Tag Archives: antiandrogens

April 29, 2021 · 10:14 am

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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September 19, 2020 · 10:17 am

Why can’t we cure this???


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A frustration for patients and physicians alike is the incurability of metastatic prostate cancer in spite of the great response that many/most patients have to initial hormonal treatment. As most readers of this blog know, almost all prostate cancer cells depend on stimulation from testosterone to grow and to get outside the prostate, moving to lymph nodes or bones (the most common place for metastases in pca). Testosterone is normally made by the testes and adrenal gland, circulates in the blood stream, and enters the cancer cells where it binds to the AR (androgen receptor). The AR then translocates to the nucleus where it binds to specific locations “upstream” from various genes (including PSA, and interestingly TMPRSS2 which has implications for COVID-19) leading to the gene being “activated”. Many of the activated genes lead to cell division and invasion that characterize/lead to metastases we detect with bone, CT, or PET scans.

Normally, the way we detect that cancer cells are “turned off” or dying is by the PSA falling. PSA in general is far more sensitive than scans, but it really tells us about the “big picture”, not what is going on with individual collections of metastatic cancer cells. Measuring PSA every 3 months is a very common way to monitor the response to drugs that stop testosterone synthesis (abiraterone – Zytiga) or block testosterone from binding to the AR (bicalutamide-Casodex, enzalutamide-Xtandi, apalutamide-Erleda, darolutamide-Nubeqa)

Although much more expensive, monitoring response by repeating scans can begin to answer the question posed for the title of this blog. Why doesn’t hormone therapy lead to cures? The reason lies in a single word, heterogeneity. As I reviewed previously, when we look at different sites of cancer metastases, the tumor deposits in one area may have a very different genetic mutation profile than those in a different area. I was very struck by how well this is illustrated in a recent article using quantitative PET scans. In patients treated with enzalutamide, the different sensitivity is graphic as shown in this figure from the article:

Compare PET1 taken at the start of treatment with enzalutamide to PET3 when disease was progressing indicated by a rising PSA. Green spots indicate partial or complete response to the antiandrogen while red ones are new or progressive locations. This is a graphic example of the result of tumors having genetic changes that make them more or less sensitive to the drug. Finding a combination of chemotherapy or hormone therapy that can attack all of the genetically different deposits is impossible at this time. However, the immune system may be able to keep up with all the changes in some patients, and this provides hope for the expanding trials of immunotherapy in prostate cancer you can find here. Glass half full or half empty? You choose!

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May 10, 2020 · 7:53 am

COVID-19 and “the news”


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This won’t be a long blog, but since I anticipate lots of news this week regarding an article that was published a few days ago, I thought I would provide a “heads up” to my prostate cancer “groupies”. What makes the news and becomes “viral” is interesting and I haven’t had the opportunity to watch the sequence up close personally before. My wife is a pediatric infectious disease expert with specific interest in Kawasaki Disease. As you most likely have seen in the news over the past few days, SARS CoV2 now seems to trigger a KD type of illness in children. This became apparent a little over a week ago with calls flying back and forth from around the world among her friends, notably because Michael Levin, from London had seen some cases and sounded the alarm among the international colleagues. So, from “insider info” to public alarm seems to take about a week.

As you know from faithfully reading this blog, I predicted that men on androgen deprivation therapy might be protected from SARS CoV2 about 6 weeks ago and that physicians/scientists with access to large databases would be able to show this. And, true to the prediction, this past week an article appeared showing just that. I have summarized the data for you on this slide:

Screen Shot 2020-05-10 at 8.33.47 AM

It will be interesting to see this get picked up and “sensationalized” by the media over the coming days. And it is already underway. I am aware of a conference call with the CDC and another being hosted by the Prostate Cancer Foundation this coming week. So consider yourselves forewarned! CNN, FOX, ABC, etc. etc. will be all over it…

Now, as I also predicted, I would bet that there will be prospective studies looking at ADT as a form of therapy for COVID19 starting soon (if not already underway). My favorite design would be with the approved agent, remdesivir in a randomized prosepective trial. Male patients sick enough to be admitted to a hospital would all receive remdesivir, and 1/2 would receive ADT in the form of an anti-androgen (e.g. enzalutamide, apalutamide or darolutamide) or a single injection of a month of a GnRH analog like degarelix (Firmagon), or the androgen synthesis blocker abiraterone/prednisone (Zytiga). I would hope that this kind of approach could help men (and maybe even women) fight the virus by blocking TMPRSS2 as I previously showed you in the graphic on the original blog. Now YOU are the insiders!

PS, I think that another approach could be starting everyone in a nursing home “under attack” could be starting all the occupants on finasteride. Blocks DHT production from T and is very well tolerated in the  pcpt trial. Lower DHT -> lower TMPRSS2 -> lower viral replication.

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March 29, 2020 · 8:28 pm

COVID-19, ADT and Prostate Cancer


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Spoiler alert: As I start to write this, my intent is to delve into some basic science readers may find too detailed/complex and some speculation that has limited/no support and should NOT be taken as anything other than hypothesis generating. I fell in love with biology in about the 8th grade and with thinking about how to answer biology questions in medical school, so this is more self-indulgent writing rather than being written to inform.

Starting with the COVID-19 story, there have been so many excellent articles that if you haven’t read too many already, you can get a one minute overview from this video. Now for some more Screen Shot 2020-03-29 at 8.47.20 AMdetailed science. This figure from an excellent article in Science shows the real details of how the virus works and some of the drugs that might be useful in stopping or slowing it down at the cellular level. If you use your best “Where’s Waldo” approach, (and if you are an avid follower of prostate cancer biology) you may find a very familiar protein hiding in the membrane where the virus binds to the exterior of the cell, TMPRSS2. This protein is an enzyme in the family of serine proteases, proteins that can cut peptide bonds at the site of the amino acid serine. Trypsin is another example of this category of enzymes we use in the lab to release cells from petri dishes, and you use various enzymes every day in your dishwasher to digest proteins stuck to your dishes. As shown in the figure, TMPRSS2 plays a crucial role in the entry of the SARS-CoV-2 virus into the respiratory epithelial cells leading to COVID-19 disease.

I first heard of TMPRSS2 several years ago in a lecture at the PCF annual scientific meeting. Investigators at the University of Michigan found that in a large percentage of prostate cancer, the androgen response elements in DNA that control the expression of TMPRSS2 have become fused to an oncogene, ERG. Every gene in our DNA is controlled by “upstream” segments of DNA called promoters or enhancers that regulate the expression of the gene. In the case of prostate cancer the androgen receptor, AR, binds to testosterone (or DHT) and then the is translocated to the nucleus where it binds to DNA at the sites of androgen response elements, leading to transcription and expression of the “downstream” genes. A reasonable analogy is to think of testosterone flipping a light switch to “on” and the AR being the wire going to the light bulb, TMPRSS2, in our case. You are familiar with this if you know about drugs like Lupron, Zytiga, or Xtandi that block testosterone signaling in various ways. Although taking any of these drugs turns off many genes related to prostate cancer development and progression, one of these genes is clearly ERG (if you have the TMPRSS2:ERG fusion), and of course you probably turn down expression of TMPRSS2 in normal cells.

So what does this have to do with COVID-19? As you may have seen, men have approximately twice the mortality of women from infection with SARS-CoV-2. There are no doubt many possible reasons. Men smoke more. Men may not practice social distancing as much. Men have more heart disease. But what if one reason is that they express higher levels of TMPRSS2 in their respiratory epithelium? The exact mechanism of TMPRSS2 in the infection can be found in this article.  A cartoon from the article illustrates the several points in the viral infection cycle where TMPRSS2 (and other serine proteases) acts to facilitate the entry, replication and budding of the virion from a cell.

Screen Shot 2020-03-29 at 10.19.32 AM

The article discusses several drugs that are being investigated to inhibit TMPRSS2 that could hopefully be effective in fighting COVID-19. One of them, camostat (seen in the first figure in this post), is already scheduled to begin clinical trial at the end of this month.

However, there is already a very interesting global “clinical trial” underway if you have followed the above (and necessarily complex …sorry!) story about TMPRSS2. If ADT, familiar to all men with metastatic or high risk prostate cancer, turns down the expression not only of ERG and other oncogenic pathways, but also the expression of TMPRSS2, it might reduce the infection rate or morbidity/mortality from COVID-19. Looking at large global databases, it may be possible to see whether men with a diagnosis of both “prostate cancer” and “COVID-19”  can be extracted from the data, and then whether within this grouping, those men on ADT have a better outcome than those not on ADT. It would be complex, of course, since some of the men not on ADT might be on chemotherapy, or more sick in general, and thus more susceptible to dying from the infection. It might also be possible to see what the expression levels of TMPRSS2 in the pulmonary epithelium of men versus women are as a potential partial explanation of the differences in mortality. Finally, and this would be the most intriguing possibility of all, a clinical trial that combined some partially effective “drug X” from the list of drugs in the first figure with or without ADT could determine whether short term use of ADT could enhance the treatment. Proof that no one ever has a “unique” idea (and of the speed with which you can share ideas in today’s internet environment), in doing a minimal amount of literature research on this topic, I came across a preprint of a beautiful article looking at exactly the hypotheses I laid out above. It was submitted only 5 days ago! The authors have found very significant differences in the levels of expression of TMPRSS2 among adults using published databases and hypothesize that this could explain why some individuals may be more susceptible to bad outcomes. They also evaluate the potential of down regulation of the gene with ADT drugs like enzalutamide or estrogens and they conclude, “Together, these results identify existing drug compounds that can potentially be repurposed to transcriptionally inhibit TMPRSS2 expression, and suggest that the activation of estrogen pathways or inhibition of androgen pathways can be a promising modality for clinical intervention in SARS-CoV-2 infection.”

In summary, if you have prostate cancer and are on ADT, the well known side effects you put up with are unpleasant to say the least. But there is a “not-zero” possibility that your ADT is also protecting you. The best advice is still to practice social distancing, wash your hands, and be vigilant regarding your health, but maybe there is a silver lining in this story. I hope so, and there are already clinical and basic scientists exploring the hypotheses discussed above. Be well and my best wishes during these trying times!

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February 19, 2018 · 9:36 am

Delaying metastatic disease – ASCO GU18


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Previously, we have discussed the conundrum of the rising PSA and when to start therapy. I also opined that for some men with a very slowly rising PSA, it might be best to just forget about it and enjoy life, comparing it to watching a clock, an opinion that understandably garnered negative comments from some. Of course the nuances surrounding PSA kinetics and their meaning are myriad. However, one graphic that helps understand this better is shown here.

Screen Shot 2018-02-12 at 2.49.27 PM

Smith, JCO 2013

This figure illustrates the fact that individuals with relatively long doubling times (>8-10 months) have a much lower risk of developing metastases or dying from prostate cancer than those with shorter doubling times. In a classic study published almost 2 decades ago, Pound et. al. followed a large number of patients who had rising PSAs following prostatectomy at Johns Hopkins. On average, men with rising PSA’s  who received no additional treatment, did not develop metastases for ~8 years. “In survival analysis, time to biochemical progression (P<.001), [i.e. the time from prostatectomy until PSA rise was detected] Gleason score (P<.001), and PSA doubling time (P<.001) were predictive of the probability and time to the development of metastatic disease.”

With these findings as a background, two studies were presented at the ASCO GU18 meeting, both involving use of improved analogues of bicalutamide (Casodex): enzalutamide (Xtandi) or apalutamide (Erleada). These drugs block the androgen receptor, thus preventing stimulation of prostate cancer growth, but are more potent than bicalutamide. Patients with rising PSA’s in spite of having low levels of testosterone from surgical (orchiectomy) or medical (GnRH agonists/antatgonists) castration, short doubling times (<10 months), but no metastases were treated either with apalutamide/placebo (SPARTAN trial) or enzalutamide/placebo (PROSPER trial). The trials were both remarkably positive in delaying the time to development of metastatic disease.

Screen Shot 2018-02-19 at 8.44.28 AM

SPARTAN TRIAL (Apalutamide)

Screen Shot 2018-02-12 at 2.42.37 PM

PROSPER TRIAL (Enzalutamide)

These are remarkable findings and great news for patients with the most aggressive forms of prostate cancer. However, there are (as usual) numerous questions raised by the trials, as was nicely discussed by Dr. Kantoff after the data were presented. These included a more careful analysis of the side effects and clinical benefits. Obviously patients are psychologically better off when they don’t have a rising PSA or metastases, but neither study reached statistical significance when it came to improved survival (both are trending in this direction). What are the side effects of being on such drugs for longer periods of time? In the enzalutamide study, there were more deaths from “other causes” – not pca within 3 months of progression. Why? In the apalutamide study there were more falls and fractures compared to placebo. Why? To these, I would add the issue of “pay me now or pay me later” – how much time/quality of life do you really lose by waiting until the first metastasis shows up, never mind the extraordinary costs (to patients, insurers, medicare, etc.) of remaining on these drugs for years. Further, neither study compared the outcome to using bicalutamide, the generic and much cheaper alternative anti-androgen, instead of placebo. And what about using the newer scans? All of the patients have metastatic disease, we just can’t see it until there are enough cells in one spot to turn a scan (e.g. fluciclovine or PSMA PET) positive. We can possibly gain advantages in staying off ADT of any sort in some patients by radiating oligometastatic disease. Nevertheless, these studies are great progress and landmarks in the fight against prostate cancer. Apalutamide became the first drug to be approved by the FDA for use in this setting with a “snap approval“. And I need to disclose that I am a paid advisor to J&J, although I have no personal stock in their company, and did not treat patients on either trial.

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November 8, 2015 · 9:33 pm

Prostate Drug Costs


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Most readers will have seen something in the popular press over the last 6 months regarding the increasing awareness of oncology drug costs. For example, there have been very nice commentaries in the New England Journal of Medicine like this one, that deals with the cost of nivolumab, a PD-1 pathway inhibitor that is approved for treating melanoma and may show promise in a number of other cancers like kidney cancer. The final paragraph is telling:

Hand clapping for science is now inextricably linked to hand wringing over affordability. Drug prices are increasing more rapidly than their benefits, and the growth in spending on drugs has started to outstrip growth in other areas of health care. Addressing this problem requires realizing that cost-effectiveness assessment — a step that we are not even ready for in the United States — has limitations when one considers the price of the comparator and the impact on overall budgets.

I have opined elsewhere in this blog site on the excitement over the new immune-stimulating drugs that show promise. Indeed, some may be able to improve the response to prostate vaccine approaches. The question is whether we can afford all of these drugs, who decides, how they decide, and what methods they use. In the past, a QALY (quality adjusted life year) has been used to benchmark some of the things we do in medicine. In a nice NEJM perspective article, the classic “$50,000/QALY” benchmark was reviewed, but the authors suggested that given medical progress and inflation, a more realistic number might be as high as $100,000 or $150,000. The costs of the newer prostate cancer drugs such as abiraterone, enzalutamide, sipuleucel-T, cabazitaxel etc. have not escaped attention. Medscape had an article on this over 2 years ago. I am no expert on Markov models, differing ways to evaluate cost-effectiveness, and the economics of medicine. But as a simple way of explaining the challenge, how much is cisplatin, a cornerstone of curative treatment for testis cancer, the number one cancer of young men in their 20’s worth? If you can answer that, then how much would it be worth if you were using the same drug as a third line to treat prostate cancer, where responses are rare except in the case of the small cell variant, but no one is cured? In the case of the young testis cancer patient, many years (or QALY’s) are achieved while in the case of even the “sensitive” form of prostate cancer, the benefit would be in months at best. Should testis cancer patients have to pay huge sums because it works so well for them and prostate cancer patients less? And how do we figure in the drug development costs in a fair way that retains a financial incentive for the pharmaceutical companies and researchers to keep working for new discoveries?

Added to this is my own experience when I have described using a highly expensive (sometimes toxic) drug to a patient with well-known, very limited (but measurable, approved, and “covered” by Medicare or insurance) benefit. Often when I am honest and say, “this may help for a while, but is not a cure,” to a patient who may have very few symptoms at all but is progressing based on a rising PSA, the reply will be “what choice do I have”? That is a great question. If someone else is paying for some very expensive drug, why not try it? Although I know that the ethicists feel “my wishful answer” is unethical, I would like to be able to say something like this: “Well Mr. Smitherton, Medicare has decided that if you would rather take the money and apply it to your grandchild’s college fund, they will be willing to divert the costs (or some proportion of them) to that cause because ‘we’ [society] feel that should be your choice, rather than having us pay for a relatively ineffective, expensive drug if you don’t think it is worth it, or if you value his/her education over a few months of additional life span.” If wishes were horses, beggars would ride. And if I was qualified in ethics, I would probably not be writing this. That’s my 2¢ – or maybe it should be my $20,000??

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June 1, 2014 · 10:01 pm

Practice changing results….chemotherapy up front.


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Adding 6 cycles of docetaxel at the outset of hormonal therapy for prostate cancer has been shown to improve survival, especially in men with a high burden of disease. The much anticipated report was presented in detail today at the ASCO annual meeting. Those of you who have followed this blog will remember that I previously highlighted the CHAARTED trial when the trial was stopped prematurely because of the positive result.

The first author, Chris Sweeney, is a good friend and led the study in which several of our patients here in Denver were participants. Thanks guys !

This study randomized 790 men who presented with metastatic prostate cancer and who had never received hormone therapy (ADT) to receive ADT alone (393) vs ADT plus chemothrapy with docetaxel (397) starting up front at the time the ADT was started.  In patients with high volume disease, defined as those men with visceral metastases or >3 skeletal mets including one beyond the pelvis and spine, there was an improvement of 17 months in overall survival from 33 months to 49 months with a p value of <.0006 for significance between the two arms of the trial. The men with lower volume of metastases are also doing better, but the curves for the two treatment arms have not met significance. There was reasonable balance in age, race, psa values, etcetera between the arms. A key point is that 3/4 of the men initially treated with ADT alone went on to receive docetaxel at the time of progressive disease, meaning that this trial can reasonably be considered to reflect a “pay me now or pay me later” with docetaxel toxicity, and the men who were on the “pay me now” arm had the most benefit from the toxicity of the chemotherapy. There was good balance between the arms in terms of the number of men who received others of the newer treatments (abiraterone, enzalutamide, sipuleucel-T).

For prostate cancer, this is akin to the studies of using chemotherapy “up front” in the adjuvant setting that really got medical oncology going in the early 1970’s in women with breast cancer. It opens the door to the study of using aggressive multimodality treatment including the newer hormonal agents, and possibly vaccines, in men with high risk disease at the very outset of their therapy, which should be the next studies. The problems with designing such studies is the very long period of time it takes to get answers. CHAARTED was opened in 2006 and only now, 8 years later, do we have a result. The time could be dramatically shortened if more men would be placed on clinical trials. 1000’s of men were treated with same old same old treatment during the time we worked on CHAARTED. If 50% of them would have been put on this trial in the first two years, we could have had this result about 4 years earlier. Since that takes a major change in how medicine is practiced in the US, don’t hold your breath.

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May 15, 2014 · 2:06 pm

Oh, no! My PSA is going up….do something….


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One of the most frustrating and frightening things that can happen to a prostate cancer patient is for there to be a recurrence of the PSA after he thought he had been cured by surgery, radiation therapy, or both. This is entirely understandable. It is no picnic to go through those treatments in the first place, and when the PSA is clearly going up, it can only mean (with very rare exception) that there are still cancer cells lurking somewhere in the body. The rate of the PSA rise can predict how long it will be until something shows up on a scan, and on average, this is about EIGHT years. The median time to death from prostate cancer after a PSA recurrence is 16 years.

For >95% of patients there is something that CAN be done to stem the rise in PSA. That is to go on hormonal therapy (androgen deprivation, ADT) which will drop the PSA, often all the way to undetectable levels, in over 95% of patients. Voila! Both patient and physician feel much better emotionally. But for the patient, there is a significant price to pay. Namely the hot flashes, loss of energy, weight gain, bone calcium loss, lack of libido and further decrease in sexual function to name a few. The question is whether this is “worth it”.

A study to be presented in the next few weeks at ASCO’s annual meeting, suggests it won’t make much difference if you start ADT early versus waiting until metastases, or perhaps even symptoms occur. Utilizing the CaPSURE database, the investigators evaluated over 2000 men who had PSA relapse. The estimated 5 year overall survival (87% vs 85%) and 10 year overall survival (72% vs 72%) were the same regardless of whether the men received immediate or delayed ADT. The same was true for death from prostate cancer…no significant difference. There are of course other considerations that may come into play like treating those patients who have highly aggressive disease earlier because one knows that there will be metastases within a year, or the patient simply can’t live with himself knowing his PSA is going up.

In my experience, it is the exceptional patient who is willing to go play golf or travel or enjoy his grandchildren and forgo PSA testing on a regular basis. I have trouble even convincing my patients to extend their PSA testing to 6 months from 3 months. The question is, does it make any sense to watch this “number”, any more than it would to have cardiac catheterization every 3 months to follow the slow but inexorable accumulation of calcium in your coronary artery? Or what about the 0.01 mm increase in your abdominal aortic aneurysm? Or the accumulation of two more tangles in the Alzheimer plaque in your brain. Just because we CAN measure PSA so easily certainly doesn’t mean we SHOULD, and I have seen far too many men let this number ruin their otherwise healthy lives.

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March 22, 2014 · 10:28 am

No surgery or radiation. Just make my PSA go down!


To read this blog on the website and have access to subscribing and older posts click here. What if you could avoid all of the well-known side effects of surgery or radiation and just take hormone therapy? (aka Androgen Deprivation Therapy or ADT) Given the incredible power of the PSA value to drive thinking of both physicians and patients, this question makes a lot of sense. >95% of patients will have a PSA response to ADT, usually in the form of GnRH agonists (e.g. Lupron, Zoladex, Trelstar, etc) or antagonists (Firmagon, Plenaxis) You might imagine that dropping the PSA would be all that is needed in some men and if they didn’t have too many side effects (weight gain, hot flashes, muscle weakness) they would benefit from the treatment.

A study just reported looked at 3435 men treated in this way between 1995 and 2008 to determine if such treatment would reduce death from prostate cancer and compared them to 11735 men who did not receive such treatment. The age ranged from 35 to >80 and as you might suspect, there was a statistically significant tendency to use treatment in older individuals, in men with higher PSA at diagnosis, and in those with higher Gleason scores. Anyone who received radiation or surgery within the first year after treatment was excluded from the analysis. The bottom line is that there was no effect of using such treatment. To quote the authors, “Our main conclusion is that PADT does not seem to be an effective strategy as an alternative to no therapy among men diagnosed with clinically localized PCa who are not receiving curative-intent therapy. The risks of serious adverse events and the high costs associated with its use mitigate against any clinical or policy rationale for PADT use in these men.”

This study adds to the complexities surrounding prostate cancer diagnosis and treatment. Screening and treating patients with surgery or radiation after age 65 may not produce any positive results in the large screening studies, or at the least, you have to treat a significant number of men who would not need treatment to save one life. While you can make the PSA go down with ADT, it also does not save any lives. Such is the challenge of whom to diagnose, whom to treat, and how to best treat anyone who you think does need treatment. On this blog you will find many entries on these issues, and as I have stated before, when you ask men who are dealing with the disease, they virtually all think their treatment either saved their life or was given too late – illustrating the difference between a population and an individual view. The silver lining is that whether you are diagnosed with pca before you die or not, regardless of treatment choice, you are more likely to die from something else.

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February 6, 2014 · 10:05 pm

The challenge of new drugs


Long long ago, I had just finished my fellowship in medical oncology and moved from Boston to Denver. In the lab, I was working on an obscure enzyme that seemed to differentiate leukemia from normal cells, cystathionase. In the clinic, we had very few clinical trials, so I wrote a cold call letter to 10 different pharma companies. Only TAP Pharmaceuticals wrote back. They had developed a new drug that ultimately became Lupron, and we had the opportunity to participate in all of the trials that led to its approval. The biggest shock I had in that experience was the cost that TAP charged, although by today’s drug standards, I guess it was a bargain.

A few years later, we were asked to participate in the trials that led to approval of goserelin, or Zoladex™. My anticipation was that if approved, the costs of both drugs would drop as the companies competed for market share. It didn’t happen. There are of course many reasons, the greatest being that physicians generally didn’t worry too much about how much a drug cost….insurance or Medicare picked up the cost. Instead, the two companies competed with favors to physicians. Many urology practices made huge profits from the mark-ups in drug, and ultimately TAP paid one of the largest fines in history for unethical practices.

With the new drugs, notably abiraterone and enzalutamide, there have yet to emerge competitors that are approved. The drugs both work on the androgen stimulation axis, but via different mechanisms I have covered elsewhere. Each is incredibly expensive, around $6000/month. But beyond the above “no compete” story, I am concerned that competitors may never even reach the “podium” to provide competition (whether financial or in marketing). The reason is that prostate cancer is inherently slow and that the FDA requires survival as an endpoint. Add to this, that if a patient is on a new drug with some modest improvement in survival, this can be overwhelmed by patients going onto one of the other actives after they progress (rising psa or new lesions on scans) that will make it difficult to see the contribution to survival by “new drug”. The placebo patients will benefit equally from the new approved drugs. This may well be what happened to orteronel, (TAK 700) that was reported to have missed its survival endpoint needed for approval at last weeks ASCO GU meeting. Although I would  like to think that approval would result in lower prices for all of the new drugs, the experience described above makes me skeptical. So how about a new approval process? If a drug is clearly (and I’m not judging whether orteronel is or isn’t the equal of abiraterone here) a comparable, approve it IF the company will provide its “me too” drug to patients at a substantially reduced price. There would still be an advantage for companies to race to be “first to market” and they would enjoy the high profits of being the winner with a new category of drug. On the other hand, competitors could still expect to enter the arena and do well, perhaps competing for first place by price rather than some minor difference in side effects or similar. HOWEVER…this assumes that Medicare, physicians, and insurers would prescribe based on cost savings, something currently forbidden by Medicare but allowed in the VA administration.  And then there would be the fancy TV ads trying to convince patients one drug is better than another based on sitting in bath tubs and looking at sunsets….

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