Immune therapy for PCa?

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Earlier in this blog, I attempted to explain the excitement surrounding the use of the checkpoint inhibitors and activated T-cells to fight cancer. Now the New York Times has done an excellent series on this approach which is worth reading, and no doubt more comprehensive and comprehensible than my effort. I encourage you to read it here.

For prostate cancer, there are both challenges and some early positive results that remain intriguing. An excellent review article published in April reviews the completed and ongoing efforts to harness the immune system in prostate cancer specifically. As the authors note, there have been variable results. One of the key challenges is to identify those patients who will benefit from the treatment and to date, using antibodies to stain the cancer cells that are making the PD-1 ligand that turns off the immune system has been challenging, since there are no accepted reproducible tests yet. Nevertheless, as demonstrated in this article, some patients do seem to have remarkable responses that offer real hope if the science continues to advance. If you read that abstract, pay attention to the issue of auto-immune side effects: “One had grade 2 myositis, one had grade 3 hypothyroidism, and one had grade 2 hypothyroidism. None of these patients had a response.” What this means is that the immune system was activated, but instead of attacking the prostate cancer, it attacked their muscle or thyroid, and apparently ignored the evil cancer cells. This has been a general problem in the entire field. Yet, in melanoma, where the greatest progress has been made, we are learning to walk the line between killing tumor cells and damaging the normal tissue with immune therapy.

My bias is that with continued progress in the vaccine field in prostate cancer (where we have one of the only vaccines approved for treating cancer, Sipuleucel-T), combining a vaccine with an immune booster type of treatment will ultimately provide the best results. Various trials of this sort are already underway.



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Precision medicine and AR-V7

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Much of the news this week in prostate cancer will be generated by the annual ASCO Meeting in Chicago where VP Joe Biden will be speaking tomorrow about the moon shot. It will be hard to miss the excitement – perhaps even eclipsing (for a day or so) the ongoing circus that is our presidential politics at the moment.

In prostate cancer, there are likely to be considerable news releases regarding precision medicine, and especially AR-V7, so I thought I would explain this a bit. Precision medicine is the broad terminology that (in oncology) refers to looking at the individual patient’s tumor genetic profile. In the broadest sense, it can also refer to all of our genetic makeup that can influence, for example, how we metabolize drugs. The optimal dose for you might be different from that for me based on our inheritance of slightly different enzymes that are involved in breaking down a certain drug. In oncology, it is now possible to perform whole exome sequencing (WES) on circulating tumor cells that give a nearly complete picture of an individual’s cancer – what is driving it, and what it might be susceptible to. In metastatic prostate cancer, as you know from my previous post, the tumor cells circulating in the blood stream could be coming from a variety of places, and likely each individual cell might have slightly different genetics – creating a considerable challenge in the long run for picking out “the” drug that is best for that patient, even with this high-tech approach. Nevertheless, WES has already demonstrated exceptional ability to find targetable mutations in cancer cells, often with several different pathways of potential susceptibility in each patient. Two challenges arise: 1) the drugs that target each “driver pathway” are often frightfully expensive, and 2) which one or ones would be the best to target?

So what about AR-V7? 14 of the 214 prostate cancer abstracts (keep that in mind when you ask your doctor, “Hey doc, is there anything new out there?”) deal with this biomarker. AR-V7 stands for Androgen Receptor – Splice Varient 7. I know…”too complicated for me to understand”. Think of it this way: The AR is the energizer bunny, and testosterone is the battery. Put the battery in the bunny, and he hops into the nucleus of the cancer cell and turns on all sorts of genes (including psa) that drive the cancer cell to do bad things (divide, invade surrounding tissue, metastasize, etc.). Now suppose the bunny becomes autonomous – no need for a battery – he can hop in and do his thing whether or not testosterone is present. This means that all of the new treatments that target testosterone (abiraterone/Zytiga™, enzalutamide/Xtandi™, etc.) really won’t do much. We call this resistance. Castrate resistant prostate cancer (CRPC) used to mean “simply” tumor progressing in spite of very low levels of testosterone (achieved with drugs like leuprolide/Lupron™, goserelin/Zoladex™, etc) or T-blockers like bicalutamide/Casodex™. What we now know is that patients whose cancers are expressing the AR-V7 form of the AR will not respond well to any of these drugs. This means that it could make more sense to proceed directly to treating with chemotherapy with a drug like docetaxel/Taxotere™. Dr. Scher and colleagues at MSKI report in this weeks JAMA Oncology and at the ASCO meeting on the utility of looking for AR-V7 in circulating tumor cells to guide therapy. Screen Shot 2016-06-05 at 8.21.17 AMUsing special immunofluorescent stains, they can identify the “bunny” (shown in white on this photograph from their publication) in the nucleus of some cells in some patients, and these patients are better treated with chemotherapy than with approaches targeting the AR. The implications of this are that we may be able to use such tests to avoid the expense and wasted time of trying to use AR directed therapies in some patients. As often happens, the science is far ahead of the insurance companies however. The Hopkins group have commercialized the test and in an abstract show that it can be cost effective in populations of patients where AR-V7 is likely to be >5% prevalent. Better yet, these insights are now in clinical trial to hopefully develop new treatments for these patients such as galeterone, which may be able to degrade (“kill”) the bunny as described in this abstract from the ASCO meeting.

So YES, we are making progress, and there is a LOT that is new “out there”. Scan the abstracts for yourself – it really isn’t that hard – and kudos to the prostate cancer researchers who are moving this fight forward so quickly.


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What does it feel like to die from this?

I have been asked some version of that question a number of times. Quite obviously, it is as uncomfortable to ask as it is to answer. Medical oncologists (myself included) deal with some version of this on a weekly basis and for the most part, answer as honestly and sincerely as they can – but necessarily at a superficial level. “We will do everything we can to keep you comfortable.” “When that time comes, I will be there for you and your family.” “That is a question I think we should address with our palliative care team or hospice – would you like me to get them involved?”

Yet the reality is much more complicated and if there is one word for the experience, I would pick “sadness”. For all of us, there is both personal and corporate/family sadness. We don’t want to say goodbye, and neither do our friends and family. I want to share some thoughts about that in a minute, but first I can deal with the physical/medical experience of death, which is one aspect of answering the question.

Whether you are a religious person or not, you are immortal. The carbon, oxygen, hydrogen, nitrogen, phosphorus and other atoms that make “you” will never be changed, or if they are, it will be in some sort of nuclear reaction that changes them into another element and involves incredible energy. After all, as Carl Sagan liked to point out, we are all stardust – made (or created if you would rather), from the stuff that happens when stars collapse. That is the root meaning of “disaster”. Beyond that, I happen to think that the energy you have put back into our universe in the form of words spoken, deeds done, mountains climbed, and so forth are immortal as well. “For every action, there is an equal and opposite reaction” is a physical principle we all learned in grade school science class. Thus, the butterfly wing that flaps in the mountains of Mexico and results in a cyclone half way around the world is not completely inconceivable in my view. You, or YOU… have made a difference in the cosmos by being alive. You have utilized chemical bonds that hold matter or elements together into energy and imparted that into your surroundings. When black holes collapse, millions of years later, we detect gravitational energy waves. When you breathed, your breath had more energy than the air you took in as you exhaled. It was warmer, had more CO2 and less O2, and velocity that forced the air around it to move. With a sensitive enough detector, there might be a way to detect that in a million years as some femtochange in some aspect of the cosmos.

When all of this melts down, the function we call “life” ends. The physicochemical reactions going on in your heart muscle, liver, and brain stop. Your consciousness is gone, and with it, what we know as “you” are gone, which brings us to the metaphysical aspects of life and death. Describing the end of “life”, if we are honest, is far more than the cessation of physical and chemical reactions. If it were not so, I cannot imagine my feeling that “sadness” is what describes the experience best. Within our conscious experience of life, “love” is what we cherish most, in all of its meanings. My favorite author, Pat Conroy, died a few weeks ago, and in looking at some of his quotes, I was most deeply moved by this one: “I do not have any other way of saying it. I think it happens but once and only to the very young when it feels like your skin could ignite at the mere touch of another person. You get to love like that but once.”

Certainly that captures a universal experience of one kind of love. But of course, all kinds of love (eros, philia, agape, pragma, philautia) are part of a pretty mysterious collection of our existential experiences, and all end with our personal demise. The result is sadness. Promises of immortality, however comforting, cannot remove the sting of death. Were it not so, the famous two line verse from the bible, “Jesus wept” [John 11:35] at the death of his friend, would not be there to ponder 2000 years later.

Dying from cancer involves all of this. It is a journey. For some, it ends unexpectedly with a sudden chest pain and unconsciousness as the heart fibrillates and oxygen is no longer delivered to the brain. However, for most, it is a series of attempts to beat back the cancer with increasingly toxic and or ineffective treatments, ultimately resulting in an admission by both the patient and physician that focusing on comfort through medication and family/support is the better option. Both the patient and the family must cross the threshold of giving the patient “permission” to die, and face the sadness. What physically comes with this is variable, depending on what organs are involved – bone pain (reasonably easily treated, although with well-known side effects of opiate administration or radiation) is common with prostate cancer, as is fatigue (not so easily treated). What is untrue is that the PSA can predict any of this. I have had patients who went elk hunting and enjoyed themselves with a PSA of 6000, and others who crossed the bar when their PSA was less than 10. Too much focus on the PSA can ruin whatever time a patient has been given either by the genetics of his own disease or by the ministrations of modern medicine.

But this sequence, to be traveled in one way or another by all of us, can also be beautiful in its own way. Life has meaning. Death has meaning beyond sadness. Immortality, in the way I have thought of it, is undeniable. Religion can (for some) be incredibly comforting as one faces the reality of death itself. Rather than try to go further in this (hopefully honest, yet inexorably sad) essay on the topic, I would strongly urge you to read a recently published book, “When Breath Becomes Air”, that I think captures a death from cancer with far more sensitivity and meaning than I am able to impart. Paul Kalanithi’s death from lung cancer in his late 30’s one year ago was a journey he captured as perhaps only a philosopher/neurosurgeon/husband/father and brilliant writer could accomplish. It was his gift to all of us, and by referring you to his writing, I hope I have extended that gift to you on a topic that we too often avoid.


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No pain, no gain?

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One of my patients last week had a heartfelt discussion regarding the survival benefit of ADT vs his quality of life. He enjoys body building and showed me some pretty dramatic pictures of himself during his last ADT cycle (on intermittent therapy) versus now, when he had been off treatment for ~6-9 months. Added to his concern was his decline in libido and sexual function during ADT, a common complaint especially among younger patients. The question of quality vs quantity of life was,of course, utmost on his mind.

Starting from the initial diagnosis, every (maybe that should be every !!) prostate cancer patient will experience a decrement in quality of life. Those who elect “watchful waiting” will nevertheless experience anxiety regarding the shadow of CANCER following their footsteps. Sure, you can put it out of your mind, but turn around and there it is, like the neighbor’s unwanted cat stalking you. Then there is the anxiety over what the next PSA will be. And if on active surveillance, what will that next biopsy show?? These issues are both real, disturbing, and often under-appreciated in the discussions surrounding screening…”we should still be screening, but not treat the men who don’t need it…” Really? What about the 80% of men who die at age 90 with prostate cancer at autopsy who never had to deal with the shadow? (The inevitable counter-argument is, “yes, and what about those who had early detection of a high grade cancer whose life was saved?”)

We also tend to ignore the impact of competing mortality in our discussions. “Sure you had a stent placed last year, and you already survived that small colon cancer, so why wouldn’t we be aggressive in treating this new problem?” Dr. Sartor provided an elegant discussion of this in an editorial on the PIVOT trial you can read here. Whatever the flaws in that study, it remains clear that we are not very good at predicting the non-prostate cancer “future” for our patients, and the older you are, the thinner the ice gets regardless of how many marathons you run.

When patients choose one form of primary treatment vs another, they are weighing the different side effect profiles of surgery or radiation as much as which is “most effective”. I often give patients a copy of this article from NEJM and encourage them to spend some time looking at the graphics in Figure 1 to get some idea of what they will face in the way of side effects from treatment. As any honest physician would tell them, treatment will involve side effects, some permanent, in the best of circumstances.

In the setting of more advanced disease, for example a patient who presents with metastases outside the pelvis, the recent CHAARTED and STAMPEDE trials both suggest an advantage to the earlier use of docetaxel chemotherapy in combination with ADT as opposed to ADT alone. These data suggest that “pay me now or pay me later” analysis favors the “pay me now” approach in terms of overall survival. But at what price for quality of life? Fortunately most chemotherapy side effects are reversible, but distinctly unpleasant, potentially making the equation something like “4 months of misery to provide 14 months of longer life….not all of which will be great anyway”.

Even in the very advanced setting, there is some evidence that greater toxicity results in improved survival. A recent analysis of the TROPIC trial of cabazitaxel suggested that the patients who had the most “toxic response” in terms of dropping their neutrophil count benefited the most in terms of overall survival.

While all of this seems incredibly negative (for which I apologize), the history of oncology as a field has been the incremental improvement in survival AND the development of newer treatments that provide such advances with diminishing toxicity. Pediatric leukemia, as discussed extensively in “The Emperor of All Maladies” is a great example of how pioneering patients and physicians worked together to find cures and reduce side effects. We may only be at the beginning of such achievement in prostate cancer, but with the advent of the newer hormonal and imaging agents, increasingly sophisticated surgery and radiation, vaccines and immunotherapy, and even the chemotherapies now available, we have  no doubt reached the end of the beginning. Onward!


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Olaparib for resistant prostate cancer

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In what is the first (and hopefully one of many) example of using modern genomic methods to match treatments to the molecular defects in prostate cancer, the FDA has just granted “breakthrough designation” to olaparib, a drug made by AstraZeneca. This followed a publication in the NEJM with nearly as many authors as patients, illustrating the power of team science and international collaboration.

Cancer cells develop numerous mutations that provide them with the ability to divide, metastasize, escape immune surveillance and so forth. One of the drivers of this mutation cascade is genetic instability, in part due to the accumulation of mutations that keep the cells from correcting DNA alterations. These mutations in DNA-repair enzymes can leave the cancer susceptible to additional inhibitors of DNA repair, one of which is PARP, an enzyme found in the nucleus that detects DNA strand breaks and initiates repair. When olaparib interferes with this enzyme, cells can become so genetically unstable they die.

In the TOPARP-A trial, 50 patients who had castrate resistant prostate cancer and had progressed on second generation anti-androgen treatment and docetaxel were given olaparib. 16 of 49 evaluable patients responded, however the exciting finding was that because these patients participated in the clinical trial and allowed the investigators to biopsy their tumors, it was possible to relate response to the presence of defects in the DNA repair genes. For this subgroup, 14 of 16 responded, indicating that using the repair defects as a biomarker you could predict high response rates, while at the same time, patients without such genetic defects had a much lower response rate (2/33). There is an excellent video that illustrates the results accompanying the publication that you can find by clicking here.

Although this is terrific news for prostate cancer patients, it brings a number of challenges. Testing for genetic mutations is a growing (and somewhat expensive) process. When compared to giving patients a drug that predictably won’t work, however, it can be very cost effective. Second, when you biopsy a tumor, the results can vary depending on where you biopsy as I discussed in this previous blog. “Liquid biopsies” of circulating DNA or tumor cells may provide some help in meeting this challenge.  Third, responses to targeted therapies such as olaparib tend to be rather short-lived, as the cancer cells continue to mutate to find ways around the new agent. The hope would be that combining a targeted treatment like olaparib with an immune approach might bring more prolonged responses. Finally, we must find a way to deal with the extraordinary costs of the new oncology drugs. The actual cost of olaparib is $13,440/month according to this article in the ASCO post. I have previously opined on this issue and invite you to join the discussion by clicking here.

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2015’s Major Advances

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One of the most frequent questions I hear in my clinic is “are we making any progress?” or “is there anything new out there?” The answer is always “yes” or more properly YES!

To keep up on the latest information on prostate cancer I have a few suggestions for places to search on the Internet. First, you can search for prostate cancer every single day if you want and get overwhelmed using the NCBI website, PubMed. Next, you can do a search on Google Scholar which will also include abstracts and patents, as well as citations that list something like prostate cancer. (I modified the clickable link to look at “prostate cancer” for 2015). Finally, you should keep track of new treatments that are being evaluated via clinical trials by looking at (link again modified to look for “prostate cancer” but you can modify to look for trials with specific agents or available in specific locations)

By posting these blogs and in other ways, many of us try to help our patients keep up on the various news alerts that circulate as well. Subscribe to this blog and you will get about one email/month from me that reflects the most pressing topic(s) I have heard about from my patients. I also highly recommend the Prostate Cancer Foundation website, which for today’s post “2015’s major advances” has an excellent list of the 2015 advances that I am hard pressed to improve upon, including video presentations. I hope that helps and wish you all a healthy 2016 which I guarantee is going to have an avalanche of progress, beginning with the upcoming ASCO GU symposium. I’ll try to post some of the highlights from there next month.


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Alzheimer’s and ADT…some perspectives

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Several of you asked for my perspective on the article that appeared last week in JCO and was widely picked up by the media. The NYT covered it with this headline: “Prostate Cancer Treatment Tied to Alzheimer’s Risk.”  NBC News said, “Common Prostate Cancer Treatment May Double Risk for Alzheimer’s”, then did a reasonable job of placing some perspective on the article in spite of the scary headline.

First, I would point out that this article is representative of the way medical investigators will be able to use BIG DATA in intriguing and effective ways. This team started off with a total of 5.5 million electronic medical records at Stanford and Mt. Sinai and used sophisticated computer algorithms to find 16,888 patients with prostate cancer and then looked further to find new onset Alzheimer’s disease among the 2,397 who received ADT therapy. They were able to control for known Alzheimer’s risk factors such as age and cardiovascular disease in doing their analyses. The statistical methods and mathematics for the study are certainly beyond anything I could understand or effectively comment on, but my congratulations to the investigators on their study!

To compare the risks of developing Alzheimer’s disease from ADT, one needs to know the benefit (if any) from taking ADT. There should be little doubt that a man who presents with painful boney metastases benefits far beyond any risk. Such an individual might expect to live 44 months with ADT alone (and might improve his prognosis to a median survival of 58 months by taking 6 cycles of docetaxel at the onset of ADT (CHAARTED trial). To give a graphical comparison of the Alzheimer’s risk compared to this man’s life expectancy from prostate cancer, I superimposed the Alzheimer’s risk onto the CHAARTED trial survival graph:

Screen Shot 2015-12-15 at 12.48.58 PM


What about someone with local disease but high risk based on PSA >20? In one of the larger trials comparing the addition of ADT to radiation vs. radiation alone in such patients, even as short as 4 months ADT resulted in cutting the disease specific mortality at 10 years from 8% to 4% (and improving overall survival from 57% to 62%) Again, this seems like a favorable equation in favor of using ADT, considering the risk of Alzheimer’s disease at 10 years in the new article is 5% with ADT and 4% without ADT. Moreover, the Alzheimer study found that shorter duration of ADT didn’t represent as much risk (< 12 months treatment resulted in an insignificant increase in risk when all the known other risks for Alzheimer’s disease were accounted for).

Thus in the larger context, I think for the majority of men who must consider ADT therapy, the risk of Alzheimer’s disease is small and for most would not be much of a factor to consider. The 5 leading causes of death for men in the United States are heart disease, cancer, unintentional injuries, respiratory disease and stroke (in that order). Alzheimer’s disease comes in at 9th place, representing just 2% of deaths, less than suicide which places 7th at 2.5%. I am currently reading one of the O’Reilly books, “Killing Patton,” which is full of quotes from the famous general. Death, he said, “in time comes to all men.” As a professional soldier, he wanted to die from “the last bullet of the last battle of the last war.” Most of us don’t imagine such glorious endings and would settle for a peaceful death in our sleep after a fine meal with our family, or perhaps, as one of my patients managed, walking back from a river with his fly rod in hand and his hip waders still on. Prostate cancer is terrible, and Alzheimer’s even worse, but most of us are destined to die of something else, and the real message is to live each day honorably and hopefully in the service of a greater cause.




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