Category Archives: Prostate cancer therapy

Money, Medicine, and Me


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In an article appearing on Medscape on September 13, a Reuters correspondent cited a recent study published in the Lancet looking at doctors who tweet. Although tweeting is a form of social media I have not embraced, I did participate in an attempt to study its use in the ASCO meetings in this article. However, the Medscape and Lancet articles did cause me to think about transparency in this blog.

I began blogging at the invitation of an internet company looking for physicians who would provide content they could use. When they were successful enough, they began using pharmaceutical advertising, and I left them, choosing to pay for my own web presence on wordpress.com. However, I now realize that I should also disclose my other relationships with pharmaceutical companies. In the Medscape article, there is a reference to a government website where you can look up the payments and transactions I have with pharmaceutical companies. What it does not reveal is the nature of those transactions which I will herewith share.

In doing drug development, pharmaceutical companies rely on [mostly] academic physicians to perform clinical trials. These activities may involve grants to study drugs in the laboratory, grants to their institutions to offset the cost of data managers, IRB costs, and reimbursement for travel to discuss the ongoing trial or its publication with other physician/researchers. In the past, I have had support in all of these categories, most notably (in terms of career influences) in the development of leuprolide, the first new drug approved for treating prostate cancer in many decades back in ~1985. It was an amazing opportunity for a young faculty member to treat the first patients in the world with a new drug, eventually present the findings to the FDA, publish the results, and then participate in teaching the medical community about its use.

Since then, the landscape of disclosure has changed for the better. Now when my colleagues and I give presentations or publish articles we sign disclosure agreements revealing which companies we consult for, and there are annual reporting requirements to our academic institutions. In my case, the current companies I have consulting relationships with include Janssen (abiraterone, apalutamide), Bayer (rogaratinib), and Seattle Genetics (enfortumab vedotin). I also have founded (and have ownership interests in) Aurora Oncology, ProTechSure, and Gonex/Cedus, three startup companies attempting to move drugs we have worked on in my laboratory to the clinic. None of these relationships involve giving promotional talks, using company slides in education, or advocating for the drugs on this blog or elsewhere. For the large commercial companies they involve insuring patient safety in ongoing trials as an independent monitor.

I have expressed my concerns about the rapid increase in medical costs for cancer care here and here. I do not have a solution for this intrinsically difficult challenge in our capitalistic system, and I realize that my own consulting and entrepreneurial activities ultimately add to those costs. Indeed, the costs of prostate cancer detection and treatment in men over 70 is 1.2 Billion dollars every 3 years. The newest targeted agents and immuno-oncology agents are phenomenally expensive, often in the $8-10,000/month range which can result in severe economic distress even for those patients who have co-pay supplemental insurance. Eventually, American medicine, with all of its amazing basic science and translational science (bench to bedside research) will need to find a balance between the profit motives that drive innovation and the altruistic care that medicine embodies in its most noble applications. What is an extra 3 months of life worth, and what toxicities (economic or clinical) are acceptable to pay for that? We need to have honest discussions as a society, and importantly, with our own families about these questions, especially when we are facing the diminishing benefits of aggressive/expensive care in terminal illnesses.

 

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A perfect death


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This week in which the country will come together to mourn the passing of a true American original, John McCain, it might be worth considering our (your) own mortality. Even as the ongoing progress toward controlling prostate cancer is underway, it remains clear that “something else” will get us. As an example, in a study I was privileged to lead among patients with high risk prostate cancer, other cancers (many of which were caused by our adjuvant mitoxantrone treatment) were as likely to lead to death and prostate cancer was the cause of dying only ~20% of the time

Screen Shot 2018-08-27 at 8.22.09 AM

As oncologists, we face the “end of life” issues more frequently than most physicians, and certainly deal with the reality of death more than folks in most other professions. I distinctly remember one lovely woman in her 50’s who was very open in discussing her wishes. She wanted to die while lying on her favorite beach in Florida watching the sunlight sparkling on the ocean – not an easy thing to arrange (and it didn’t happen). My own fantasy would be to have a lovely vacation in Hawaii (without this week’s rain) with my entire family, say my good-byes as I put them all on the plane, and stay over an extra day to pay for the hotel and be sure all of my financial affairs were up to date – then die of a heart attack on the way home the next day. Perfect. The airline would be carrying my carcass home for the mere cost of a coach seat and I wouldn’t even have to suffer that long in the crunched position with no leg room.

Short of these fantasies, however, I recently undertook an exercise that anyone could do and I herewith commend to you as well. My wife and I were lucky enough to score tickets to the London production of Hamilton last February. In it, there were two numbers that grabbed me by the heart. First was Washington’s “teach ’em how to say goodbye” song, “One Last Time”. As with John McCain’s final commentaries over the past few months, Hamilton’s farewell speech written for Washington was masterful (as is Lin-Manuel Miranda’s reprise).

But the song that most moved me to tears (and action) was “Who Lives, Who Dies, Who Tells Your Story”. After listening to it about a dozen times, I realized that we all have a story. It may not be as honest/noble as John McCain’s, or as consequential as Hamilton’s or Washington’s, but for some small group of your relatives or children or grandchildren, your story will have special meaning. If you don’t write it, your memories of your father, your grandfather, your family in general will die with you. In my case, I read a couple of autobiographies, self-published, from friends/acquaintances and decided that their stories were highly personal, and not terribly interesting. But when I started writing the story of my own grandfather and father, and my story, it was a joyful experience of reliving many happy memories, and a way of reconnecting with my first love affair, our children’s births, and the many blessings that have come my way. The result is not a literary masterpiece, but I am going to have it bound and give a copy to each of my kids to gather dust on their bookshelves.

In the arc of history, some things have not changed. “Our days may come to seventy years, or eighty, if our strength endures; yet the best of them are but trouble and sorrow, for they quickly pass, and we fly away.” (Psalm 90:10). Although trouble and sorrow are a part of life (and of dying), there can be real joy in pausing to appreciate all life has given you. Carpe diem!

 

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Human Sexuality and Prostate Cancer


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My first academic encounter with the field of human sexuality as a topic was a series of lectures by none other than William Masters and Virginia Johnson at Washington University in 1970. The sexual revolution afforded by birth control pills and the reactionary politics of the late 60’s have been well chronicled in many places but were fairly remote to someone like me who had been studying hard to achieve medical school admission and then trying to keep up with an exceptionally bright group of classmates. Never-the-less, as a prostate cancer specialist, I have been drawn into countless differing situations that impact individual patients and their sexuality issues. While discussing sexual function has become far easier than it was when Masters had the doors locked at the back of our lecture hall in order to show videos of the human sexual response to our class, it is still a delicate topic for most patients, and, I suspect, for most physicians.

Every patient I have encountered has a different history, sexual relationship, and level of interest in delving into the side effects of prostate cancer treatment. There are a few givens that every patient should understand, however. First, in my experience there are virtually no patients who don’t experience negative side effects of ANY prostate cancer treatment, although with active surveillance and focal treatment of a small cancer with a technique like cryotherapy or HIFU , many have minimal side effects (if they are lucky). Even these patients must deal with the psychological burden of being diagnosed with cancer and the possibility that further treatment may eventually be necessary.

A second observation is that even though for most of my patients, sexuality is a “couples experience”, only about half of the men have had a spouse or significant other with them during my initial consultation. In addition, the spouse/SO has her/his own issues regarding the sexual side effects their partner may experience. As a relatively common observation I have noted among heterosexual, married patients, the wife often expresses some version of the following statement: “I just want it out of [George/John/Billy] – we don’t care that much about the side effects…I just want him to be alive 10 years from now…” Often, George is sitting quietly in the patient chair looking somewhat forlorn after such a revelation/statement. There are many books etc. written about the highly variable but often differing interest in sexual relationships among aging couples.  I am certainly not an expert, just an observer, but I have pondered the larger meaning of these sentiments compared to the relatively intense emotions that some attach to, for example, breast reconstruction after a mastectomy for breast cancer. In any case, I think those men who have supportive SO’s who come to their doctor visits with them are fortunate and should express their appreciation to their partners. Sometimes these life challenges can be opportunities for growth in a relationship. Sometimes they are a disaster…

Most of the prostate cancer support groups, and the very large body of literature available on the internet and elsewhere, have sessions and chapters devoted to sexuality, recovery from treatment, and references to other resources. Examples include the ASCO patient website, and a similar one from the AUA. I have cared for a few men from the LGBT community and I was recently sent a book, Gay & Bisexual Men Living with Prostate Cancer,  that I scanned and seems to be a well written and fine resource for those men, but there are also a very large number of websites devoted to that community as well.

The bottom line for men with prostate cancer is that there will be sexual side effects, even if only emotional ones. The same could of course be said for aging itself. Whether one chooses to talk about it or “just deal with it” is an individual decision, and different for each man/couple and no doubt different for men of differing ages. In reality, as with the many competing causes of death/debilitation as we grow older, prostate cancer is but one of the many challenges we all will face. In this regard I rather enjoy this perspective from Willie Nelson:

“I have outlived my pecker.”
The Penis Poem–by Willie Nelson

My nookie days are over,
My pilot light is out.
What used to be my sex appeal,
Is now my water spout.
Time was when, on its own accord,
From my trousers it would spring.
But now I’ve got a full time job,
To find the f***in’ thing.
It used to be embarrassing,
The way it would behave.
For every single morning,
It would stand and watch me shave.
Now as old age approaches,
It sure gives me the blues.
To see it hang its little head,
And watch me tie my shoes!!?

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An Amateur Explanation of Immunotherapy


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For as long as I can remember, there has been lurking excitement regarding the possibility that our immune systems can find and destroy cancer cells. The history of well-documented spontaneous remissions goes back decades and is briefly reviewed here. I have personally never seen a spontaneous remission of cancer, although I have had patients who have done far better than anyone would have expected, suggesting that something must have slowed down their tumor progression.

In prostate cancer, one of the early hints that it might be possible to stimulate an immune attack on the disease came from the studies on Provenge (Sipuleucel-T). My colleagues and I placed several patients on the trials that led to approval of this “vaccine” by the FDA. These studies have continued to demonstrate improved survival of patients with metastatic disease who have failed hormone therapy, although the trials were all done before the availability of the newer ADT drugs abiraterone, enzalutamide, and apalutamide. On the other hand, in spite of the optimistic data we obtained in another vaccine trial on a product known as prostvac, the pivotal trial to prove efficacy failed. It is possible that the vaccine produced modest efficacy, but the signal was drowned out by treatment with the new ADT agents.

As anyone who watches the evening news or other TV-ad-saturated programs aimed at us seniors, other cancers – especially melanoma, lung, bladder, kidney and a few additional ones have been more “easily” treated with newer immune therapies known as check point inhibitors. The idea here is that our normal immune system has built in “braking systems”, the best studied and clinically utilized to date being the PD-1/PDL-1 mechanism. If we immunize you against, for example, measles – you want a vigorous immune response, but you don’t want your entire immune system to keep working on fighting measles. There are other threats it needs to be on guard against. Shutting down the T-cells that fight viruses and cancer involves the Programed Death receptor-1 on these T-cells with a specific protein, Programed Death receptor Ligand-1. Cancer cells can take advantage of initiating this same braking system by releasing their own PDL-1 that will kill the incoming tumor-fighting T-cell. This devious cancer mechanism to avoid our immune systems can be blocked by therapeutic antibodies directed against either the receptor or the PDL-1 ligand protein.

At the recent ASCO meeting, it was revealed that selected metastatic lung cancer patients who have an activated PD-1/PDL-1 braking system are now more effectively treated with pembrolizumab (Keytruda) than chemotherapy. It is emerging that the subgroup of patients who have tumors that are genetically highly unstable, (regardless of tumor type) with lots of mutations leading to abnormal proteins that can stimulate an immune response, may all benefit from PD-1/PDL-1 directed therapy. These patients, including prostate cancer patients can be identified by testing their tumors for microsatellite instability or mismatch repair deficiency. At a practical level, however, when and how to test prostate cancers for such biomarkers remains challenging. Last week at the ASCO annual meeting, Dr. De Bono from the UK reported results on treating patients with metastatic prostate cancer who had progressed on hormones and chemotherapy (docetaxel) with pembrolizumab. 17/163 patients had ≥30% shrinkage of their tumors, but overall results were disappointing with only 11% of patients having ≥50% decline in PSA. Testing for the presence of PDL-1 was not particularly predictive of which patient would benefit most. However, this way of treating prostate cancer will eventually lead to important progress in my opinion. Combining vaccines with the checkpoint inhibitors is currently being studied, and there are other checkpoint drugs and targets that are in development as well. Timing the checkpoint drugs with hormonal therapy or radiation therapy may also find optimal ways of stimulating an immune response. The field of immuno-oncology is an exciting new frontier and well worth keeping your eyes on.

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Improving our focus


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I have had two life changing experiences in focusing. The first was when my wife discovered the Myers-Briggs personality classification system and found I am a “strong P”. This meant I couldn’t help it when I was on my way to take out the garbage, noticed a light had burned out, put the garbage down and went to get a light bulb, but found that there was a spot on the carpet that needed cleaning and finally found the carpet cleaner but an hour later wondered why there was a garbage sack in the hall. Prior to her discovery, she just thought I was an idiot, but she became [somewhat] more tolerant of the foibles when she could “classify” me. The second was when I had my congenital cataracts removed and new lenses inserted in my eyes. It was a whole new world of color. I had been living in a fish tank with scum on the glass and “wow, the world is really pretty!” was my response when I took the patches off the next morning. “Trees have LEAVES!”

Focus in understanding prostate cancer is becoming clearer as well. For several decades we have known that the Gleason scoring system is pretty darn good at predicting the cancer’s behavior, adding a lot to what we knew when there was only the digital rectal exam… “Oh, oh, that feels like a really big tumor” or “Maybe I’m feeling something but I can’t be sure”.  Then came the number of biopsies positive, the percentage of each core, differentiating 3+4 vs 4+3, and now an avalanche of new molecular markers, briefly reviewed here. Combining the old standby risk categories with the newer methodologies has been challenging.

A recent paper in the JCO provides us with one way of integrating the old risk categories with the newer molecular classifications. Using the widely adopted risk categories of the NCCN, the authors added to this, one of the more mature molecular classifiers, the 22 gene Decipher™ scoring system to reclassify (focus) a new model to predict outcomes. As I explained previously, these genetic tests are typically developed looking at the level of gene expression in biopsies or in removed prostates in a group of patients for whom an outcome is known (examples include prostate cancer free survival at 10 years or freedom from metastases at 5 years). The investigators (or companies) then go to a different institution or collection of biopsy material and see if their gene expression model developed from the first group accurately predicts the outcome in the second group. This is called “validation” of the test. Decipher has done all of this. The question is how it might change the risk classification of the “old” system.

This figure illustrates how it plays out when a large number of institutions collaborate to study the information gained and develop a new model.Screen Shot 2018-04-28 at 10.16.05 AM

As an example of how this can be used in the “real life” clinic, we are often faced with a patient who has a “favorable intermediate” prostate cancer. Let’s say this is a 75 year old man with excellent health. Should we advise that he adopt a “watchful waiting” strategy, given his age and the relatively low risk? By adding the genomic test, you can see that 27% of the time, this might be a bad recommendation. Similarly, in the unfavorable intermediate group, 40% of patients are moved into a high risk category. Such a patient might be well advised to “do more” (example: more prolonged ADT with radiation, or use of brachytherapy in addition to external beam radiation if they had chosen radiation therapy as their preferred treatment modality).

These kinds of improved focus will allow investigators to do better studies prospectively as well. In breast cancer it is already a standard of care to do molecular classification of certain stages and types of tumors, allowing women to make far better decisions on whether (for example) to take chemotherapy in addition to surgery/radiation. In prostate cancer, where I have been concerned that we aren’t “racing for the cure“, rather we are “crawling for the cure”, it looks like we may be catching up. Research is the answer – sign up and contribute!

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Are we any closer to cure? (yes and no)


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I have at least three thoughts on the issue of curing advanced prostate cancer. First, the number of new treatments that are life prolonging has been incredibly gratifying. See my posts on abiraterone, enzalutamide, apalutamide, Sipuleucel-T, and Radium 223, to say nothing of cabazitaxel and docetaxel. That said, my second comment (and yes, I DO say this in the clinic to try and keep some perspective on a deadly, but often slow disease) is that “if you die of a heart attack or a stroke, we call that a CURE!” Many patients have very slow moving prostate cancer that just grows old with them, and some of the drugs listed above can slow it down still further, even though the side effects (particularly of ADT itself) are definitely unpleasant. The third thought is an old saw: “For every complex problem, there is a simple answer, and it is often wrong.” I looked it up, and it is attributed to H.L. Mencken, who actually said, “Explanations exist; they have existed for all time; there is always a well-known solution to every human problem — neat, plausible, and wrong.”  I found he also said, “We are here and it is now: further than that, all human knowledge is moonshine”. Pretty cynical, but we digress…

Thus, the article that made me think about how complex a problem prostate cancer actually presents us was this one. The authors are very much the Who’s Who of prostate cancer research, and what they did was sequence the exomes from 1,013 prostate cancers. They were looking for so called, “driver mutations”, that is, mutations in a gene(s) that are the underlying cause, or at least the accelerators of prostate cancer. Their abstract conclusion states, “We find that the incidence of significantly mutated genes (SMGs) follows a long-tail distribution, with many genes mutated in less than 3% of cases. We identify a total of 97 SMGs, including 70 not previously implicated in prostate cancer…”

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The list of mutations found

This means that although we might see some drugs developed for the most common mutated driver genes, there lurks a host of others for which developing a drug for the very small number of patients (even if that is possible – not all mutated genes are “druggable”) with a given driver may not be economically attractive. And then there is the issue that if one of the common driver pathways (for example the androgen receptor) is effectively knocked out, as has been done with the second generation inhibitors, it is likely there are other mutated drivers in the wings. 

On the other hand, the study of metastatic prostate cancer has uncovered a wealth of new genomic classifiers that may be of real utility in further separating the “bad” cancers from the more indolent variety. As they state, “this analysis, which includes more advanced cases, has identified new and biologically and clinically relevant events and creates an opportunity to prospectively assess a metastasis-associated genomic marker for clinical stratification in localized prostate cancer.” All well and good, but don’t forget the issue of tissue heterogeneity. If you biopsy one metastatic site, or even one site within the primary tumor, you might get a different answer from a site only a few millimeters away or from a different metastasis, as I previously pointed out in another very sophisticated article by some of the same authors.

Nevertheless, be of good cheer. To have so many outstanding biologists and physician scientists uncovering the underlying mechanisms of prostate cancer is a good thing. The more we learn, the more opportunities we have to slow the disease down, even if there may never be a “cure” other than a heart attack. Immortality may be elusive, but your friends and family are not…carpe diem!

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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.

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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.

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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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