Keeping up…(or not)


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In my book club (all old men from various backgrounds – medicine, law, business, politics, academia, etc.) we read a book called “Artificial Intelligence: Confronting the Revolution“. In it, the author describes the various scenarios underway to deal with massive amounts of information. Far beyond Deep Blue, the chess computer that beat Kasparov in 1997, AI may help physicians of the future make great diagnoses and decisions and is already being tested in difficult settings like the early detection of pancreatic cancer.

Until then, for me at least, drowning in the information for oncology in general, and even just for prostate cancer is becoming daunting. Gone are the days when reading the New England Journal of Medicine would keep you abreast of the most important advances. This is a photograph of the journals that arrived just this week, all provided for “free” (and without my request) by the endless advertising in the first pages.

In “GU Oncology Now” there is a summary of important papers presented at the Society of Urologic Oncology 2021. For prostate cancer two papers on PSMA imaging and therapy (which I have covered elsewhere), one on racial differences and treatment patterns, and an ad for “why is precision medicine complicated in advanced prostate cancer?” (See the answer here) Hematology and Oncology covers “highlights from the 2021 European Society for Medical Oncology Congress and the 2021 AUA Meeting”. That one has 4 articles on darolutamide, 3 on enzalutamide, 2 on PD-1 inhibitor trials, and “meeting abstract summaries with expert commentary”. Scanning them, I find that for the most part I have already commented on many of them in this blog, so I move on to: This week’s NEJM. There, in looking at the table of contents, I find articles on diabetes control using “closed loop” glucose monitoring and insulin administration, use of oral microbiome therapy for c. diff infections, antibiotic prophylaxis for rheumatic heart disease, and one on 24 hour urinary sodium excretion and cardiovascular risk. Whew…nothing on prostate cancer –but wait, there IS one on an antibody drug conjugate for treating lung cancer…I wonder if it could have any role in the small number of prostate cancers that also have HER-2 mutations??

Oh, well, let’s move on… The Lancet Oncology has 12 original articles, 11 commentaries and 6 letters to the editor, and there are a couple of the letters that deal with prostate cancer from researchers I know personally. But wait – they are available online at “e7” and deal with “radiographic progression-free survival in the ACIS trial”. I already know about that since I was a monitor for that trial, so guess I’ll pass. That leaves JAMA Oncology. OMG! The first three articles I really do have to read. Here it goes:

  1. “Changes in Prostate-Specific Antigen Testing Relative to the Revised US Preventive Services Task Force Recommendation on Prostate Screening” This turns out to be an analysis of Blue Cross Blue Shield beneficiaries (some 8 million or so) aged 40-89 between 2013 and 2019. During that time, the USPSTF changed its guidelines from “not indicated” to “shared decision” and sure enough, PSA testing increased 10% among men 40-54 years old, 12% in those 55-69 years old, and 16% in the group least likely to benefit, aged 70 to 89. Hmmm.
  2. “Association of Treatment Modality, Functional Outcomes, and Baseline Characteristics With Treatment -Related Regret Among Men with Localized Prostate Cancer” Wow – I talk to men about treatment decisions like this almost every week. This one looked at 2072 men with localized prostate cancer diagnosed in 2011 and 2012, then analyzed in late 2020/early 2021, so almost 10 years of followup. The number of interesting observations in the 3 tables and 2 figures found in the article are too numerous to go over in this blog, but among them are more treatment regret among patients who received surgery or radiation vs those who chose active surveillance, less treatment regret in college or more graduates, and as expected more regret in men who had health problems related to treatment. But the concluding paragraph says it all:
    The findings of this cohort study suggest that more than 1 in every 10 patients with localized prostate cancer experience treatment-related regret. A disconnect between patient expectations and outcomes, both as it relates to treatment efficacy and adverse effects, appears to drive treatment-related regret to a greater extent than factors including disease characteristics, treatment modality, and patient-reported functional outcomes such as urinary incontinence and other urinary symptoms, erectile dysfunction, or bowel dysfunction. Thus, improved counseling at the time of diagnosis and before treatment, including identification of patient values and priorities, may decrease regret among these patients.” I guess this validates the way I often end up my own counseling sessions: “Unfortunately, Mr. (and Mrs. in some cases) XYZ, there just isn’t any way to treat the prostate gland without causing some side effects.”
  3. “Outcomes of Screening for Prostate Cancer Among Men Who Use Statins”. This one is from Finland where we spent a lovely year on sabbatical in the mid-1980’s. My wife studied the Finns’ vaccination data for childhood meningitis, and I did a year in a molecular biology lab. We both were impressed with the Finnish Public Health system. The article utilized that system’s extensive database to evaluate the effect of statin use among 78,606 men who were part of a randomized study to evaluate PSA screening effects. The incidence of low grade (Gleason 6) cancers was reduced among the statin users, whereas detection of high risk cancers (Gleason 8-10) was similar. Buried in the data (3 figures, 2 tables) is a nugget. There is a trend towards decreased risk for all kinds of prostate cancer among statin “ever” users vs. non-users although no difference in mortality. Still…the study seems to support my bias that if tolerated (~5-10% of patients on statins develop muscle inflammation) most of my patients might benefit from being on statins.

Well, that’s it for this week’s journal arrivals. I won’t bother you with the 5-10 emails I scan every day from all sorts of “Web MD” and “Grand Rounds in Urology” places with even more to try and digest. How anybody can be a general medical oncologist these days and care for everything from lymphoma to breast cancer is truly amazing. Fortunately, there are expert resources like the NCCN Guidelines that are really helpful. Goodness knows we need them, and maybe AI will save us, but I’m not so sure.

Take a look, for example, at just the number of articles published so far in 2022 on statins and prostate cancer. Good luck 😁.

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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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