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 Clinicaltrials.gov. (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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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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Gentlemen, Start your Moustaches !


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Movember is both a month and a cause, the latter being one you should commit to supporting. Adam Gerone described his journey starting this remarkable movement in a TED talk that you should watch, just for it’s inspirational value if nothing else. This year, Movember has morphed ahead and is challenging all of us to not only support the research into men’s health (and especially prostate and testicular cancers), but to get off the couch and MOVE, with the tagline “30 MOVEs in 30 days“. As my faithful readers will know, exercise is an incredible way to fight both cancer and the side effects of androgen deprivation.

So here’s the deal: I think you should sign up with Movember to raise money for our cause AND you should commit to exercising more this month. If you don’t have a team to join or don’t want to grow your own moustache to remind your friends of how important our health is, you can support my scraggly moustache by clicking on THIS LINK, but in any case, enjoy this fabulous month and get off the couch! That’s it for today – I’m off to the gym.

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The PCF Meeting and Heterogeneity


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Let me just say again that the Prostate Cancer Foundation Annual Retreat is overwhelmingly my favorite meeting of the year. The organizers bring in the very best researchers, both clinical and basic science oriented for a two day intense update. Trying to take notes during the sessions leaves you with writer’s cramp and brain ache, but each year brings incredible progress. You can get some idea of the progress for this year from an excellent overview lecture given by Jonathan Simons. Thanks to PCF for getting this up on the web quickly! If you are a patient or family member, please spend 30 minutes viewing Jonathan’s talk and you will definitely not need to ask your physician, “is there anything new?”. (But try not to embarrass him/her with your new insights, either!)

I think the facet of cancer most commonly misunderstood by non-scientists (patients/families) is heterogeneity. While there were several presentations that touched on this, Steven Bova’s talk, reviewing the Nature paper he and his colleagues published this year, probably illustrates the phenomenon best. This international group was able to do whole genome sequencing on cancer metastases (and primary tumors) in 10 patients who had just died from prostate cancer. You can think of this as looking at a fingerprint of different small pieces of tumor found in the prostate, a lymph node in the pelvis, another in the neck area, and maybe two more from some spots you identified on a bone scan. When you look at your fingerprint, there are lines that divide, curve, end, and so forth in patterns that are completely unique to you. Thus each individual tumor metastasis could be identified by the unique set of mutations found at that site and you could look back at the primary tumor to see how many of the mutations and other genetic alterations (deletions, amplifications, etc.) were present in the original tumor or were shared (or not) by another metastasis. What emerges from such investigation is a phenomenal picture of genetic instability starting even in the primary tumor (about which we simply say, “all right, you have a Gleason 3+4 cancer in 3 out of 12 biopsy cores” – an incredible oversimplification of what is really there under the microscope) You can also think of it as tree trunk with multiple branches, then leaves. Here is an illustration from the paper for two patients.

Screen Shot 2015-10-30 at 11.00.13 AMThis is the trunk and tree illustration of genetic alterations found in a patient’s metastases. As you can see in the trunk (site of the original tumor) there are already a host of changes, each of which might be related to tumor suppressor genes or oncogenes that drive the tumor. You can appreciate how much more complex this is than simply saying “Gleason pattern 3+4”, and if you look in the same tumor, just a few millimeters away, you might find different alterations. Indeed, in some studies like this, it was the “not dangerous” Gleason 6 pattern tumor from one area of the prostate that spread and led to metastases, not the “more dangerous” Gleason 7 pattern tumor found somewhere else in the patient’s prostate. This gives you some notion of why it may be challenging to send off a bit of tumor for genetic analysis, then make a clinical decision based on just looking at “the worst” area for predicting what to do in terms of treatment. In the figure, you can also appreciate that if you spent millions of dollars finding a drug that worked for the “CTNNB1” amplification, it would only be part of the story. However, it might be a better drug to develop for this patient than one for MYC amplification shown at the lower right, since that target is only present in one branch of the tree. Also note that androgen receptor amplification (AR amp) is found in the “leaves” , illustrating that the tumors in sites D and E have figured out a way to get around hormone treatment by increasing the number of receptors for the tiny amount of testosterone that might not be suppressed by drugs like leuprolide/goserelin/abiraterone or blocked by drugs like bicalutamide/enzalutamide.

Screen Shot 2015-10-30 at 11.02.16 AM

In this figure, we can see the incredible picture of how the cancer has spread from the prostate to different sites, but also from one site to another, and even from a metastatic site back to the prostate itself. During the conference, there were numerous similar examples of heterogeneity shown. As one example, using the most modern of imaging techniques (such as PET scanning), patients who were initially treated with hormone therapy, and who had “complete remission” as determined by dramatic drops in PSA and disappearance of all metastases on routine bone scans, were in fact shown to have mixed responses with the more sensitive scans. While most of the spots on the sensitive scan went away, a few got worse, and actually new ones appeared elsewhere – all the while, we clinicians are telling patients that “everything looks great” because the regular bone scans and PSA have responded so nicely.

I think all of this leads to the conclusion that no one will ever walk out of a lab with a single new drug that represents “the cure” for all patients with prostate cancer. Instead, we should be able to figure out how to better  attack the trunk of the trees for individual patients, rather than just picking off a leaf. For now, the trunk target most tractable relates to the androgen signaling pathway, and the good news is that with the newer drugs available, we seem to be making real progress in turning prostate cancer into more of a chronic disease like diabetes, even if “cure” remains elusive. For many men, the remissions that are available with existing drugs are “good enough” to extend life for many years, sometimes decades. And as I sometimes joke with my patients (in my black humor sort of way… but there is truth here, none-the-less) “If you die of a heart attack at age 90, I’m going to count that as a cure!”

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Support the petition for reasonable drug prices.


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I hereby confess that when it comes to healthcare, I am somewhat of a socialist. I feel healthcare should be a right, not a privilege. However, I would draw some sort of line for certain conditions, even including cancer. For example, there is little evidence that 3rd or 4th line therapies for many cancers have any significant impact on survival, yet we often prescribe them for patients who are healthy enough to try them with the rationale that “even a 5% chance” is worth taking. Weighing that 5% chance against a 25% chance of causing further toxicity and NOT improving someone’s quality of life requires sensitive counseling and is part of the “art” of practicing medical oncology. We already don’t pay for cosmetic surgery when it comes to face-lifts, but breast cancer patients enjoy coverage for breast reconstruction, while men with erectile dysfunction following surgery or radiation don’t have coverage in most instances for ED drugs or other treatments. Thus, there is a lot of room for improvement in our health care system. The ACA is not the best answer, but it may provide at least a start through inclusion of coverage for end-of-life counseling and funding of the Patient-Centered Outcomes Research Institute. We should not tolerate having the most expensive health care system on the planet that delivers care that ranks dead last in the developed world.

One of the most disturbing trends in our broken health care system has been the introduction of numerous new cancer drugs that have (in some cases) remarkable activity but are priced beyond any reasonable value consideration. Trying to decide about “value” itself is an extremely challenging undertaking. Numerous articles like this one have proposed guidelines through which value might be better quantified. Now a group of oncology physicians have published a position statement regarding cancer drug costs that deserves your attention. They propose a number of solutions that could help the cancer community move toward the kind of progress made by the AIDS community when they were faced with similar challenges of highly expensive drugs. You should read the whole article to see the context, but their enumerated suggestions are as follows:

If you agree that these actions should become a part of our national discussion, please join me in signing the petition these thoughtful oncology leaders have started. You can click on this link to sign up, and please invite your friends to join you.

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