Molecule of the year: PSMA


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We made it around the sun another time, and in spite of Covid 19, are still here to thank you for your interest in this blog and most especially for your support of prostate cancer research via my annual efforts to grow a moustache and help Movember raise funds for prostate cancer research. A heartfelt thankyou!!

With all of the “Ten best” and “top songs” lists that appear this time of the year, I thought I would expand a bit on PSMA as a real game-changer that is coming on strong to change our management of prostate cancer. So what is Prostate Specific Membrane Antigen?? Well, first of all, I think you know what an antigen is, or if not, here’s a timely clue: Spike protein. When you received your vaccination with Moderna, Pfizer or J&J vaccine, you were exposed for the first time to a foreign protein that the SARS CoV2 virus (COVID-19 disease causing) uses for entering the cells that line your airways. Your body responded to this antigen (foreign protein) by developing antibodies – the levels (titers) of which prevented you from getting COVID, or at least prevented you from getting very sick. Antibodies are very specific proteins made by the B-cells of your immune system that bind to foreign antigens and are the first line of defense against invaders.

Now, if you inject a mouse with human prostate cells, the mouse will recognize all sorts of the proteins as “foreign” and make antibodies against them. In such an experiment, Wright and colleagues in the early 1990’s found that one such antibody could be useful in detecting prostate cancer. It turned out that the antibody was detecting a protein expressed on prostate cells, but also tumor blood vessels and the salivary gland that became known as PSMA. Unlike PSA, this protein is bound to the membrane of the cancer cells and doesn’t circulate in the blood stream. PSMA is actually an enzyme involved in the normal absorption of folate (a vitamin) from the intestine, but for unclear reasons, it is dramatically over expressed by prostate cancer cells. Over the next 25 years, numerous researchers worked on tagging radioactive isotopes to antibodies that would bind to PSMA and therefore could be used to detect prostate cancer or if the radioisotope was powerful enough, kill prostate cancer cells. One of the challenges, however, in using radio labeled antibodies is their size, resulting in a lot of non-specific “sticking” in the liver, spleen and elsewhere. A better approach evolved by finding small molecules that would stick to the PSMA enzyme activity site as illustrated in this figure:

As a result of this research, it became possible to develop highly sensitive PET scans that can detect much smaller metastases of prostate cancer than any previous bone or CT scans were able to do. Gallium and Fluorine isotopes hooked to the peptide (617) are rapidly becoming available in PET scan centers across the United States (and have been available for the past 3-5 years in Europe, Australia and elsewhere) and will likely become approved as the new standard for staging newly diagnosed and PSA recurrent metastatic prostate cancer. Moreover, the isotope Lu177, that emits strong beta radiation (electrons) can be attached to peptide 617 and kill cells that express PSMA.

In the VISION trial, published this year in NEJM, the use of Lu177 PSMA to treat advanced prostate cancer patients who had progressive disease after previous treatment with a second generation hormone agent (such as Zytiga or Xtandi) plus chemotherapy with a taxane (Taxotere or Jevtana) were scanned with Gallium labeled PSMA then treated with Lu177 PSMA. The treated men were compared to alternative “standard of care” which might have included other forms of chemotherapy for example. The results were extraordinary as shown in these curves.

So for this year, I’m nominating PSMA as the molecule of the year. PSMA PET scans will likely be the only scans needed to follow prostate cancer metastases, and are already being used in newly diagnosed patients with high risk disease to make sure we don’t miss something. Further, if there are only a few metastases, we can treat these at the same time we treat the prostate with hopes that some of the patients with metastatic disease can still be cured. And ongoing research is underway to evaluate the use of Lu177 PSMA in earlier patients without resistant disease. Great progress and I leave you with fond wishes to you and your family for a healthy (VACCINATED) 2022!

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Join me fighting prostate cancer in the “Hairiest month of the Year!”


It’s that time again. A scraggly moustache may be better than none at all, and this is the organization that has done the most, along with PCF, to make prostate cancer history. Start your own fund raiser here.

Or if you don’t want to fund raise on your own, feel free to join my campaign by visiting my Movember Website.

Movember has made a HUGE difference in prostate cancer awareness globally by sponsoring research at every level -from clinical to basic science and the creation of data bases like the GAP3 project. Many of the posts I have written this last year like the ones on PSMA PET scans and Lu177-PSMA therapy are the direct result of Movember funding. Let’s keep the progress rolling!

Thanks for your consideration,
Michael Glode

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Here’s what you should “eat” to fight prostate cancer…


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OK, I will admit right up front to bait and switch. In the last month I have seen two of my patients who are what the public health aficionados call “positive deviants“. One man is a professional who still goes to work every day. I have been seeing him for about 5 years; he has metastatic cancer in many bones and lymph nodes, a PSA in the 100’s, yet other than being a bit too thin, carries on with his life helping other people in his chosen profession. The second gentleman looks like an olympic athlete – great muscle preservation, a military posture, and also continues to work at his regular job in spite of having “mCRPC” which most readers will know as metastatic castrate resistant prostate cancer. What is it they do far more than most of my other patients? What is their secret diet? …EXERCISE

In this piece from the New York Times on heart health, Dr. Emery, a cardiologist, refers to exercise as a magic pill. “It’s just that you can’t swallow it, you have to earn it,” he notes. You need to click on that hyperlink and read the whole article. These are the benefits for heart health:

  • It enhances the cardiorespiratory system.
  • It increases HDL cholesterol.
  • It lowers triglycerides, a type of fat that circulates in the blood.     
  • It reduces blood pressure and heart rate.      
  • It lowers inflammation and improves blood sugar control.

Best of all, exercise is the type of medicine that appears to produce benefits no matter how small the dose.

But what about prostate cancer you might ask? The studies there are compelling. In a recent article from Taiwan, 125 patients who were treated with ADT and radiation for high risk prostate cancer were studied for changes in body composition. The patients experienced a 5.5% loss in skeletal muscle over 180 days, and each 1% loss of the skeletal muscle index resulted in a 9% increase in non-cancer mortality! Although it is a small study and it is shocking, but it illustrates the problem of taking testosterone away from older men. You don’t need to rely on small studies however. In the Health Professions Follow-Up Study, 2705 men diagnosed with prostate cancer were followed from 1990-2008. “Men with ≥ 3 hours per week of vigorous activity had a 61% lower risk of PCa death (HR, 0.39, 95% CI, 0.18 to 0.84; P = .03) compared with men with less than 1 hour per week of vigorous activity. Men exercising vigorously before and after diagnosis had the lowest risk.”

So, the message is clear. Compared to any “diet changes” you can make, or supplements you might take, exercise is definitely more important to enhance your chances of surviving prostate cancer. Ideally, you should work with a trainer who can help you develop an individualized program that takes into account your current physical fitness. From the NYT article, here is a place to start if you don’t have access to a trainer:

“Anything is better than nothing. But the ideal dose of exercise for adults, according to the Centers for Disease Control and Prevention, is as follows:  

  • 150 minutes of moderate-intensity aerobic exercise a week.      
  • 2 sessions of about 30 minutes each of resistance training a week.

You can spread the aerobic activity throughout the week however you like, such as 30 minutes five days a week, or 50 minutes three days a week. Examples include running, swimming, brisk walking, riding a bike, playing basketball or tennis, and doing yard work. As for strength-building activities, ideally, you should set aside at least two days a week for 30 minutes of exercise that works the major muscle groups, such as the legs, back, shoulders and arms. What counts as strength training? Lifting weights, using resistance bands, doing bodyweight exercises like yoga, push ups and sit ups, and even heavy gardening with a lot of digging and shoveling. Vigorous exercise should get your heart rate up to 70 to 85 percent of your maximum heart rate. Not sure what that is? Here’s how to calculate it.” I also recommend your resistance training should utilize weights that cause your muscle group to “fail” on the second or third set of repetitions.

So there you have it – how to change your “diet” to beat prostate cancer. Definitely not as easy as just avoiding red meat and increasing soy products, but almost certainly the most effective thing you can do. Movember is coming up. Time to MOVE!

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The Future of [Prostate] Cancer Screening


As I’m sure most of you know, this has been a controversial topic for more than 2 decades. The problem is fairly simple: Screening can pick up earlier disease, save some lives, but treatment has side effects for virtually 100% of men who get treated, and “active surveillance” is not a picnic with repeat biopsies every 2-3 years. We may have to treat as many as ten men to save one life. On the other hand, if they live long enough, more than half of men probably develop prostate cancer, usually of the low grade (Gleason 6 or less) type that will never bother them. Here is a nice article that shows how autopsy series over time have found prostate cancer in up to half of men, dependent on age, race, etc. but notably pointing out how seldom autopsies are now performed compared to earlier eras. The reality is that we have no idea these days how many 90 year old men would have a small cancer if we really looked hard for it. What we understand is that they didn’t need to know they had a prostate cancer if they were never treated and died from something else.

Now, add to these challenges the revolution in cancer detection provided by molecular testing. This field is moving so fast that the “old idea” of PSA screening is becoming passé. For example, Illumina, the company that makes automated next generation sequencing machines spun off a startup, GRAIL that developed a “pan-cancer” test that looks for fragments of DNA circulating in the blood, the fingerprints for most of the common cancers. This test, called “Galleri” is undergoing real world testing in the UK, but is not covered or approved in the U.S. Proponents (some of whom are consultants for biotech companies) suggest that it could save “millions of lives”. The test, because we live in a free, capitalistic society is already marketed on the internet for an out-of-pocket price of only $949 with payment plans available. But…and the prostate cancer community knows this perhaps better than any other…the challenge of knowing whom to test, when to test, and what to do with a positive test may take decades to figure out. Here’s an article covering some of those promises and challenges (false positives, lead time bias, costs for treatment, etc.)

But for prostate cancer, the same DNA technology is making real progress. What we want are tests that not only tell us who has prostate cancer, but who has the kind of cancer that NEEDS to be treated or followed closely, and lowers the detection of clinically insignificant cancers. An example of this kind of testing sophistication appeared in NEJM this month from a group in Stockholm. This group has developed a test called Stockholm3 that is “a risk-prediction model that is based on clinical variables (age, first-degree family history of prostate cancer, and previous biopsy), blood biomarkers (total PSA, free PSA, ratio of free PSA to total PSA, human kallikrein 2, macrophage inhibitory cytokine-1, and MSMB), and a polygenic risk score (a genetic score based on 254 single-nucleotide polymorphisms [SNPs] and an explicit variable for the HOXB13 SNP) for predicting the risk of prostate cancer with a Gleason score of 7 or higher.” They then took men at risk of having prostate cancer (PSA>3 and Stockholm3 >11%) and either did “blind” 12 core biopsies or did an MRI first and included targeted biopsies of high risk lesions only if seen on the MRI.

Outcome for Stockholm3 high risk screened men with PSA > 3 who did or did not have MRI targeted biopsy in addition or instead of standard biopsy.

Note that the number of biopsies needed went down, as did the number of benign or clinically insignificant cancers. This is the sort of effort that will eventually reduce the number of men having unnecessary biopsies or treatment by combining all of the great new molecular and radiology technologies (dynamic contrast enhanced MRI’s). We now routinely use some of the molecular tests to help us in screening and deciding about treatments as I reviewed in this blog.

While we are still a long way from applying this kind of technology to “every man over 50”, the future for the next generation (our sons and grandsons) will be much better – fewer unnecessary biopsies and treatments. Hopefully this type of approach can be applied to the pan-cancer type of “Galleri” screening being proposed, and make such testing cost effective as well. Congratulations to the prostate cancer researchers and their patients for leading the way!

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Cancer Camp and Survivorship


A cancer diagnosis affects every patient in a different way. However, regardless of what type of cancer is involved, it is a cold water “slap in the face” that we all share the same fate: “our days are numbered” – something everyone knows but we generally find it more convenient to simply not think about.

Prostate cancer, in my opinion, is somewhat different in this regard for most men. First, like all cancers, it is clearly a disease of aging, but even more so. The median age at the time of diagnosis is 66 years. This means the majority of newly diagnosed men have lived a reasonably long (and hopefully healthy) life. There has been time to deal with other health threats, watch children grow, and usually face the deaths of parents or close family members. However, the good news is that the vast majority of men will still have the opportunity for enjoying many more years of living.

Taken from the US SEER database: https://seer.cancer.gov/statfacts/html/prost.html

In fact, regardless of race or ethnicity, over 90% of men newly diagnosed with prostate cancer will be alive in 10 years. These data hold true even for men with regional disease, but fall off rapidly if metastatic disease develops. And there is continued improvement in treatment for the metastatic patients as well. In a recent article looking at three large studies for the benefit of second generation androgen receptor antagonists (enzalutamide, apalutamide, darolutamide) to delay metastases and improve survival, even men >80 years of age clearly did better than before.

From Lancet Oncology, July 23, 2021 https://doi.org/10.1016/S1470-2045(21)00334-X

So the question becomes, “what will you do with the time you have left?” regardless of how long that is. My thought, having just returned from volunteering at the Epic Experience cancer camp, is that it always good to take some time and reflect on how you want to spend that time. Write another paper? Start another company? Make even more money? Grasp for the latest treatment option? Or potentially reconsider family and friends and what really matters to you. The Epic organization has had trouble recruiting men to their camps, but for the men who have come, their perspectives have been altered in very positive ways as you will see in this video. Many more women come to the camps, just as women have led the way in advocating for breast cancer research, and in general reaching out via support groups. We have a lot to learn from them!

There are many support groups out there for prostate cancer survivors of all stages. Prostate Cancer Foundation has put a nice list together here. And if you would like online support for specific issues, Movember’s True North initiative has great articles to help you here.

The bottom line for me, having had a chance to “get back to camp”, is that we can all use a little encouragement to get out there and live again as we come out of our COVID isolation. I hope you will do just that this summer!

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Lu-177-PSMA-617 and “what’s next?”


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The presentation that received the most attention from readers of this blog and the press at this year’s ASCO meeting was the one about Lu-177-PSMA-617 for patients with advanced, metastatic castrate resistant prostate cancer (mCRPC). I have previously posted about PSMA and this approach to treatment as you may want to review here. Briefly, Prostate Specific Membrane Antigen, is a protein expressed on the surface of prostate cancer cells. There are molecules (ligands) that bind to this protein and can be tagged with radioactive isotopes. Thus, the tagged ligand, once injected, carries the isotope to the tumor cells. If the isotope is a positron emitter, a CT-PET scanner (Positron Emission Tomography) will light up the tumor’s location. Examples include Ga-68 and F-18. If the isotope releases stronger radiation, (for example Lu-177 releases strong beta particles that can kill cancer cells, just as the approved agent, Radium 223 -aka Xofigo™ -is a bone seeking agent that seeks out bone metastases and kills cancer cells by releasing strong alpha particles) then prostate cancer cells expressing PSMA will be killed.

The data presented at ASCO 2021 on Lu-177-PSMA-617 was from a large phase III trial comparing Lu-177-PSMA-617 with “standard of care” in patients who had progressed on most other therapies. The results are shown in the following figure:

Slide from presentation on Cancer.net, 6/16/2021.

These data will be evaluated by the FDA and it seems likely this new therapy will be approved. The answer to the question of “what’s next?” for a new drug is usually to study its use in earlier stages of disease. What if patients who have metastases but have not yet been treated with hormonal manipulation were to receive the drug at the same time they start hormonal treatment? What if used before prostatectomy? There are 9 such ongoing trials you can read about here. The hope is, that by using the drug earlier, even more benefit will result, and this is often the case in cancer medicine – for example using early “adjuvant” chemotherapy in high risk breast cancer, or using apalutamide (Erleda™) at the outset when initiating prostate cancer ADT in high risk patients.

As we progress in our understanding of when and in whom to use more aggressive therapies, it will also be helpful to identify the patients at greatest risk for failing one treatment or another. In an article appearing this month in Annals of Oncology, investigators evaluated tumor DNA levels after a single cycle of abiraterone (Zytiga™) and found that patients who didn’t have circulating tumor DNA at the start or converted from positive to negative had significantly better overall survival than patients who did not convert to negative. This means that as soon as 30 days after starting abiraterone, you could already pick out patients in whom you might want to change therapy or add other agents to treatment. They also showed that patients with alterations in specific genes like TP53, RB1 or PTEN either at pretreatment or after one cycle had significantly shorter overall survival. This kind of individualizing risk analysis will further enhance the ability to introduce new drugs like Lu-177-PSMA-617 earlier in patients who need it and avoid toxicities in those who don’t.

For those who helped support my mustache during Movember, these findings are tangible evidence of real progress we can all be proud of. You can share in the great feelings and read about your accomplishment here: https://au.movember.com/story/new-treatment-for-men-with-advanced-prostate-cancer-more-effective-than-chemotherapy?tag=prostate-cancer. Our donations DO make a difference and thanks for your help!

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Immune-oncology seminar tomorrow: May 4, 1:30pm EDT


Dear subscribers,

My normal goal is to send out a new post only once/month since, if you are anything like me, getting more and more emails is annoying to say the least. I am making an exception this month because I just received a reminder about a seminar I think many of you might enjoy. I have tried to do a few posts on this rapidly evolving treatment modality for you here, and here, and here.

For a more sophisticated education, designed for patients and taught by real experts, you may wish to register for the American Association for Cancer Research Seminar, “The Promise of Immuno-Oncology.” Here is the link:

Happy learning from the AACR, one of my favorite societies!

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The Androgen Receptor (more than you wanted to know…)


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The treatment of prostate cancer by depriving the cancer cells of testosterone is now over 70 years old. Charles Huggins along with Clarence Hodges, a medical student at the time, discovered that by either administering estrogen (which will inhibit the brain from signaling the testicles to make testosterone) or surgically removing the testicles, patients with prostate cancer would have remissions, sometimes lasting for years. He received the Nobel prize in 1966 and there is a nice article reviewing the discovery and Huggins’ humility here.

Nothing much changed in prostate cancer treatment after that until the early 80’s when leuprolide, a peptide that could inhibit the signaling (like estrogen) from the brain to the pituitary entered the picture. This is the hypothalamic-pituitary-gonadal axis, and another Nobel prize was awarded to Andrew Schally for elucidation of the role of GnRH as the key hormone driving the system. (leuprolide is an analog of GnRH) Surprisingly, given the rapid development of anti-estrogens for breast cancer, truly effective anti-androgens took another 25 years or so to emerge. The past decade has yielded several new drugs that are now in standard use for prostate cancer as shown in the following table.

https://www.hematologyandoncology.net/files/2021/04/ho0421IsaacsonVelho-1.pdf

But blocking androgen synthesis by the cancer cells (abiraterone), or blocking the androgen receptor (all the other drugs listed in the table) kills most of the cancer cells, but not all. How do they survive? The answer lies, in part, in the complexities of the androgen receptor (AR) itself. This is where it gets really interesting (but probably more than you wanted to know).

In an absolutely superb recent review article, Velho and colleagues review how the AR works and drugs that are in development to block its activity when resistance to the above drugs develop. You need to download the PDF to see the figures, but this one illustrates the basics. Androgens get into the prostate cancer cell, then bind to AR, which then partners (dimerizes) with another AR molecule, and the dimer enters the nucleus of the cell and sits on specific genes, causing their expression. PSA is the gene you would know best, but there are many other genes that are activated, some of which lead the cells to divide or develop characteristics that lead to them metastasizing to lymph nodes or bones.

Testosterone (androgen) drives gene expression via the Androgen Receptor (AR)
https://www.hematologyandoncology.net/archives/april-2021/new-approaches-to-targeting-the-androgen-receptor-pathway-in-prostate-cancer/

The good news is that understanding how this system works has led to a wealth of drugs that can inhibit various steps in the AR pathway of cell/gene activation. These are shown here:

New drug categories being developed to block T (androgen) stimulation of prostate cancer.

Although the details are very complex, two of the more interesting approaches are bipolar androgen therapy (BAT) and the category shown as PROTACs. BAT consists of giving patients large doses of testosterone monthly while they remain on drugs like leuprolide to suppress the normal levels. In the recently published TRANSFORMER trial Denmeade and colleagues demonstrated that BAT was a better first choice in patients who had failed abiraterone when compared to the anti-androgen, enzalutamide. Further, BAT can re-sensitize some patients to abiraterone after BAT stops working.

PROTACs are drugs that can target various cell proteins for destruction by normal cell machinery. As shown in this figure, the proteasome is like a disposal that chews up proteins that have been “tagged” by attaching a protein called ubiquitin to them. Imagine that the green folded protein is the AR. If you can tag it, you will get rid of AR altogether, and that is what an experimental drug called ARV-110 does, attaches ubiquitin to the AR.

Folded protein could be the AR, and ARV-110 can lead to degradation of AR.

Ongoing clinical trials with ARV-110 have shown impressive PSA responses in a few patients who have been heavily pretreated and are resistant to all the other approved AR targeting drugs.

So, the good news is that there is still room for improving on treating prostate cancer patients with drugs that attack the testosterone axis, even 80 years after the first proof of principle was shown. However, it is also true that cancer cells are very “smart”, and can learn to survive via other cellular pathways having little to do with AR signaling. Other approaches, such as stimulating the immune system to recognize these cells is under equally intense study. If this doesn’t make you a believer in “science”, and a cheerleader for further investment, I give up! 😁

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Return to Estrogen?


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Remarkably, estrogen was discovered to be a cancer driver for breast cancer by surgeons in the late 1800’s but it was 5 decades before the relationship of hormones to prostate cancer was discovered. George Beatson had considered performing oophorectomy for women with breast cancer because the procedure was successful in prolonging lactation in cattle. His first patient experienced a complete remission from soft tissue breast ca metastases and lived another 4 years. He later said that he thought this treatment would induce “fatty degeneration” of malignant cells.

The relationship of testosterone as a driver of prostate cancer is credited to Huggins and Hodges, who found that either surgical castration or administration of estrogen to men with prostate cancer could reduce what was then the only known marker of prostate cancer, acid phosphatase. Additionally, if they administered testosterone to these patients, the acid phosphatase would increase. This built on observations that the enzyme was present in the prostate gland and would go up in patients as they developed metastases, usually in the bones. For this work, Huggins was awarded the Nobel prize in 1966. The use of surgical castration or estrogen administration remained the mainstay of treating metastatic prostate cancer until the introduction of leuprolide in the early 1980’s. I had the extraordinary opportunity to participate in those trials, which we published in 1984. We compared leuprolide to DES, an oral form of estrogen that works on the same endocrine axis as leuprolide, causing the pituitary gland signaling hormone, LH to drop, and subsequently the testicles stop making testosterone. Leuprolide worked as well as DES, but oral estrogen is dangerous – leading to blood clots and increased risk for heart attacks or strokes. Thus, leuprolide (and other GnRH analogs…including the recently approved oral GnRH antagonist, relugolix) became the standard for ADT therapy of prostate cancer.

But estrogen still works. In fact, it may have some significant advantages over surgical castration or GnRH therapy. Our team found that DES could still produce meaningful responses in patients with rising PSA’s who had failed GnRH even though we did see blood clots. But, you can also give estrogen via transdermal patches which avoids many of the problems of oral DES. This week, the PATCH trial program in the UK reported the safety results of using estradiol patches (E) to treat prostate cancer patients compared to GnRH agonists. The ability to produce therapeutic (castrate level) testosterone was the same, but the E treated patients had lower cholesterols, lower blood pressure, less diabetic tendencies, and far fewer hot flushes. Previous study analyses have shown that E is better for bone health with no calcium loss. The only thing that was worse was breast enlargement (gynecomastia) which was seen in 86% of E patients compared to 38% in the GnRH agonist patients. To some extent, gynecomastia can be treated by radiating the breast tissue. The efficacy of E in treating the prostate cancer in these patients will be reported in 2023 and 2024. The cost of E treatment (4x .025mg/24h patches every 3.5 days) is about $62/week ($750/3 months) which is definitely less than any of the GnRH agonists or antagonists. It will be terrific if this “old fashioned” treatment can again join the treatment options for men with advanced prostate cancer. I think it would also be reasonable to try in patients who are failing the newer second generation agents before trying the more expensive/complicated/toxic alternatives like taxane chemotherapy or radionuclide agents (Radium 223, Lu177-PSMA, etc.) With PSA monitoring, it should be relatively easy to find patients who benefit from such treatment.

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Pills vs Shots for Androgen Deprivation Therapy (ADT)


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My own interest in prostate cancer began with what, in retrospect, seems quaint and naive. When I arrived at the University of Colorado in 1978, as the first board certified medical oncologist, there were very few clinical trials underway. Having trained (at DFCI) with teams of researchers, my philosophy had evolved to the thought that “every patient should be treated on a protocol, and there should be a protocol for every patient”. This idea (in academic centers, at least) is how we make progress in treating cancer. I continue to urge every patient to participate in clinical research whenever possible, recognizing that for reasons of geography, convenience, or eligibility, it may not be possible. Clinicaltrials.gov lists all of the ongoing clinical research trials for patients and physicians, a dramatic advance in keeping everyone informed. You can learn how to use this tool in one of my previous blogs, here.

With few clinical trials going on at our cancer center, I wrote a naive letter to a number of pharmaceutical companies asking if they had any drug development trials that I might participate in. A single company, Abbott, wrote back inviting me to Chicago to discuss “Abbott 43-818”. This drug was an analog of gonadotropin releasing hormone, GnRH, a peptide (10 amino acids in this case) that looks like this: Pyr-{His}{Trp}{Ser}{Tyr}{Gly}{Leu}{Arg}{Pro}{Gly}-NH2. The 43-818 analog came to be known as leuprolide, and I had the opportunity to participate in taking it all the way from the first dose in men to a final clinical trial resulting in its approval as Lupron™. I’ve been caring for prostate cancer patients and doing clinical trials in prostate cancer ever since – fate!

The way Lupron™ works is shown in the figure below. Normally a part of your brain called the hypothalamus (1) releases a “pulse” of GnRH several times/hour. The peptide travels to the pituitary gland (2) and lands on cells called gonadotropins, causing them to release hormones LH and FSH that travel to the gonads (4) where the ovaries release estrogen or the testes release testosterone. Leuprolide interrupts this process by “over stimulating” its receptor on the pituitary cells and they turn off their LH/FSH production. Because of the small and relatively simple peptide sequence 100’s of other analogs have been made, and the molecular interactions with the receptor have been extensively studied. Some are agonists (like leuprolide/Lupron™/Eligard™, or goserelin/Zoladex™ and others are antagonists (degarelix/Firmagon™).

The hypothalamic-pituitary-gonadal axis

After a long research path, an oral antagonist (relugolix/Orgovix™) has now been synthesized, tested, and approved for treating prostate cancer. It is not a peptide, has the advantage of not having to be injected, and may be safer in patients with a cardiac history. The HERO trial evaluated 934 prostate cancer patients, 2/3 of whom received relugolix and 1/3 received leuprolide. As expected (based on the history of antagonists research), relugolix resulted in more rapid reduction in testosterone, faster recovery upon discontinuation, and faster reduction in PSA.

The frequency of the common bothersome side effects, hot flashes and fatigue, was similar. More patients on relugolix (12.2%) had diarrhea than those on leuprolide (6.8%). However, the leuprolide treated patients had more serious cardiovascular events (myocardial infarction, central nervous system hemorrhages and cerebrovascular conditions, or death from any cause), especially if they had a cardiac history. The incidence was 6.2% in the leuprolide group vs. 2.9% in the relugolix group.

All things being equal, use of relugolix would seem to be a superior choice for ADT in prostate cancer patients. However, as usual, “all things” may not be equal. First, while the biology above may seem to favor the antagonist, there are no data on whether this affects survival or time to progression of prostate cancer. The biology of reducing testosterone as the mainstay of treatment has not changed – we are attacking the same target: testosterone stimulation of prostate cancer cells. Indeed, the more rapid recovery of testosterone upon discontinuation of therapy (for example in a patient who receives several months of relugolix in combination with radiotherapy) might result in better quality of life with rapid recovery, but have a higher rate of recurrence due to the shorter overall duration of ADT treatment. Some patients will prefer pills to shots. On the other hand, insurance coverage for injections might be much better than that for an oral medication. The internet reported cost for a month of relugolix is reported to be $2313. The cost for a one month leuprolide dose is around $1700. However, the cost of a myocardial infarction is not insignificant, and thus comparison of one form of treatment vs another is always more complex than it initially seems.

I am writing this because I suspect there will be “news” articles and other advertising efforts for “Orgovyx™” in coming weeks/months and I hope to refer my patients to this article (and all the other ones I write). If a newly diagnosed patient has impending spinal cord compression, or major organ involvement or a history of cardiac disease, I would recommend the antagonist (relugolix/Orgovyx™) over the agonists (like leuprolide/Lupron™/Eligard™ or goserelin/Zoladex™). If a patient is already on one of those agonists, is doing well and has no cardiac history, there is probably no reason to change therapy. For a patient who is about to start therapy, I will discuss the options, and am happy to prescribe either an agonist or antagonist – it may well depend on insurance issues for a given patient. As with the Covid vaccine, the scientific progress in developing a non-peptide, oral agent is a testament to “our” (medical science) phenomenal scientific advances. The cost of such research (dating back at least to 2013 for relugolix) and what represents fair costs to patients or to Medicare and fair reimbursement to the pharma companies remain concerning to me.

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