent, and men identified with “genetic predispositions to prostate cancer,” he says.  “We’re doing a study now of men who come from families with known genetic abnormalities that predispose to cancer.”  Eligible for the study are men without prostate cancer, ages 30 to 70, who have tested positive for mutations in one or more of these genes:  BRCA1, BRCA2, HOXB13, ATM, NBN, TP53, MLH1, MSH2, MSH6, PMS2, EPCAM, CHEK2, PALB2, RAD51D, and FANCA.

Already, Choyke says, “We are finding cancers in younger men from those families.”  This is important:  Many family doctors don’t recommend prostate cancer screening until men are in their fifties.  Men at higher risk should start screening earlier, in their early forties.  Men with a family history of prostate cancer, or of other types of cancer (such as colon, breast, or ovarian) tend to develop prostate cancer at a younger age.  Some men can develop prostate cancer in their thirties and even younger.  MRI, Choyke hopes, may one day play a role in diagnosing higher-risk men sooner.  “It may be that if you have one of these predisposing genetic conditions, you would get an early MRI, way earlier than it’s now recommended and catch the disease at a curable state,” as part of a precision medicine approach to screening and diagnosis.

Also at higher risk of developing prostate cancer at an earlier age are men of African descent.  “African American men have a greater predisposition to prostate cancer, and are much more likely to die of it,” says Choyke.  “Many of these men live in medically underserved communities, so this is a population I would think well worth targeting for MRI.”

What if you want an MRI but your insurance won’t pay for it?  “We see this problem all the time,” says Choyke.  His advice:  get your urologist to help!  For many doctors in the U.S., trying to get past an insurance company gatekeeper is a daily occurrence – which means, you’re not the first person this has happened to.  Your doctor is used to it, and may be able to cut through the bureaucracy.  Here’s a battle plan suggested by Choyke:  “First, discuss the need for MRI with your urologist and make sure you’re on the same page.”  Then, if your urologist agrees that an MRI would be beneficial, team up:  “The patient and urologist working together have a better shot at convincing the insurance company than either alone.”

Another issue: prostate MRI is not available everywhere.  “MRI scanners are difficult enough to access, and centers with expertise in prostate MRI are even less common.”  You may need to travel to a bigger medical center in another city.  Even if you’re in a major city, this doesn’t guarantee easy access, Choyke adds:  “I know of patients and urologists in Washington, D.C., who can’t get MRIs.  We will be conducting a study with patients from underserved parts of Washington to determine if we can make earlier diagnoses and have better outcomes.  If we can show that patients in this community benefit – and I think they will! – then maybe those communities can argue for more resources based on data.  In contrast, in the UK, every patient gets an MRI, no questions asked, because of their more socialized system of medical care.”

This is part 2 of 3 stories on MRI, precision cancer screening, and MRI’s potential use in 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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PSMA-Targeted Treatment:  Why Side Effects Matter

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:

We have talked a lot about the amazing results in some men with metastatic prostate cancer of PSMA-targeting radionuclides, being used in Europe, Australia, and elsewhere, but still in clinical trials here in the U.S.  Now, I’m all for moving drugs right along, damn the torpedoes, and giving anyone who wants to take the risk a chance to beat a terrible disease.  But there’s a good reason that the U.S. is taking this cautiously:  because some of these PSMA-targeting treatments – not all – can harm the salivary glands and tear ducts.  When these treatments become FDA-approved in this country, I believe the side effects will not be so severe.  Scientists like Neil Bander and Martin Pomper are developing agents that have much milder side effects.

The whole time I’ve been writing about PSMA, I have been thinking of Nathan (I changed his name to protect his privacy), a remarkable, tough and courageous man I interviewed in 2018.  He is one of the pioneer patients of PSMA-targeting treatment.  I want to tell you his story now.

On a dark day in 2013, Nathan was diagnosed at age 57, with stage 4 prostate cancer that had spread to his lymph nodes, his spine and hip.   His cancer was very aggressive: Gleason 9.  The prognosis was grim, and Nathan had a choice to make:  do what his initial urologist suggested, start on androgen deprivation therapy (ADT), hope it works for a long time and wait until the cancer gets worse, or go into “high-gear mode.”  He chose option B.  “If I have an aggressive cancer, I want to deal with it aggressively.”

So, in addition to starting on ADT and an androgen receptor blocker, abiraterone (Zytiga), plus prednisone – a combination that is now FDA-approved, but was about five years ahead of its time in 2013 – Nathan underwent a radical prostatectomy.  The surgery did not cure him, but eliminating the primary tumor dealt the cancer a severe blow and bought him more time.  “The plan all along was, kick the can down the road until science can catch up,” he says.  He assembled a team of doctors who had the same philosophy.

Next, Nathan got radiation:  high-intensity radiation to the spots of cancer in his spine, followed by 40 radiation treatments over two months to his pelvis and prostate bed.  Despite a change to a different androgen receptor blocker, enzalutamide (Xtandi), his cancer picked up steam.   Soon, his PSA was doubling every three weeks.  A PET scan showed new metastases, including a big one in his elbow.  In 2016, Nathan learned about the PSMA-targeted radionuclide treatment being done in Heidelberg, Germany.  He talked to his oncologist, who expressed concern about the side effects.  Nathan decided to go to Heidelberg.

The most worrisome side effect of this treatment was damage to the salivary gland.  As it turns out, PSMA doesn’t quite live up to its name; it is not entirely “prostate-specific.”  This molecule normally exists in small amounts in the salivary glands and a few other places of the body.  The drugs that target the PSMA-containing cancer cells don’t know the difference, and they can kill or damage these normal cells, too; there is also a risk of kidney toxicity.  “The salivary gland problem happens right away,” Nathan says.  “But the treatment also works right away.  They give you an infusion and the cancer cells are dying within hours.”

Despite the risks and the unknowns, Nathan wanted to go ahead – sooner, rather than later.  “I knew they had done this treatment on no more than 30 to 40 patients.  But I also didn’t want to get to a point where I was going to be in bad shape,” before the cancer burden grew bigger and began causing pain, “and then get the treatment.”

Before he could undergo the treatment in Germany, Nathan had to have a PSMA-PET scan.  “My body lit up like a Christmas tree with PSMA-PET: it showed cancer in my ribs, sternum, manubrium, scapulas, upper extremities, femur, and numerous places on my spine.”

Nathan weighed the risks of side effects against the possibility of getting a true remission of his cancer.  The hope of remission won.

What’s it like?  The treatment itself is given by infusion and only takes 10 minutes – and in 10 minutes, prostate cancer cells throughout Nathan’s body started to die.  Before and after his treatment, he drank “tremendous amounts of electrolyte fluids,” to minimize the risk of kidney damage:  “The more you drink, the more you can flush out the radioactive materials.” Nathan was given ice packs to put around his neck to help protect the salivary glands.  He was supposed to use them for six hours; he kept icing his neck for 12 hours, and also drank as much water as he could.  “I think in those two days, I drank between 10 and 12 liters of electrolyte water.

“This treatment was only approved by the German government on a humanitarian basis,” he notes, “basically, to treat people in extensive pain, who were far along in the disease, and who didn’t have much time to live.”  Nathan was the only man on the ward who was not taking morphine.  “One guy came in in a wheelchair, in bad shape.  He got discharged before me.  He walked out – didn’t use the wheelchair.  That’s how quickly it alleviated his pain and was killing the cancer cells.”  The man in the next room had an exceptional response, as well:  “He was from the Netherlands.  He told me he came in when his PSA was 964, got his first treatment, and his PSA went down to 11, then his second treatment was two months later, and his PSA was down to 3.5, and now he was there for his third treatment.”

Two weeks later, when Nathan went to see his oncologist back in New York, his PSA was undetectable.  A second treatment was scheduled.  “I was already experiencing significant salivary gland problems,” Nathan says, “and we thought he might reduce the dosage.”  However, he doesn’t know whether the dosage was reduced for the second round.

Going Off Enzalutamide

Enzalutamide may have helped make the treatment more effective:  some studies have suggested that enzalutamide enhances PSMA.  Otherwise, Nathan wasn’t sure how helpful it was.  Six months after his second treatment in Germany, he asked his doctor: “What do you think about me getting off enzalutamide, and staying on Lupron?  He said, ‘I don’t know if it ever really worked on you; it only lowered the PSA for a few weeks.’”  So Nathan tapered off, then stopped taking it altogether – which led him to another milestone:  “I said, ‘So, am I still castrate-resistant?”  His doctor told him, “’From a scientific standpoint, once you’re castrate-resistant, that’s it.  They don’t change that.’  But I don’t think they’ve ever come across a situation where people start dialing back their medicines.”

“Not for the Faint of Heart”

About a year after the treatment in Germany, Nathan got a PET scan.  “There was no evidence of cancer, which is great news,” he says.  However, “they said I had a compression fracture in my spine.”  Previously, when he had the high-dose radiation to his spine, he asked about side effects.  The radiation oncologist told him, “In rare cases, people can get compression fractures.  Don’t jump out of any planes.”  But back then, this was a new treatment, and there was no long-term follow-up.  To treat the fracture, he underwent a procedure called kyphoplasty, done by an interventional radiologist.  It involves a balloon – like angioplasty – that restores space in the collapsed vertebra, which then is filled in with glue and cement to restore the bone and relieve pain.

In 2018, Nathan got another PSMA-PET scan at Weill Cornell.  “Thankfully, I was PSMA negative.”  But Nathan cautions that the radionuclide treatment he received is “not for the faint of heart.”  The loss of salivary gland function “has not been pleasant.  It encompasses many things.  I can swallow, and I can taste, but I get a tremendous amount of dry mouth.”  A CT scan showed esophagitis – inflammation of his esophagus from lack of salivation, and thyroiditis.  “I have to constantly keep lubrication going.  It has gotten slightly better, and they told me it’s possible that if the treatment didn’t burn off all my salivary glands and there were some cells left, they could possibly regenerate, but it would take a long time.   I think I’ve gotten about 20 percent back over the two years.”  Nathan uses gels in his mouth every night.  “Otherwise, I wake up choking.”  He also uses prescription toothpaste and extra fluoride to protect the enamel on his teeth.

He is trying to limit scans that will subject his body to more radiation (MRI, for example, has no radiation; CT does).  “Over the last couple months, my creatine level (reflecting kidney function) has slowly increased.   It’s not out of the range of normal, but at the high end.  I’m conscious that these radioligand therapies can produce kidney damage.”

“It’s an amazing age we’re living in,” Nathan says.  “I’m happy to be here, grateful that I was able to kick the can long enough to have gotten this treatment.”  Whenever he sees his oncologist, the conversation ends with the doctor saying, “Grow old.”  And Nathan says:  “I plan to.”

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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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

 

 

 

 

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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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