I’m on a bit of a sabbatical from writing for the blog. I will probably pick it up again in the spring and at least try to write something quarterly. Meanwhile I hope you will join me in supporting Movember your own way. I won’t have a personal site this year, but you can set up to make a contribution here if you wish: https://us.movember.com
Please consider starting your own campaign and invite your friends and family to support the cause. It’s not that hard!
Meanwhile I hope everyone has a safe and happy holiday season and I’ll see you next year.
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“Our patients lives and identities may be in our hands, yet death always wins. Even if you are perfect, the world isn’t. The secret is to know that the deck is stacked, that you will lose, that your hands or judgment will slip, and yet struggle to win for your patients. You can’t ever reach perfection, but you can believe in an asymptote toward which you are ceaselessly striving.” -Paul Kalanithi in “When Breath Becomes Air“.
This week, after considerable thought and with great ambivalence, I began saying goodbye to my patients. I have intentionally made my “retirement” a prolonged process, stretching back nearly 15 years and beginning with turning my research laboratory over to a wonderful trainee/fellow, Tom Flaig (now Vice Chancellor for Research at CU). I began to stop writing grants (for the most part), working more in the clinic on other people’s ideas, and continuing to write this blog while serving on various boards and IDMC panels (including with the two authors of that IDMC link). Eventually, I reduced my clinic time to one day/week, focusing entirely on prostate cancer and seeing patients only at our outreach site, the Shaw Cancer Center in Vail. But, as I anticipate turning 75 this summer, and as my wife has pointed out, “no one really wants an ‘over the hill’ physician” (even if that doctor is still doing well by his/her patients). It is time to leave the clinic. As Kalanithi points out, inevitably “your hands or judgment will slip”. And even if they haven’t or never do, I believe there is joy and elegance in stepping aside at the right time to provide opportunities for younger physicians to take your place and to the extent they wish, offer advice (wisdom?) if needed.
But what to do with a blog?? As an early adopter, I had great satisfaction helping ASCO develop its website, www.ASCO.org and wrote about what I envisioned as the evolution of internet oncology in this article. My colleagues and I assisted in moving much of the society’s print media online as well as hosting what I think may have been one of the first “virtual meetings” of a medical society in 1995. With the help of a contractor, we digitized 35mm slides, recorded audio, then merged them “by hand” and posted presentations on the internet (within hours of their live presentation) for viewing around the world. Shortly thereafter, I was invited to write medical blogs, and when that effort became commercialized with ads, I elected to start writing this blog “commercial free”. As the internet technology continued to evolve with the evolution of social media (twitter, instagram, tiktok, etc.) I opted out, and so this blog is all that remains of my “brief but spectacular” foray into content creation for the digital world.
The statistics on 733 subscribers to this blog suggest that relatively few visit the website, although I suspect more read the essays themselves which are sent out by the site as emails. Here are the stats for the last quarter:
The way you got this email (or link if you are reading on the wordpress site) is “push technology”. You opted in/subscribed to receive the emails. This led me to wonder what happens to an email or blog when you change pages or “delete”. We all know that they stay somewhere “forever”. I know this means bits and bytes on some server. But when I tried to think about it in Kalanithi terms to title this essay, I tried to imagine “When Pixels Become Electrons” or something similar. I failed. Here is how pixels work and this is how electrons control them. What happens to blogs is still mysterious to me, but I’m switching formats to “pull technology”: responding to queries/ideas rather than guessing what you might want.
There are now numerous online sources for prostate cancer information. If you want excellent push technology to keep you up, I recommend subscribing to “The Prostate Cancer Daily” written by and for experts in the field. If you want to look something up, like the latest clinical trials, please read this blog I previously posted.
Thus…I have decided to change states – just like the LCD crystals that change the polarization of the pixels that have turned black to provide you this text. Going forward, I will use this blog to try and help patients/families only IF they want, by responding to questions, but not by trying to guess what subjects may be of interest and creating a post. I am happy to do whatever research is necessary to explain advances and comment on the science behind them if you send a topic or question to me at prost8blog@gmail.com. I will post monthly answers here as essays on www.prost8blog.com so everyone can see them who is a subscriber. The person(s) who submit questions/ideas (if any) will remain anonymous and I will NOT provide case specific advice. I will also not send return emails from the gmail account except to indicate I have received your request/idea.
BOTTOM LINE: This will be the last post on this blog unless I receive a topic request or question at prost8blog@gmail.com. I will monitor that email site on a monthly basis and post here as needed. I have loved being a part of helping prostate cancer patients/families and wish the best to all of you who have subscribed. If the new approach works, great! And if not, I thank you (and your computer pixels) for sharing some of our lives together. Godspeed…
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This week brought excellent and exciting news from the ASCO GU Meeting about management of high risk prostate cancer using “triple therapy” for metastatic disease. Adding further evidence for the “kitchen sink” approach, Matt Smith from MGH presented data from the ARASENS trial. The study involved 1306 patients with metastatic prostate cancer (86% of whom presented with metastases and the remainder of whom developed mets while being followed after primary treatment). The trial evaluated whether adding the potent anti-androgen, darolutamide aka Nubeqa® (similar to enzalutamide and apalutamide) to standard ADT (e.g. orchiectomy, leuprolide, or other GnRH analog) plus docetaxel (Taxotere®) could improve survival. We already knew that 6 cycles of docetaxel added to ADT in this situation improved survival from the CHAARTED trial I wrote a blog about several years ago. This was the trial design:
The results of the trial were very positive and represent a new “standard of care” for patients with metastatic prostate cancer:
Although it is too early to say whether some of the patients in this or similar trials, such as PEACE 1, have been cured, it is clear that throwing the “kitchen sink” at prostate cancer can offer real improvement in survival. Now the questions become: Who are the patients most likely to benefit? What kind of toxicities do these patients have to put up with? How much does this kind of treatment cost? What if we added other known effective treatments like Lu-177-PSMA or PARP inhibitors to appropriately selected patients? Would adding this kind of treatment cure some patients with oligometastatic disease? And perhaps most intriguing, could we imagine applying this kind of treatment to patients with newly diagnosed, localized (but high risk …e.g. Gleason 8,9,10, or node positive) disease as part of a plan that involved prostate surgery or radiation?
The answer to all of these questions will come only from appropriately designed clinical trials. I am reminded, too, of the famous quote from one of the pioneers in prostate cancer treatment, Dr. Willit Whitmore who said, “Is cure possible? Is cure necessary? Is cure possible only when it is not necessary?” There are obvious differences between the 52 year old man who presents with high risk prostate cancer and is otherwise healthy versus a 79 year old gentleman who had prostate surgery 15 years ago, a pacemaker, and now has a rising PSA with only one or two metastases showing up on a PSMA-PET scan.
The progress in prostate cancer research has accelerated dramatically during my career. As well, the costs of oncologic care are rising at a faster rate than can be maintained, “National costs for cancer care were estimated to be $190.2 billion in 2015 and $208.9 billion in 2020 (2020 U.S. dollars), an increase of 10 percent that is only due to the aging and growth of the U.S. population… National oral prescription drug costs were highest for female breast, leukemia, lung, and prostate cancers” (See this reference) As an aging (rapidly…) man myself, I can only hope we are able to fall back on the precepts taught in Sir William Osler’s essay, “Aequanimitas“, combining the qualities of “imperturbability” and “equanimity” to achieve “”coolness and presence of mind under all circumstances”. If so, we should be able to navigate the avalanche of medical knowledge and associated costs with compassion, empathy, and wisdom. Meanwhile, hats off to the researchers and men who participated in clinical trials and brought this advance and many others you can see here to fruition.
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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:
“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.
“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.”
“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.
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!
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.
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.
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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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.
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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.
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.
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.
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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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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One of your co-subscribers to this blog contacted me and asked if I would write a blog about CAR-T cells, and I have decided to include the closely related bi-specific antibody therapies. I am very intimidated by even attempting this, because the complexities of this field are daunting, so please do NOT show this post to your PhD immunologist cousin.
As most readers probably know, the immune system consists broadly of the “humoral” and “cellular” arms. When you get corona virus, (or any other virus) both arms are activated. Broadly speaking, your B-cells (lymphocytes that live in the lymph nodes and also circulate in your blood stream) make antibodies that attach to targets (“antigens” – in the case of corona virus, the spike protein you are tired of looking at on TV is the target antigen we hope a vaccine can be made from) and can inhibit the virus or can clear the antigen from your circulation. Antibodies consist of proteins (chains) that combine with each other and this is where things start getting VERY complex, but a single B-cell can make only one type of antibody (called a monoclonal antibody). Whether you know it or not, if you have an interest in prostate cancer, monoclonal antibody technology is “why you are here” – PSA detection was made possible by isolating a monoclonal antibody that would bind to Prostate Specific Antigen. But with modern recombinant DNA techniques, the chains that make up these antibodies can be combined in highly variable ways never found in nature. The history and complexity of the antibody story is illustrated here from this article.
The Y-shaped figure above is “an antibody” and the colored chains are the proteins in the antibody that can be extremely variable and give the antibody its ability to bind to any target. Note that the two arms of the antibody could be designed so that one arm would bind to one target and the other arm could bind to a different target. Voila! You could design one arm to bind to PSMA and another to a killer T-cell that would link a killer cell to your cancer cell.
This is the general idea behind an innovative cancer approach you may hear about called BiTE. In this figure, the working part of the tips of two “Y” antibodies have been linked and when injected into a patient, in theory the “killer” T-cell is forced to bind to the tumor cell via its “TAA” or tumor antigen. If you are a dedicated reader of this blog, you already are thinking about a great target antigen I previously introduced you to, PSMA.
Now on to my VERY oversimplified description of CAR-T cells. The terminology refers to Chimeric Antigen Receptor – T cells. The science of these is related to the above description of antibodies in the following way: On the surface of the T-cells in your lymphocyte library is a completely different group of proteins that allow the T-cells to bind to and recognize antigens, much like the antibody system we discussed above. These proteins combine in chains on the surface of the cells to form “T-cell receptors”. Unlike the antibody system, their interactions with antigens are further modified by requiring recognition of “self”. Non “self” is why people who receive a kidney or heart transplant must receive drugs to suppress the immune system that will reject the transplant. Unfortunately cancer cells are mostly recognized as “self” so we don’t reject them. BUT… again using recombinant DNA technology, the T-cell receptors (TCR) can be re-designed so they DO recognize a tumor target, even though it is “self”. You can start with lazy, somewhat unresponsive T-cells that might be in the blood or even infiltrating a tumor, take them out, modify the receptor (dramatically as shown in the following figure), and force them to recognize a cancer, then re-infuse them into the patient like any blood transfusion.
In the figure (taken from this article), the “antibody like” part of the receptor that controls “self” is CD3 and the “antibody like” part of the TCR receptor that binds to a tumor antigen or virus infected cell are the green proteins marked alpha and beta. The recombinant magic that is WAY beyond this blog is everything on the right. If you have the time and interest in really delving into CAR-T therapy for cancer, you really do have to read this article. But, for those who wonder “so why aren’t we doing this?”, the Cliff’s Notes answer is that (1) it is VERY expensive – each patient has to have his/her T-cells taken out and modified, expanded, then re-infused; (2) it has only worked well for blood cancers like leukemias so far; and (3) even though PSMA or some similar tumor target might be thought to be “tumor specific”, it turns out these targets are often expressed in low levels in places like your brain or lung. When the CAR-T cells begin attacking your normal tissues, you are in a world of hurt. If you have followed the COVID-19 story, you may have heard about the “cytokine storm” that is killing people by destroying their lungs. As you might imagine, combining these approaches with the other “hot” area of immunotherapy, the PD-1 inhibitors I have previously written about could make CAR-T treatment more effective but the toxicities even worse.
I hope this has been helpful and that your immunologist cousin or highly informed oncologist will forgive the effort to simplify a very promising but challenging field. I’m also grateful to the myriad of incredible researchers who have put this all together for us “cancer fighters” and their dedication is equally as worthy of honor as other warriors on front lines.
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