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Conversations With Prostate Cancer Experts


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Switching from One Chemo Drug to Another

Dr. Emmanuel Antonarakis is an Associate Professor of Oncology and Urology at the Johns Hopkins University Sidney Kimmel Comprehensive Cancer Center.

Prostatepedia spoke with him recently about his work on the benefit of switching men from Taxotere (docetaxel) to Jevtana (cabazitaxel)— or vice versa—if his PSA doesn’t go down by 30% in the first twelve weeks of treatment.

You’ve published a paper on switching patients from Taxotere (docetaxel) to Jevtana (cabazitaxel) and vice versa. What is the thinking behind switching chemotherapeutic agents? Why would you want to switch agents earlier as opposed to when the first chemotherapy drug stops working?

Dr. Emmanuel Antonarakis: The motivation behind this paper was that the FDA-approved recommended dosing schedule for both Taxotere (docetaxel) and Jevtana (cabazitaxel) is a course of ten doses, given three weeks apart. When patients begin FDA-approved Taxotere (docetaxel) or FDA approved Jevtana (cabazitaxel), they’re often told by their oncologists that they should expect to receive this chemotherapy once every three weeks for up to ten doses. A patient may not receive ten doses or might stop the therapy before he reaches ten doses because he cannot tolerate the therapy and has unmanageable side effects, or his cancer begins to progress before he ever get to dose number ten. If his PSA begins to increase again at dose six or seven or the tumors begin to grow again, his oncologist might ask him to stop chemotherapy.

We then wondered whether the ten doses was a reasonable time to wait or whether there could be an early indicator, or an early sign, of therapy resistance or therapy futility without having to go through six, seven, eight, nine or ten doses.

The idea that we had was to test an early intermediate marker of sensitivity or resistance to the chemotherapy. The best marker of early sensitivity or resistance that we could think of was whether or not a patient had a 30% PSA drop within the first four cycles of therapy. As you recall, if the therapy is given once every three weeks, four cycles basically means 12 weeks, which roughly equates to about three months.

The decision to use this intermediate endpoint was not arbitrary; it was based on some large retrospective meta-analyses that have shown that the strongest predictor of overall survival in patients receiving both Taxotere (docetaxel) and also separately Jevtana (cabazitaxel) was whether or not patients had a 30% PSA reduction after 12 weeks.

Patients who do achieve at least a 30% or greater reduction in the first 12 weeks have a survival that’s longer than patients who don’t achieve that endpoint. We thought, well if this endpoint is strongly correlated to survival, perhaps we can use it as a decision point. If after four doses of therapy or 12 weeks of therapy a patient don’t achieve a 30% reduction in PSA perhaps we should switch him to the other chemotherapy, rather than sticking with it and just waiting for either the toxicity to develop or the PSA or the radiographic disease to progress. That was the hypothesis.

We designed a relatively small study of about 63 patients. We used a 2:1 randomization so they were twice as likely to get Taxotere (docetaxel) compared to Jevtana (cabazitaxel). Approximately 41 patients got Taxotere (docetaxel) first. The other 22 patients, got Jevtana (cabazitaxel) first. Irrespective of which arm they were randomized to, they received the first four doses of chemotherapy in 12 weeks. We checked their PSA every three weeks.

At the end of the fourth dose, if the PSA level had dropped by 30% or more, the patients would continue on the same therapy on which they started. However, if patients did not achieve a 30% reduction or more, they would be switched to the other chemotherapeutic agent.

If a patient had a 25% reduction, we would switch him to the other agent because we thought that was not good enough. If someone received Taxotere (docetaxel), and their PSA dropped by 25%, even though it dropped by 25%, it did not meet that 30% threshold so they would then switch for the fifth dose to receive Jevtana (cabazitaxel) for the remainder of their chemotherapy. The inverse was also true. If the patient received Jevtana (cabazitaxel) first and also did not get a 30% reduction by week 12, in other words four doses, they would also switch to receive Taxotere (docetaxel). The interesting thing that we found in both treatment arms was that the chance that a patient had a favorable PSA response, which was defined as a 50% or more decrease, was higher than we had seen in historical trials using each drug by itself without switching. To put some numbers on that, we found that there was about a 54% chance that patients would have a 50% reduction in PSA if they had to the opportunity to switch from one chemotherapy to the other, compared to about a 45% chance of PSA reduction in the historical data where patients did not switch.

Did it matter if they got Jevtana (cabazitaxel) first or Taxotere (docetaxel) first?

Dr. Antonarakis: What we found out is a bit of a paradox: people could benefit from the switch in both down over time and the availability of non-chemotherapy agents is going up. A lot of these patients who may not have a 30% PSA reduction with one chemotherapy, might choose to do another hormone therapy, a radiopharmaceutical drug like Xofigo (radium-223), immunotherapy like Provenge (sipuleucel-T), or even a PD-1 inhibitor, or potentially a PARP inhibitor.

It might be difficult to convince a patient who has just failed one chemotherapy after four doses to go immediately to a second chemotherapy. I’m not 100% sure what the future will hold. I also don’t think this is a trial that we could have conducted today.

What would you say to a man reading it? That this is worth talking to his oncologist about or is this just something interesting for him to know about?

Dr. Antonarakis: Patients who are beginning their first chemotherapy should discuss this trial with their oncologist, and together with the oncologist decide in a joint fashion whether switching from one chemotherapy agent to another after four doses might be right for him, especially if he’s tolerating the chemotherapy well. If he tolerates the drug and his PSA has not dropped by 30% or is continuing to increase, then in my opinion rather than continue with the potentially futile therapy, a patient and his oncologist may wish to consider using this trial to guide or justify their choice of switching drugs earlier rather than later. directions. That was fascinating to us because, as we all know

Jevtana (cabazitaxel) was specifically approved by the FDA as a second-line curative therapy only indicated in men who have failed Taxotere (docetaxel) first. Based on that reasoning, one might expect Jevtana (cabazitaxel) to work better after Taxotere (docetaxel) but not Taxotere (docetaxel) after Jevtana (cabazitaxel).

This is not what we found.

We found that in both directions, both from the Taxotere (docetaxel) to Jevtana (cabazitaxel) switch, but also in the Jevtana (cabazitaxel) to Taxotere (docetaxel) switch, there was a significant amount of patients, approximately half, who were salvaged by the crossover therapy. By salvaged, I mean those who did not achieve a 30% PSA reduction with the first drug but did achieve a PSA reduction of 50% or more after crossing over to the second drug.

As I mentioned before, this occurred in both directions, both in patients receiving Jevtana (cabazitaxel) after Taxotere (docetaxel) and Taxotere (docetaxel) after Jevtana (cabazitaxel).

Are the side effects of Jevtana (cabazitaxel) a little bit easier to take than the side effects of Taxotere (docetaxel)?

Dr. Antonarakis: Interestingly, the side effects of Jevtana (cabazitaxel) in the published literature indeed appear to be slightly better. In this particular trial, which was very small obviously, they seemed comparable. In other words, we did not see any appreciable difference between the Taxotere (docetaxel) and the Jevtana (cabazitaxel) overall in terms of side effects. Taxotere (docetaxel) had a little bit more neuropathy nerve damage, which Jevtana (cabazitaxel) did not do. On the other hand, Jevtana (cabazitaxel) had a little bit more neutropenia, while the Taxotere (docetaxel) did not.

I would say that when patients receive these agents in a first-line setting, in other words, when they had not received another chemotherapy previously, their side effects were fairly comparable. I don’t think there was a clear signal in terms of one drug being clearly safer than the other.

Does it matter which you get first?

Dr. Antonarakis: From a side effect perspective, they’re both fairly equivalent in terms of tolerability, with slight differences in neutropenia, which is worse with Jevtana (cabazitaxel) and neuropathy, which is worse with Taxotere (docetaxel).

What is the next step? Are you going to run a similar trial with more patients?

Dr. Antonarakis: One question that arises is if this small randomized trial is enough to change practice. Should a community oncologist or urologist give Taxotere (docetaxel) for four doses and wait to see if the patient’s PSA drops by 30% or more? If it doesn’t drop to 30% or more, should he to switch to Jevtana (cabazitaxel)?

I have to admit that this is something that I have done in my practice a few times, but I really don’t believe that this is ready for clinical practice yet. Yes, in this trial, we showed that the PSA response rates could potentially be improved by this switch strategy. What we did not demonstrate was whether this improves overall survival.

The ultimate question is does switching chemotherapy agents after four doses improve survival, compared to just waiting until we see radiographic or clinical progression to switch agents. That would, as you mentioned, require a larger Phase III randomized study. The idea of study design would be to randomize patients to the switch strategy versus no-switch. We would randomize one group of patients to receive chemotherapy and switch if their PSA did not drop by 30%. The second group of patients would start chemotherapy but would not be given the opportunity to switch, even if their PSA did not drop by 30% or more. The randomization would not necessarily be the randomization to the chemotherapy, but would be randomization to a switch strategy versus a stick-with the first-chemotherapy strategy.

Sanofi, which makes both Jevtana (cabazitaxel) and Taxotere (docetaxel), have not been eager eager to respond to such a study because of financial considerations and also because the patent life of Taxotere (docetaxel) is over and the patent life of Jevtana (cabazitaxel) will be expiring soon.

Unfortunately, we might be left with a Phase II study that may, potentially, not translate into a Phase III study. I think individual patients and individual oncologists may look at these data and might be convinced that some patients might potentially benefit from a switch strategy, especially those who did not have any degree of PSA reduction after four cycles.

An added complexity is that the popularity of chemotherapy is going down over time and the availability of non-chemotherapy agents is going up. A lot of these patients who may not have a 30% PSA reduction with one chemotherapy, might choose to do another hormone therapy, a radiopharmaceutical drug like Xofigo (radium-223), immunotherapy like Provenge (sipuleucel-T), or even a PD-1 inhibitor, or potentially a PARP inhibitor.

It might be difficult to convince a patient who has just failed one chemotherapy after four doses to go immediately to a second chemotherapy. I’m not 100% sure what the future will hold. I also don’t think this is a trial that we could have conducted today.

What would you say to a man reading it? That this is worth talking to his oncologist about or is this just something interesting for him to know about?

Dr. Antonarakis: Patients who are beginning their first chemotherapy should discuss this trial with their oncologist, and together with the oncologist decide in a joint fashion whether switching from one chemotherapy agent to another after four doses might be right for him, especially if he’s tolerating the chemotherapy well. If he tolerates the drug and his PSA has not dropped by 30% or is continuing to increase, then in my opinion rather than continue with the potentially futile therapy, a patient and his oncologist may wish to consider using this trial to guide or justify their choice of switching drugs earlier rather than later.

Join us to read more conversations about chemotherapy for prostate cancer.


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Dr. Ken Pienta: Chemo For Prostate Cancer

Dr. Kenneth J. Pienta, of the Johns Hopkins University School of Medicine, is an international expert in the development of novel chemotherapeutic agents for prostate cancer. He was the recipient of the first annual American Association for Cancer Research Team Science Award and is the author of more than 300 peer-reviewed articles. He frames this month’s conversations about chemotherapy for us.

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In 2018, chemotherapy for prostate cancer continues to be one of the many options we have to lengthen the lives of patients suffering from metastatic prostate cancer. There are still multiple other therapies that we don’t consider chemotherapy. Second-generation anti-androgen therapies like Zytiga (abiraterone), Erleada (apalutamide), and Xtandi (enzalutamide) are all now standards of care in castrate-resistant prostate cancer. We also have Xofigo (radium-223) as an option for patients with bony metastases.

There are two chemotherapies that have been approved for prostate cancer: Taxotere (docetaxel) and Jevtana (cabazitaxel). Now, the real challenge for patients and providers is when to use those chemotherapies.

Multiple studies have demonstrated that, when you’re newly diagnosed with metastatic prostate cancer, it may be beneficial to receive a limited number of doses of Taxotere (docetaxel) at the start of hormone therapy. That’s especially true if you have multiple places where the cancer has spread. That’s not correct for all people, but for some patients, it is a good option. More and more physicians are prescribing Taxotere (docetaxel) with a luteinizing hormone-releasing hormone (LHRH) antagonist at the start of therapy.

However, that doesn’t mean you cannot use Taxotere (docetaxel) after other things have failed. If you failed second-line hormone therapy or have failed radium therapy, Taxotere (docetaxel) is still a good option that helps people live longer.

Jevtana (cabazitaxel) continues to be a good chemotherapy option if patients have failed Taxotere (docetaxel).

Thank goodness we’ve seen over the last several years an increase in the number of drugs available to treat metastatic prostate cancer in addition to chemotherapy. Chemotherapy has been around for quite a while now, but there is still a role for it.

Again, the challenge for all of us is: when do we slot them in for you? The chemotherapy we use for prostate cancer is really a single agent chemotherapy, either Taxotere (docetaxel) or Jevtana (cabazitaxel). This is not the multi-agent therapy we use for other cancers, so the idea of major side effects is a bit overblown. For example, nobody vomits from chemotherapy for prostate cancer. The drugs we use to prevent that are too good.

We also have gotten much smarter about limiting the number of doses we use. We don’t necessarily give chemotherapy until it doesn’t work anymore. Often, we just give several doses and then take a break. If you get more than a couple doses of chemotherapy, you will still lose your hair temporarily.

Chemotherapy can make you feel more tired when it lowers your blood count, and it can make you more susceptible to infections, but people are very rarely hospitalized now for an infection from chemotherapy. It’s virtually unheard of that somebody would die as a side effect of chemotherapy.

The major side effect of Jevtana (cabazitaxel) tends to be diarrhea, but again, as we’ve learned about the dosing of that drug, that has become more manageable.

Another side effect of both drugs can be peripheral neuropathy, which is tingling in the fingers and toes. But we watch for that too. If you start to develop that, we tend to stop the drug. These are very tolerable medicines.

The word chemotherapy always evokes images of horror, but chemotherapy in 2018 is a lot different than it was even five years ago. We just know how to give chemotherapy much better. When I started in the field 30 years ago, if you had metastatic castrate resistant prostate cancer, survival was 6 months. Now, with the advent of all these newer therapies, we’ve gotten much better. The landscape of how to treat prostate cancer has changed completely in the last five years. It will change completely again in the next five years. The challenge is in what order are we going to use all these powerfully good drugs rather than having only one drug to give or none at all.

For us as physicians, it’s an exciting time to take care of men with prostate cancer.

Join us to read this month’s conversations about chemotherapy for prostate cancer.


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Chemotherapy For Prostate Cancer

Pp_Aug_2018_V3_N12_Thumb

This month we’re talking about chemotherapy for prostate cancer.

Dr. Snuffy Myers offers his thoughts about this month’s conversations:

Patients are often under the impression that chemotherapy drugs like Taxotere (docetaxel) and Jevtana (carbazitaxel) won’t significantly improve survival and will only dramatically impair quality of life. A patient once said to me, “That sounds like a bad deal.” I hope this issue of Prostapedia changes your view of chemotherapy.

The potential benefit of chemotherapy depends on where you are in the natural history of metastatic prostate cancer. If you have just been diagnosed with widespread metastatic prostate cancer, Lupron (leuprolide) plus Taxotere (docetaxel) can have a major benefit in terms of your survival. At this point, you are likely to tolerate chemotherapy better than you would if you had already been through multiple other treatments. However, even in patients who have been extensively treated before chemotherapy, this treatment can often provide significant relief of bone pain that outweighs the drug side effects.

The major alternatives to Taxotere (docetaxel) in this setting are the new androgen blocking agents, such as Zytiga (abiraterone), Xtandi (enzalutamide) or Erleada (apalutimide). Each of these drugs can cause side effects more severe than Taxotere (docetaxel) in some patients. Also, Taxotere (docetaxel) treatment extends for just six treatments done every 3 weeks. In contrast, the androgen blocking agents are typically given continuously until they fail to control your cancer.

In many other cancers, patients benefit greatly when we combine drugs. While the search for effective Taxotere (docetaxel)-based combinations has been going on for decades, no combination has survived rigorous Phase III testing. I, and many others in the field, think that this may be because prostate cancer is a very heterogeneous disease. The path to success requires that we understand at a molecular level the various forms of this disease and the key vulnerabilities of each variation.

One example is the sensitivity of prostate cancers with a BRCA2 mutation to Paraplatin (carboplatin). Another example is the activity of Jevtana (carbazitaxel) + Paraplatin (carboplatin) in anaplastic prostate cancer.

There are several reasons to be optimistic about progress. First, research into the molecular heterogeneity of prostate cancer and the clinical implications thereof is proceeding rapidly. Second, leads that emerge from this research are being tested more rapidly and with greater sophistication than at any time in the past.

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Shop Around For A Radiation Therapist

Dr. William Hall of the Medical College of Wisconsin offers advise to patients looking for a radiation therapist.

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Dr. Hall says: Radiation therapy is an extremely technical specialty that is rapidly evolving. Many patients think that radiation therapy is the same, regardless of where they receive it.

That is not so.

Expertise, delivery methods, and the unique methods of radiation therapy administration can vary tremendously from hospital to hospital. That’s extremely valuable for patients to understand.

You should seek a radiation oncologist who specializes in your type of cancer, someone who focuses their research and clinical efforts on a few types of cancer. In larger academic centers, radiation oncologists tend to do that.

Join us to read the rest of Dr. Hall’s comments on radiation therapy for prostate cancer.


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Radiation Therapy + The Abscopal Effect

Dr. Charles G. Drake of New York Presbyterian/Columbia University Medical Center, discusses the rare but intriguing abscopal effect.

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Dr. Charles Drake says: There was an article in the New England Journal of Medicine showing an abscopal response with Yervoy (ipilimumab) anti-CTLA-4 in a patient with melanoma. It was a beautifully done paper with nice immunological correlates. After that got published, we found that radiation oncologists and medical oncologists were giving people a combination of immunotherapy and radiation and were telling patients they would get abscopal responses. But that’s a bit overly ambitious. In the clinic, it’s not that easy. It’s going to be a while before we understand what’s needed therapeutically to be able to induce abscopal responses in the majority of patients. It’s going to take a little more work before we can have that happen broadly. On the other hand, if we can make it work, it’ll be fantastic. Dr. Hammers’ trial combining anti- PD-1, anti-CTLA-4, and radiation in kidney cancer is perhaps a more clever approach. That may be what we need to do.

In other words, abscopal responses do happen, but we don’t exactly know why or how and can’t reproduce it?

Dr. Drake: Exactly. And it doesn’t happen nearly as often as we’d like.

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Health/Tech Collaborations For Prostate Cancer

Dr. Paul Nguyen is an internationally recognized expert in prostate cancer clinical care and research. He has published over 250 original research articles, has various national leadership roles and is the Dana-Farber Cancer Center Genitourinary Clinical Center Director for Radiation Oncology, Vice-Chair for Clinical Research in the Department of Radiation Oncology, and Associate Professor at Harvard Medical School.

Prostatepedia spoke with him about collaborations between healthcare and tech industries for prostate cancer.

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Have you had any particular patients or cases that changed how you view your role as a doctor or how you practice medicine?

Dr. Paul Nguyen: Several years after treating him, I heard from a patient who recounted for me what it was like to meet with me when he had first been diagnosed with recurrent disease. He said he’d had a lot of uncertainty and anxiety about his future. He said that the way I spoke with him had changed it entirely for him. He said I had a plan for him, knew exactly what we were going to need to do, and that we were going to do it.

I didn’t do anything particularly different in that encounter than I normally do, but hearing that made me realize how patients really hang on our every word, our every facial expression, our every cadence, and the emotion that we project when we speak. This made me so aware and conscious of making sure that, at all times, in every encounter, I have that combination of being sure about what I need to do and maintaining hope and optimism in every part of our discussions.

That was a good learning cycle for me. I hadn’t thought of it that way when I was with a patient. You just don’t think that every intonation, every gesture has such a huge impact. But it does. That was a very valuable learning experience for me that has really shaped how I think about every patient encounter before I walk into the room.

What are your current research projects? Which are you most excited about?

Dr. Nguyen: I have spent my entire career using information from the medical record about patients’ health status and tumor characteristics to figure out which men should get hormone therapy and for how long. Now, I’m incredibly excited about the opportunity to unleash the power of genetic testing of tumors. This will help us understand, on a genetic and molecular level, which patients should be given hormone therapy and for exactly how long. This will be a lot more precise than the clinical information by itself. I’m working with Dr. Felix Feng and others, which has been a wonderful collaboration.

How do you see evolving technologies impacting prostate cancer research? Dr. Nguyen: Technology gives us opportunities to do the kinds of studies we never dreamed possible, which is amazing.

I’ll give you an example. Dr. Feng and I are about to take prostate cancer samples from biopsy tissues taken 25 years ago from men who had cancer, samples stored without a clear purpose in mind. I give a huge amount of credit to the people who designed these studies in the early 1990s. They had no way to analyze this tissue, but they knew that someday, this tissue would be important to humanity. There wasn’t a specific test that they were storing these samples for, but they knew some kind of technology could decode what was going on in those tumors, to study how the tumors work, and who should get which treatment.

I feel so fortunate to come along 25 years later, when we do have the technology to analyze this tissue, and research it. This is the research I’m about to do now, which would never have been possible without new technologies.

Do you see technology impacting how we design clinical trials from the get-go?

Dr. Nguyen: Absolutely, because now people are designing trials with technology. There’s a trial being led by Dr. Feng from UCSF and Dr. Dan Spratt at the University of Michigan that incorporates genetic technology.

All the patients are tested upfront with this new technology to help decide which arm the patient goes into, which is really cool. This new scientific technology is being worked into clinical trial design.

Which innovations or technologies have the biggest impact?

Dr. Nguyen: There are two kinds of impacts. One is the ability to do large-scale genomic studies for a relatively low price. That has been a game-changer because it used to be so expensive to sequence the DNA of patients, but now you can approximate that rather cheaply and then do studies on thousands of patients. This way, we can pick up very small signals, which are very valuable.

The other invaluable impact is the ability to detect very minute amounts of tumor in the blood, very tiny traces that can tell us a lot.

In the circulating tumor cell?

Dr. Nguyen: Exactly.

Do you think artificial intelligence will play a role?

Dr. Nguyen: For sure. I’ve spent most of my career working on simple, clinical data. You can see the patterns of simple data yourself by doing simple statistical analyses. But now, the patterns are much more complex. Instead of five datapoints, you might have two million datapoints per patient. So we need AI. We need sophisticated machine learning to help us discern some kind of pattern out of that huge amount of data, to help us make sense of it.

Are there any specific collaborations, other than the ones we’ve already discussed, that you think look promising?

Dr. Nguyen: We’re seeing a lot more collaborations across specialties and disciplines to get research done. So much of what we’re seeing now is team science whereas people used to do studies with their own group.

Now, if you look at a paper, it’s not just one group or one discipline. At each institution, it’s five disciplines, and then you might have ten institutions on a paper, each contributing something different because that’s just what it takes now.

Every group has its own, little special expertise that gets put together to get a big paper or a big trial done. That’s what has really exploded. We’ve all recognized that, in order to get good science done, we have to team up.

Is just it easier to collaborate with people now via email and sharing of data? Or is there something about the way cancer research has been funded that has fostered that collaboration?

Dr. Nguyen: Yes. Those factors definitely contribute. It is definitely easier to share data now with the internet. Efforts to fund team science have definitely led teams to be created that might not have been created organically before.

There’s something fundamental about the increasing use of technology in studies and trials where only certain groups have this kind of technology expertise. You might have one group that knows a lot about the technology and another group that has a large number of patients and ideas. And you have to reach outside of your little sphere in order to get these kinds of exciting studies done.

It seems like before everything was pretty much siloed: you had tech, you had healthcare, and then, within healthcare, you had prostate cancer versus pancreatic cancer versus breast cancer. But now, the walls are coming down between those silos, with things like increased genetic testing. Would you say that’s true?

Dr. Nguyen: Absolutely. For example, some of the cool studies done in prostate cancer genetics were modeled on similar research done in breast cancer genetics several years before. Breast cancer had the Oncotype study, and then prostate cancer developed the Oncotype test many years later. We’ve seen molecular subtypes of breast cancer (luminal A, luminal B, and basal), and now there’s a study led by Dr. Feng suggesting that you’ve got similar kinds of subtypes in prostate cancer. We have to be knowledgeable about other fields. You can’t just be in your own silo now.

Last week, I spoke with engineers at University of Pennsylvania who are working with microchip-based technologies and machine learning to increase liquid biopsy’s usefulness in pancreatic cancer. They said this allows them to process much more data than they could before. They hope this has potential in other cancers. I know that’s more along the lines of diagnostics than what you’re doing, but do you have any thoughts about that?

Dr. Nguyen: We are all trying to take those same kinds of approaches with the folks who do machine learning. We need them desperately now because we’ve got so much data, and we just can’t figure it out on our own.

That’s exactly where we’re all headed.

Join us to read the rest of Dr. Nguyen’s comments on collaborations between the health and tech fields for prostate cancer.


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Clinical Trial Eligibility + Black Men

Ms. Marie Vastola is a Clinical Research Assistant in Radiation Oncology at Dana-Farber/Brigham and Women’s Cancer Center. She works on Dana-Farber-led and international clinical trials that accrue men with multiple stages of prostate cancer. She is an author on six research articles focusing on prostate cancer and has presented her research at a national conference.

Dr. Paul Nguyen is an internationally recognized expert in prostate cancer clinical care and research. He has published over 250 original research articles and has various national leadership roles and is the Dana-Farber Cancer Center Genitourinary Clinical Center Director for Radiation Oncology, Vice-Chair for Clinical Research in the Department of Radiation Oncology, and Associate Professor at Harvard Medical School.

Prostatepedia spoke with them about how eligibility requirements for prostate cancer clinical trials may unfairly exclude African American men.

How have black men been underrepresented historically in prostate clinical trials? What are some of the prevailing theories or ideas about why that might be?

Dr. Nguyen: It’s multifactorial, and that was something that our research aimed to get at. Because of the historical experiences like the Tuskegee experiment, some African- Americans may have been more leery of engaging in clinical trials. Because trials require certain costs and extra time away from work, this can be more difficult on certain populations. Or it could be from the doctor side. Some doctors may not be as willing to engage African-American patients to enroll them on trials. There are multiple factors, so it’s hard to know exactly what is the main driver.

Ms. Vastola: We have patients come from long distances to Dana-Farber, and they do that because they know that Dana-Farber is a good place for them to get treated. Many patients, especially ones who travel long distances, either have connections in the medical field and that’s how they found out about this, or they’re highly educated and they have the resources to look into research and potential treatments themselves. These are tools that only people who are a little more privileged have.

Why did you zero in on eligibility criteria? What were you looking at?

Ms. Vastola: Actually, a patient is what started this research project. I had been screening an African-American patient for one of our open trials, and filling out the paperwork to determine if he was eligible. Most of this paperwork is related to the cancer, to make sure that patients have the type of cancer that we’re studying. But other sections of the checklist establish that the patient is otherwise healthy. We wouldn’t want to give an experimental treatment to a patient who wasn’t healthy for their sake and for the research’s integrity. He didn’t meet the criteria for one of those health checks.

One of the ways we determine that a patient is otherwise healthy is to look at their immune function, and his white blood cell count was too low. I hadn’t seen that before, and we ran his blood test again. His medical oncologist said the patient had benign ethnic neutropenia, which I had never heard of it until then. Because of that he couldn’t go on the trial that we had. It wasn’t a trial that we were running out of this hospital, but we talked to the sponsors. And as with many big trials, they don’t allow exceptions, no matter what.

He didn’t get the opportunity to be on a trial that was designed for men just like him, and that was really frustrating. Everyone involved with his treatment was frustrated with that, and so we looked into if that could be happening to other men. We also looked at creatinine. It’s well known in the medical field that black patients have a higher serum creatinine, and so you have to use a special formula that accounts for race when you’re looking at their kidney function. We looked at benign ethnic neutropenia because that’s what started it, and it was something that people seemed unaware of.

Dr. Nguyen: In a research group, the ideas usually come from the lab principal investigator (PI), and then the junior people carry it out. In this case, Marie actually came up with this idea herself because of a patient experience that she had, seeing an African-American patient not be able to get on one of our trials. It’s what led to this Journal of the American Medical Association Oncology paper, which is impressive.

That is. What did you look at?

Ms. Vastola: We wanted to know how often this happens. Was this a fluke, or does this happen to other African-American men? The best way to find out was to look at the eligibility criteria of other trials. Every trial records when people don’t meet the criteria. They don’t often record why though, so we couldn’t just look at the internal records of our trials. The website clinicaltrials.gov lists all trials available to patients in the United States and also a lot of international trials, and it usually lists the eligibility criteria. Not all the trials go into detailed criteria, but many do. We went through 401 trials that had endpoints that we thought meant that they had the potential to reach large audiences and change practice. We looked at all of them and pulled the eligibility criteria to see how many of them had this white blood cell criterion.

We expected some would have it. We did not expect that almost 50% of trials would have either of these two criteria. We were also surprised that the serum creatinine criterion was so common that a quarter of the trials have it.

People are aware of this, and they know to calculate kidney function accounting for race. A lot of trials would use serum creatinine, which is just the blood test, but then they would also say that if a patient meets formula criteria (based on race), then they’re okay, which is what we want to see. Not all trials do that, and that’s the issue. Every single lab result you look at that measures creatinine says at the bottom that if the patient is African-American, apply this formula. But over 25% of these trials weren’t including that formula.

What else did you find?

Ms. Vastola: Those were the two criteria that we looked at. We also broke it down by year, size of the trial, the phase, and toxicity of the therapy. We were glad to see that, over time, people are using the serum creatinine eligibility criteria less and less, which may mean that more people are aware of it. That’s not the case for the white blood cell criterion though.

Dr. Nguyen: We looked only at trials that have survival as an endpoint, so these are trials looking to make people live longer. We think it’s especially important that all patients have equal access to these kinds of trials. There are a few consequences of not having African-Americans on these trials. Patients who go on trials can sometimes get access to new drugs, so it’s a problem if African-American patients aren’t getting on trials. We also don’t get to learn enough about whether certain drugs perform particularly well in African-Americans, and so we don’t get to learn about the specific benefits or lack of benefit of certain agents for African-American patients. We wind up extrapolating from the larger patient pool, which probably works most of the time, but perhaps there’s something special that we can learn from having African-American patients on trials so that we could find better cures that can be tailored for African-American patients.

Ms. Vastola: Exactly. Not having access to these clinical trials hurts the individual because they don’t have access to treatment that could potentially help them. But the lack of access also hurts the whole population.

It also skews your results, so that what you’re learning about isn’t really prostate cancer in all men, just prostate cancer in a subset of men.

Ms. Vastola: Exactly.

What do you hope this will mean for clinical trial design and eligibility recruitments?

Ms. Vastola: We presented this research letter at the Prostate Cancer Symposium of the American Society for Clinical Oncology in poster form. We got a lot of feedback from academic investigators, people who devote their lives to this. Their papers define the field. They said they’d never thought of this, and that some didn’t know benign ethnic neutropenia existed. This section of the eligibility criteria—the part that defines whether a patient is healthy—is just carried over from trial to trial because it’s so standard. It’s not something people think about when they design trials because it’s so standard.

It’s textbook. We hope that, as more people understand this, they will consider it when they design their trials.

Dr. Nguyen: We were guilty of it in our own trials, and that’s how this all came about. We just used standard entry criteria copied over from previous studies. We were surprised to learn that this could disproportionally disadvantage African-American patients from being able to enroll in our trials. Given all the barriers that African-American patients face in getting on clinical trials in the first place, the last thing that we need is yet another barrier.

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