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Dr. Thomas Hope: New Directions in Prostate Cancer Imaging

Thomas Hope, MD, of UCSF and the San Francisco Veterans Affairs Medical Center, is keenly interested in novel imaging agents and therapies for prostate cancer and neuroendocrine tumors.

Prostatepedia spoke to him about novel imaging for prostate cancer.

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What are some of the newer imaging techniques available across the globe? How do they work, and when are they used?

Dr. Hope: I do a lot of radiopharmaceutical imaging. We inject radioactivity into people, and then we image it with a positron emission tomography (PET) scanner to locate where the radioactivity has gone. We label these small molecules (proteins) with the radioactivity and use those proteins to target different places in the body. In this case, we try to figure out where prostate cancer is.

There’s been a whole host of developments over the past 20 years of increasingly improved detection strategies for prostate cancer. The old-school fluorodeoxyglucose (FDG) PET imaging technique has been around for 30 years in the United States, and they have used sodium fluoride worldwide for just as long. For bone imaging, sodium fluoride can tell you where obvious metastatic bone disease is. FDG is actually the stable for the majority of PET/ CT imaging we do in the world, but it’s used primarily for other cancer types that are hypermetabolic or use a lot of glucose. When prostate cancer is in the earlier stages, it typically does not use a lot of glucose.

There’s been this hole in prostate cancer treatment for patients with biochemical recurrence. These are patients who have undergone definitive therapy and have a rising PSA. Neither of those two imaging modalities really help them. But a couple of new agents have been developed.

Choline-based agents, such as fluorocholine and C-11 choline, have been used in the United States and Europe. The Mayo Clinic brought choline C-11 to market in the US. Those radiotracers are certainly better than FDG PET or sodium fluoride PET in localizing particularly soft-tissue metastases, but they fail at lower PSA values.

When your PSA gets below one, you really don’t see much disease, and the studies are also quite difficult to interpret. The next imaging agent, is Axumin (fluciclovine). Fluciclovine is another amino acid tracer, just like C-11 choline, that’s used in biochemical recurrence. It was FDA-approved two years ago and has been used fairly frequently with biochemical recurrence. It’s probably, in my mind, equivalent to choline imaging. Fluciclovine itself is not really used outside of the United States because, if you have the availability of other radiotracers, you wouldn’t use fluciclovine. Yet in the United States, fluciclovine has become the mainstay because it is reimbursed by Medicare and readily available. Prostate specific membrane antigen (PSMA) compounds have been developed by a number of groups and companies over about ten years. The big change came with the gallium PSMA-11 compound, which is a small molecule that was first developed at the University of Heidelberg in Germany. Gallium PSMA 11 is a unique compound in that it wasn’t patented. No company controlled it, and so any site that wanted to use it could just sign up and get the precursor delivered to them. Very quickly, a large number of sites around the world started using PSMA-11 to image patients with prostate cancer. It is not approved in many counties, although technically, it is approved in Switzerland and Israel. Outside those countries, it is used on a compassionate-use basis. In the United States, it is being used under Investigational New Drug (IND) authorization from the FDA. The fact that it was so quickly adopted and widely used led to a huge number of articles in the literature.

In addition to PSMA-11, there is a whole host of other PSMA compounds. Gallium PSMA-R2 is being developed by AAA, DCFPyL is being developed by Progenics, PSMA-1007 is being developed by ABX Chem. There is a whole family of PSMA compounds coming to market on the back of the experience of PSMA-11. There are questions as to which is better, and although there is not a lot of head-to-head literature published, it’s fairly clear that PSMA 11 is better than, for example, the choline radiotracers and fluciclovine. The question is: how do these other PSMA tracers rate against one another? In my mind, they’re much better overall as a class, but I’m not sure there is a huge difference between them in terms of detection activity. We’ll find more about that as things progress.

You said the PSMA compound is widely available because it was not under the auspices of a specific company but that it is not approved everywhere. Does that mean that patients can get access to it, but it is not necessarily covered by their insurance?

Dr. Hope: You have to go country by country, so it gets complicated. In the United States, for example,

PSMA-11 is not owned by a company, and there’s no company paying for clinical trials. Centers like ours are running trials through Investigational New Drug (IND) authorization, which means it’s being studied in clinical trial aiming to get FDA approval. In the United States, everything is done under a clinical trial. There are a couple of methods to pay for the studies. There are a few insurance companies that will pay for these imaging studies under a trial setting. But I would say that the majority do not, and patients end up having to pay out of pocket.

The FDA allows you to use a cost recovery mechanism if you are acquiring data to eventually support an NDA application, and that’s how the majority of these studies are paid for. There are other institutions that use research funds in order to have a small number of studies performed. The two major institutions in the United States are UCSF and UCLA, and each uses cost recovery mechanisms and billing patients’ insurance companies directly in order to perform the study.

Are the studies expensive?

Dr. Hope: Yes. I would say they range between $3,000 to $5,000 apiece, so they’re quite expensive. There is clearly an ethical dilemma in having patients pay for an imaging study that’s not FDA-approved. What do you do with that? I think it is a reasonable approach as long as the institutions are actually using that data in the way that they state they are, which means that it’s up to us to use the data to get the agent approved. If the data isn’t used productively to get the drug approved so that insurance companies will pay for it, then I have an issue with the ethical aspect of it. As long as I’m doing the work, then it may be reasonable, although different people might disagree.

I’m sure there is a wide range of opinions.

Dr. Hope: There’s no right answer. For example, two weeks ago, we went to the FDA for our pre- NDA meeting and presented all of our data, which we are doing in collaboration with UCLA. The FDA was very positive and said that we had enough clinical data to support an NDA application, which is pretty exciting. Hopefully, we can get the drug approved within the next 6 to 12 months.

How have these newer imaging techniques impacted how we treated prostate cancer? We’re detecting smaller and smaller amounts of cancer earlier and earlier. What do we do with that information? How is it changing how we treat patients?

Dr. Hope: These newer techniques are changing current patient care. But is that actually improving the outcome? For example, if you have a low PSA, and your PSA is 0.2 after radical prostatectomy, the standard treatment is to radiate the prostate bed and maybe the pelvic nodes. Now you get a PSMA PET, and it shows a node somewhere over here. So, now the radiation oncologist zaps that PSMA-positive node. Everyone thinks we did a good job, and maybe we did. But we just don’t know.

What we don’t understand fully is whether or not PSMA PET is the tip of the iceberg. If you have a PSMA positive node, are there many nodes we do not see, or does it mean that those nodes are the extent of the patient’s disease, which we can potentially cure if we hit it? Right now, the care is changed in maybe over 50 percent of patients who get a PSMA PET, but whether that change in care or treatment planning has improved outcomes, no one has a handle on that yet. There are some clinical trials starting that use varying radiotracers. The question in the community is: how does PSMA PET impact this care, and does that change improve the outcome of the patient who we’re imaging?

Is it just a matter of time before we answer this question?

Dr. Hope: Yes, but it is not that straightforward. You cannot take a cohort of patients who got PSMA PETs, check what happens to them, and conclude that things got better. You have to do it in a trial setting with a cohort of patients who do not get PSMA PETs and a cohort who did, and see if there’s a difference between the two. Otherwise, there are a lot of biases if you have a one arm study. You cannot tell if the patients have improved outcomes for other reasons or even how you compare the data. You really do need a randomized trial in order to demonstrate this improvement in outcomes.

That will come, but those trials will take a very long time to perform. These drugs will all be approved well before the length of time that these trials take to perform. This becomes a big issue. If you have an imaging agent, and we all believe it’s better than the previously existing ones, how do you randomize patients to not get it once it is FDA-approved? We are going to face difficulty showing that PSMA PET improves patient outcomes because we are going to be bottlenecked based on the availability of agents in the near future.

That’s an interesting position to be in.

Dr. Hope: It has happened in imaging over the years. Take sodium fluoride PET, which was never approved. It was grandfathered into FDA approval. No one ever did any clinical trials showing impact and outcome, and that is why Medicare has chosen not to reimburse sodium fluoride PET CT. This has happened over and over again.

It is mainly because imaging trials are unique. Drug trials must have outcome benefits as the endpoint in order to obtain approval. Imaging trials only need to show that we saw something we thought we would see. For example: “I think there is prostate cancer, I looked at a cohort of patients, I biopsied them, and the biopsies came back as prostate cancer. Therefore, this imaging study is good.” But that doesn’t work in a therapy world. Therapy data is a lot stronger.

Do you have any thoughts for men considering travel to get one of these newer imaging techniques or participating in a clinical trial if it’s not available in their community?

Dr. Hope: That is a hard position to be in right now. Think about it in a different setting. Let’s say you were at your institution, and you were thinking about participating in a clinical trial for an investigational therapeutic agent. Most men would not travel too far outside their institution for that therapy. With PSMA PET, patients are traveling all across the country for this agent and paying out of pocket for it. It’s an unusual circumstance. Two years ago, it would not have occurred to people to do this.

I think in the United States, you have to think about the cost and the marginal benefit. It really depends on your PSA. It depends on discussions with your oncologist or urologist in terms of where you are and what type of therapies you are thinking of. Outside of imaging studies, there are therapeutic aspects of PSMA targeted radionuclide therapy. That becomes a much bigger issue. Outside of the United States, the vast majority of sites that offer it do so outside of trial settings.

There are potential huge ethical issues with doing that. Sites are treating patients with therapies that have significant toxicities, and that data is not being collected prospectively, is not being reported, and the trial is not being done in a way that will lead to data that will help us determine what to do with patients moving forward. Centers should run clinical trials and publish results so that we learn, but there’s a large number of centers around the world offering some of these agents out there to treat patients with limited to no follow-up.

It’s really important that, if we’re going to treat patients with a non-approved drug, the trial or the setting where it’s administered does so in a way that leads to actionable, usable information for the community at large, and not just the individual institution or patient.

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Should You Travel For Prostate Cancer Imaging?

This month, Prostatepedia is talking about newer imaging techniques for prostate cancer. As our ability to image prostate cancer becomes ever more precise, controversy over what to do with this newer information is coming to the forefront. Also at stake are whether or not American insurance companies will pay for newer scans. When a man’s insurance doesn’t cover an imaging study, many patients with the financial means are paying for the scans themselves and often traveling to sites within and outside of the United States.

When your PSA begins to rise after initial treatment, you have what is called a biochemical recurrence. If you’re scanned with one of these newer imaging techniques—the Gallium-68 PSMA, for example—and discover 1 or 2 spots of metastases, you have what is called oligometastatic disease.

Prostate cancer experts are divided on how to treat men with only a few metastases. Traveling—and paying out of pocket—for a scan when doctors are still grappling over what to do with any information such a scan would reveal—may not be the wises course of action. Unless, of course, you understand that the scan results may just be interesting information for you and your doctor to consider and will not necessarily change your course of treatment immediately.

Drs. Thomas Hope and Stefano Fanti help us place PSMA imaging and the controversies mentioned above within the context of conventional prostate cancer imaging and treatment. Dr. Fanti’s offers us the European perspective: imaging has been more widely available in the United Kingdom and continental Europe. Many Americans are now traveling to these countries to obtain newer imaging studies. Dr. Nina Tunariu, of the United Kingdom, talks about whole body MRI as a way of staging prostate cancer. She also offers a note of caution for Americans traveling abroad for scanning.

Dr. Rodney Ellis talks about how newer imaging techniques are changing the treatment landscape at the community level. UsToo offers the support group network and patient advocacy’s view of how imaging impacts prostate cancer diagnosis, staging, and treatment.

And finally, Mr. John Moore talks about his prostate cancer journey and the experience of traveling from his home in North Carolina to California for imaging studies.

The bottom line is that more information is always useful. Newer imaging techniques are detecting cancer in smaller and smaller amounts. How to treat these small amounts of cancer is still under debate, especially since the side effects of prostate cancer treatment can be particularly difficult for many men. If you have the means to obtain a newer scan, do so: but understand that there are controversies over the meaning of their results within the global prostate cancer community. A frank and open discussion with your doctor about what you’ll do with any information you learn before you get scanned is the wisest course of action.

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Imaging Prostate Cancer

In November, we’re talking about imaging prostate cancer.

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Dr. Snuffy Myers frames this month’s discussion for us.

Our ability to image prostate cancer metastases has improved dramatically over the past few years. CT and bone scans, which have been the standards for decades, typically image a cancer mass larger than 1 cm (0.4 inches). Newer imaging techniques have lower limits that approach 1-4 mm. Dramatic changes like these have a way of disrupting the status quo.

The current guidelines for the treatment of metastatic prostate cancer are based on clinical trials where metastases were detected with CT or bone scans. Do these treatment guidelines still hold for metastases too small to be found by CT or bone scan, but detectable with the newer, more sensitive imaging techniques? There are reasons to suspect we might begin to detect prostate cancer at a different stage in its evolution.

The concept of cancer dormancy is commonly used to explain a long interval between initial treatment with surgery or radiation and subsequent appearance of metastatic disease. For both breast and prostate cancers, more than 10 years can pass between treatment with curative intent and the appearance of detectable metastatic disease.

Several mechanisms have been identified that can lead to cancer dormancy. Two of these mechanisms might result in cancer masses potentially detectable by the newer imaging techniques. First, cancer dormancy can result when the cancer mass fails to attract a blood supply and thus is starved of both oxygen and food. The second is that cancer dormancy can result from ongoing immune attack on the cancer. Both mechanisms can allow cancer masses above 1 mm that overlap with the lower limit of the newer scans.

Cancer dormancy is associated with greater resistance to cytotoxic chemotherapy and hormonal therapy. The implication is that we may increasingly detect prostate cancer metastases that pose no immediate threat to the patient because they are dormant. Additionally, these metastases may respond poorly to standard treatment options. All of these factors would argue for caution in making treatment decisions based on the newer generation of scans.

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Clinical Trial: Combining Erleada (apalutamide) with Zytiga (abiraterone)

Dr. Eleni Efstathiou is an Associate Professor in the Department of Genitourinary Medical Oncology at The University of Texas MD Anderson Cancer Center in Houston, Texas.

She spoke with Prostatepedia about her clinical trial combining Erleada (apalutamide) with Zytiga (abiraterone).

What is the thinking behind your trial combining Erleada (apalutamide) with Zytiga (abiraterone) in men with metastatic castrate-resistant prostate cancer? Why this combination as opposed to another?

Dr. Efstathiou: Here is the idea. There is a large trial on combining Zytiga (abiraterone) and Erleada (apalutamide) for all patients who have failed original Lupron (leuprolide) injections or standard androgen deprivation therapy. This trial is for men with metastatic castrate-resistant disease; it compares that combination to just one of the agents alone. I’m part of the steering committee for that international trial.

The trial that I just initiated here at MD Anderson is a smaller trial. This trial is trying to identify and confirm a subset of men who harbor cancers that are going to be exquisitely sensitive to the combination and may need no further treatment for years and not just an average of about a year

This all started with my first trial, now 11 years old. That specific trial was characterized by the fact that the men who received Zytiga (abiraterone) underwent biopsies of their bones while on treatment so I could study what was going on in the cancer realtime. It showed me that 70% of the men would respond. There was a reaction in the cancer cell while the androgens were dropping and they were undetectable. Their androgen receptors were going up. The next trial that I did used a drug that is very close to Erleada (apalutamide) called Xtandi (enzalutamide). That trial showed exactly the inverse, that as you gave that drug the receptor was switched off, but the androgens went up. All of this is in the tumor cells. This means there is some feedback happening, but does this feedback contribute to resistance? Could the combination actually help these men who get both drugs survive longer and get better responses?

But there is a caveat. I looked more carefully to find the characteristics in the tumor samples taken prior to treatment and found that there were specific molecules that, if expressed, were associated with a benefit. It made sense to me to focus on those specific characteristics in the cancer and try to combine.

I then did another trial where I combined Zytiga (abiraterone) and Xtandi (enzalutamide) and looked to see if my theory made sense. It did. It looked like the men who had these molecular characteristics responded better on the combination than those who didn’t.

But that was all hypothesis. The next thing you need to do when you discover something is test it. Then you need to confirm it to validate it. I used a 180-patient trial to test it. The next step would be the validation if testing looked promising. A validation means you have preset the parameter of the research trial; you’re trying to become agnostic to the outcome so you’re not biased in any way.

The testing also panned out. The trial we’re now discussing is the validation. Patients who come in the door accept to undergo a biopsy. We don’t need to do the old-school bone marrow biopsies anymore. We have great radiologists who go in with very fine needles and take several samples so the patient has no pain, just the discomfort of the process. Then we look at the cancer cells to see if they have these characteristics. I would tell you that about 30% of the cases have these characteristics that would make them eligible for the trial. The men who do have these characteristics in their cancers start treatment. If my hypothesis is correct, the validation will be that 90% of these men should respond in an outstanding and protracted fashion. I’m trying to hone in on who would be the ideal candidate for a combinatorial trial. The way the field is going, we’re throwing all the drugs at all patients; that helps a lot of people to a degree, but on the other hand, it causes a lot of toxicity, especially if you combine two rather than one agent. That is the main gist of this trial.

What can men expect to happen step by- step?

Dr. Efstathiou: You get a biopsy. In about a week, we tell you if you area candidate or not. You start the treatment. Then it’s quite straightforward: we follow you just as you would be followed in your doctor’s office. You come once a month to see me. This may go on for years, if all goes well. I have some patients who have been on treatments like this for years. Sometimes after six months of treatment, apart from seeing us to evaluate toxicity, we also perform imaging again to see what is going on with the cancer.

What images studies will you be using?

Dr. Efstathiou: CT scans and bone scans. We have not included, unless it’s needed for this trial, more advanced imaging such as PET scans. As we monitor these imaging studies, we see how the cancer cells seem to be more quiescent. The lesions become smaller. If, God forbid, the disease tries to progress again, then we would repeat a biopsy Remember, as I’m sure you’ve discussed with a lot of other specialists in prostate cancer, one of the main concerns is prostate cancer’s heterogeneity. When I’m doing biopsies, I’m actually looking at a snapshot of a specific subset of cancer cells. What if there is a cohort of cancer cells in there that is very resistant and expresses completely different molecules?

This clinical experiment gives me the opportunity to see if the way I am assessing things is actually capturing well what is happening with regard to the prostate cancer activity. There are a lot of investigators out there who are huge advocates of liquid biopsies without having done the basics of assessing what is going on in the actual tumor that has grown in the bone, lymph nodes, or liver. I understand that the dilemma for most people is the difficulty of doing biopsies, but if we want to be honest in all other malignancies, that’s how the development of all the targeted agents started. At the end of the day, it is going to be important to not ignore the actual tumor samples and to try and characteristics those well. Above and beyond this specific trial, one of my main efforts is to hone in on a classification of the disease that allows you to appropriately designate specific treatments to specific patients. There was some nice work recently presented in a meeting that supports that idea. Some of the mutations or alterations can be found early on.

If we know which these are, then we can pursue them. If we know that others change over time, then we can do real-time biopsies.

Which tumor biomarkers are you looking at?

Dr. Efstathiou: One of the most important parameters is androgen signaling. I was the one who reported for the first time the association of AR-V7 in the tumor sample with lack of response to these drugs. Right after that came the liquid sample data from the Johns Hopkins and Memorial Sloan Kettering groups who were doing it in the circulating tumor cells.

One of the markers is related to AR-V7, but I went a step further. The androgen receptor needs to be intact. I’m looking at the two ends of the androgen receptor. The one end is the end where the androgens go and attach themselves. The other end is the stable end, the one that never changes. The end to which the androgens attach themselves is the one that is affected by mutations and variants. I measure both ends and then I look at the difference in the ratio between the two. That’s another important marker.

I also look at PTEN, which is a very known marker. I look at RB loss, p53 mutation, and the proliferation index of the cancer.

What are the eligibility criteria?

Dr. Efstathiou: It’s very simple. Patients must have not received previous new agents such as Zytiga (abiraterone), Xtandi (enzalutamide), or Erleada (apalutamide). They must have failed standard hormonal approaches, such as androgen deprivation therapy or bicalutamide. They also have to have metastatic disease. These are the main criteria. It’s very straightforward.

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Merel Nissenberg On Non-Metastatic Castrate-Resistant Prostate Cancer

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Non-metastatic castrate-resistant prostate cancer (nmCRPC) is a clinical state in which a patient on androgen-deprivation therapy (ADT) has a rising PSA but there are no radiological findings of metastases on CT or bone scan. Management of nmCRPC is evolving quickly, but it is a field in which there have been recent drug approvals amid a strong and growing interest in keeping patients metastasis-free for as long as possible. About 10-20% of prostate cancer cases are castrate-resistant, but nearly 16% of those castrate-resistant patients have no evidence of metastatic disease at the time their castrate-resistance is diagnosed.

Not all nmCRPC disease is the same. For some patients, observation is a viable option; for other patients—especially those with a PSA doubling time of less than or equal to 10 months—randomized Phase III clinical trials have shown a benefit and an increase in metastasis-free survival with the use of Xtandi (enzalutamide) or Erleada (apalutamide). New imaging techniques on the horizon may also be very helpful in assessing nmCRPC patients.

In February 2018, the FDA approved Erleada (apalutamide) for nmCRPC patients and was the first such FDA-approved treatment for this subset of patients—i.e. those who are no longer responding to ADT but who have no radiological evidence of metastasis. The Erleada (apalutamide) approval followed the release of the results of SPARTAN, a randomized clinical trial of 1,207 patients in which patients received either Erleada (apalutamide) or placebo, discussed at the American Society of Clinical Oncology Genitourinary (ASCO GU) Meeting in February of this year. All of the patients who were enrolled also received hormone therapy. The exciting results showed that the median metastasis-free survival for patients in the Erleada (apalutamide) arm was 40.5 months versus 16.2 months for the placebo group. Both applications received priority review from the FDA due to the exciting results with clear benefit for nmCRPC patients.

The results of another trial known as the PROSPER Trial were also first presented at the 2018 ASCO GU Meeting. In PROSPER, with 1,401 participants, men with nonmetastatic castrate-resistant prostate cancer (nmCRPC) were given either Xtandi (enzalutamide) or placebo; these were men in whom the PSA doubling time was 10 months or less, but, again, there was no evidence of disease seen by CT or bone scan or by MRI. Those nmCRPC patients receiving Xtandi (enzalutamide) had delayed time to metastatic disease or death (whichever occurred first) by a median of 21.9 months, versus placebo (36.6 months compared to 14.7 months), signifying a 71% reduction of the risk for metastasis or death. Another result: Xtandi (enzalutamide) delayed the time until men needed additional cancer treatment, compared to placebo (a median of 39.6 months compared to 17.7 months). On July 13, 2018 the FDA approved Xtandi (enzalutamide) for the treatment of nmCRPC patients.

This means that men with nonmetastatic castrate-resistant prostate cancer now have two choices that they did not have before, when they would simply be continued on ADT. We still do not know, however, if the added Xtandi (enzalutamide) or Erleada (apalutamide) will increase overall survival for these patients.

[This article deals only with nonmetastatic CRPC. There have also been various trials conducted in the metastatic space, and there are other trials currently underway or planned involving anti-androgens such as Zytiga (abiraterone), including some in combinations with other types of therapy, dealing with metastatic disease (mCRPC patients). One of the trials looking at the metastatic disease space is the PEACE1 Trial, which is looking at the benefit of Taxotere (docetaxel) plus ADT, with or without Zytiga (abiraterone) and prednisone, and with or without radiotherapy. This trial is expected to conclude in October 2018 and may help answer the question of whether it is of benefit to patients to add Zytiga (abiraterone acetate) to Taxotere (docetaxel) in metastatic disease that is still castrate-sensitive. The Phase III STAMPEDE Trial showed that adding Zytiga (abiraterone/ prednisone) to standard ADT lowered the relative risk of death by 37% and improved progression-free survival by 71%, versus ADT alone. The CHAARTED Trial looked at Taxotere (docetaxel) plus ADT or ADT alone in patients with metastatic, castrate-sensitive disease, resulting in a greater median survival in the ADT + Taxotere (docetaxel) arm (57.6 months versus 44.0 months with ADT alone).]

Learn more details about these drugs by viewing the Evidence Report from Institute for Clinical and Economic Review (ICER). ICER also held a public hearing on the topic on September 13, 2018 in Chicago.

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Dr. Bertrand Tombal On Making Prostate Cancer A Chronic Disease

Dr. Betrand Tombal, Chairman of the Division of Urology at the Cliniques universitaires Saint Luc and Professor of Urology at the Université catholique de Louvain (UCL) in Brussels, Belgium, is the current President of the European Organization for Research and Treatment of Cancer (EORTC), the leading European academic research organization in the field of cancer.

Dr. Tombal is keenly interested in treating advanced prostate cancer and in the development of hormonal treatment and new biological agents

Prostatepedia spoke with him about how newer agents like Zytiga (abiraterone), Xtandi (enzalutamide), and Erleada (apalutamide) have changed the prostate cancer arena.

Join us to read the rest of this month’s conversations about Zytiga, Xtandi, and Erleada.

How have the newer agents, like Zytiga (abiraterone) and Xtandi (enzalutamide) changed the treatment landscape for men with castrater esistant prostate cancer?

Dr. Tombal: These drugs changed treatment in three ways. First, urologists know that hormone therapy may have a profound effect on some patients. Having said that, in the late 90s, we had hormone therapies of limited efficacy. For better or worse, there was no regulatory platform development for historical hormone therapy, so we are missing good evidence that they increased overall survival or even significantly delayed progression. These two new hormones build upon things we already knew for years, but they are far more effective, and more importantly, they have been developed following a strong regulatory context so that we know exactly their benefit.

But before that, the Taxotere (docetaxel) story was interesting for me because that’s one of the first studies I participated in. Seeing all these guys dying from prostate cancer, I thought it was unbelievable that we could increase overall survival. I was thus extremely surprised that urologists in charge of managing advanced prostate cancer at that time would negatively react to chemotherapy and claim that the benefit was limited and toxic. Hence, patients would be referred by the physicians. I thought that was strange. From day one, I thought that we should ask what the patients think. But the landscape changed again when we saw the results of the post-chemotherapy trials with Zytiga (abiraterone) and Xtandi (enzalutamide), how much they increased overall survival, and their major effect on PSA. We realized that we had game-changers.

But to me, changing the game was not necessarily about having patients live a little bit longer. I always go back to the many discussions I have had with patients who ask not whether they will live longer but if they will live better.

That’s why I was so excited about being one of the Principal Investigators on the Prevail trial. The Prevail trial was really not about Xtandi (enzalutamide); we already knew the drug worked. Prevail was about having a discussion early on in the course of the disease, when the patient was becoming metastatic and castrate-resistant. We would ask: what do you want to do? Do you want to wait a bit and only start chemotherapy after you’ve got symptoms? Or do you want to start the drug immediately?

The patient would then ask about the side effects. I would say that there are side effects, but to give it a try, and if they didn’t want to live with them, we could simply stop the drug and the side effects would go away. These are oral drugs, so if you have side effects that are severe, you can just stop the drug.

That’s what was new, that not only could we help the patient live longer, but we could delay complications of the disease and buy him quality time It has really changed the way we treat patients.

If you look at newer trials, like Prosper and Spartan, they are having the same discussion but going one step further.

You have no metastases, but your PSA is progressing rapidly. What do you want to do for the rest of your life? Do you want to do nothing, enjoy a few additional months until you develop metastases and then start the treatment? Or do you worry enough that you would like to try one of these drugs to see if you tolerate it? To me, it’s no more complicated than that. These drugs, Zytiga (abiraterone), Xtandi (enzalutamide), and now Erleada (apalutamide), have brought the possibility of discussing early on in the course of the disease what is important for that particular patient. Do you want to delay progression? Because in the end, these drugs are not very toxic.

That’s why these drugs are so important.

And this is just the beginning. We’re not going to speak four years from now about giving Xtandi (enzalutamide) or

Zytiga (abiraterone) in the metastatic castrate-resistant prostate cancer space because we’re going to give these drugs earlier and earlier to patients with high-risk disease together with radiotherapy and surgery. We have a chance. What we want is to have prostate cancer patients die from something else.

A few years ago, Andrew C. von Eschenbach, a urologist that became the twelfth Director of NCI, said that his grail was to make cancer a chronic disease. That’s what we’re doing with these newer drugs: we’re making prostate cancer a chronic disease. We have never said we were going to make someone immortal, but hopefully we still delay the appearance of metastases and symptoms, so that they will die from something else. That’s the beauty of trials like Spartan, Prosper, and (hopefully) Aramis in which Xtandi (enzalutamide), Erleada (apalutamide), or darolutamide are given at early signs of rapid PSA progression to delay the metastases. We used to say that at that stage of the disease, everybody will die from prostate cancer, but now we’re delaying progression so much that patients are going to start dying from something else and not have to go through all of the suffering associated with prostate cancer. That’s a major change. That’s the change these drugs are bringing. They bring the possibility of intervening early and making prostate cancer a chronic disease. And yes, there is a slight increase in toxicity. And yes, at a huge increase in cost. But that’s how the world is.

Do you think it’s of any concern that we don’t really understand the longterm impact of these drugs?

Dr. Tombal: When people discuss this aspect, they assume that we have effective treatments to treat the progression. That’s not true. It’s the same with bone-targeted therapy. I remember when bone-targeted therapy came on the scene, a famous medical oncologist said that what we are delaying is simply giving a little bit of cheap radiotherapy to the spinal column (on the lumbar spine). I said that was true, but you assume that cheap radiotherapy to the spinal column is effective. And it is not.

When are bone-targeted therapies like bisphosphonates and Xgeva (denosumab) traditionally used, and how has their use changed now that these newer drugs have come onto the scene?

Dr. Tombal: Less frequently. And that’s a major drama. Once again, it comes from a wrong interpretation of the data, from that oncological view that overall survival drives all decisions. When the major study on zoledronic acid and Denosumab was published, people said it doesn’t make patients live longer or increase overall survival. I said that I didn’t care: increased survival is not what we expect from this drug.

What we expect from this drug is that it delays skeletal complications. It reduces the total number of bone complications in a patient’s lifetime. This means that, if you’re a gentleman of 70 years, and God has written in your book that you’re going to live another two years, you’ll get your first skeletal event in 12 months. Xgeva (denosumab) will not make you live longer, but it will delay your first skeletal complication to 16 months. Once again, you’re buying quality time. You define that quality time as time without bone complications.

Then came Taxotere (docetaxel), Xtandi (enzalutamide), and Zytiga (abiraterone). They all extend overall survival and skeletal events. Physicians are starting to not prescribe these drugs because they say we don’t need them now that we have Zytiga (abiraterone) and Xtandi (enzalutamide).

Recently, Bayer conducted a clinical trial comparing Xofigo (radium-223) plus Zytiga (abiraterone) versus Zytiga (abiraterone) alone. The trial ended after a little more than one year because there was a significant excess of fractures and death. One of the striking observations is that only one-third of the patients in the trial received bone-protecting. The European Medicines Agency’s statement says that, most likely, this excess of fracture happens only in patients not receiving bone-targeted therapy. Clearly, avoiding bone-targeted therapy has been a big mistake. We believe that if we have drugs that increase overall survival, we don’t need bone-targeted agents. But now we realize that if patients live longer with bone metastases, we increase the likelihood that they’re going to have complications. These drugs are even more important than they were before.

Would you say that most men on drugs like Zytiga (abiraterone), Xtandi (enazlutamide), or Erleada (apalutamide) should consider bone protecting therapy?

Dr. Tombal: If they have bone metastases, I would say yes. The question then becomes what to do if you only have one bone met. In Europe, we use a lot of modern imaging technologies, such as PSMA and whole-body MRI. Sometimes, you see a man with a rising PSA and one or two bone mets that you don’t see in a bone scan. If that man has two, three, or four bone metastases that show signs of progression, such as increased alkaline phosphate, he should be on bone-protecting agents.

What sort of combinations do you think seem the most promising or have the most benefit?

Dr. Tombal: At this point in time, we have failed to show that any combination is better than a single agent for prostate cancer. When I’m speaking about combinations, I’m speaking about combining drugs to increase overall survival.

When Taxotere (docetaxel) came out, there was an epidemic of shotgun experiments where everybody tried to combine Taxotere (docetaxel) with all sort of agents, all usually having shown a strong rationale in the lab. Not one of those trials was positive. Most of them showed a benefit in favor of Taxotere (docetaxel) alone. When Bayer said we’re going to combine Zytiga (abiraterone) with Xofigo (radium-223), that seemed like low-hanging fruit. They were combining two drugs with different modes of action and different toxicities that both showed an increase in overall survival when used alone. Nobody could have imagined that it would end in catastrophe—that combining the two agents would shorten survival.

At this point in time, there is not a single indication that one combination is better than a single agent in prostate cancer.

What should patients take away from that?

Dr. Tombal: These agents: Zytiga (abiraterone), Xtandi (enzalutamide), Erleada (apalutamide), Taxotere (docetaxel), Jevtana (cabazitaxel), and in the United States, Provenge (sipuleucel-T), have been used sequentially, but not in combination. Combinations don’t have any benefit.

Do you think that is because there is some synergistic effect in terms of side effects?

Dr. Tombal: I have absolutely no idea. That’s where we stand today.

Do you have any thoughts for men who’ve been prescribed Zytiga (abiraterone), Xtandi (enzalutamide), or Erleada (apalutamide)?

Dr. Tombal: I would say that one of the great messages of the Prosper and Spartan trials is that we probably do too much imaging, that it’s probably better to follow a patient just with PSA. Then when his PSA starts to increase rapidly, that is probably the time to talk about earlier treatment with one of these agents. That is when to have the overall discussion about what you want to do and where you want to go.

Why shouldn’t we use imaging as much?

Dr. Tombal: Because we are tempted to offer additional treatments, such as radiotherapy, which have limited value, when we have at least five or six large Phase III trials that establish the philosophy of starting Zytiga (abiraterone), Xtandi (enzalutamide), and Erleada (apalutamide) earlier.

In Europe, we do a lot of imaging and a lot of salvage treatment. But we have to be honest, it’s driven by belief more than data.

Europe is ahead of the United States in that regard.

Dr. Tombal: Being ahead has started to make us realize that we probably over-treat more patients than we help.

That’s a huge issue because men can live for a long time with often debilitating side effects.

Dr. Tombal: Exactly.

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Dr. Bertrand Tombal On Why He Became A Doctor

Dr. Bertrand Tombal, Chairman of the Division of Urology at the Cliniques universitaires Saint Luc and Professor of Urology at the Université catholique de Louvain (UCL) in Brussels, Belgium, is the current President of the European Organization for Research and Treatment of Cancer (EORTC), the leading European academic research organization in the field of cancer.

Dr. Tombal is keenly interested in treating advanced prostate cancer and in the development of hormonal treatment and new biological agents

Prostatepedia spoke with him about why he became a doctor.

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Why did you become a doctor?

Dr. Bertrand Tombal: My mother was a nurse who went to patients’ homes. When I was young, I went with her on weekends and became interested in healthcare. I was very scientific. I have always been driven by science, so it was natural for me to become a doctor.

When I was around 17, I got interested in archaeology. Maybe because of Harrison Ford’s movie, I wanted to be an archaeologist. But I wasn’t sure what major to declare for college, so I decided to become a doctor while still enjoying archeology.

For a long time, I wanted to be a pediatrician, and I was quite good at that, so I was preselected to do pediatrics. In Belgium, we had a certain number of obligatory rotations. You have to do four months in internal medicine and four months in surgery. Because I so wanted to be a pediatrician, I skipped one month of surgery, but they wouldn’t let me graduate without that month.

I ended up working in a peripheral hospital for a month with a private urologist. I became crazy about urology, went back to my professor in pediatrics, and told them I didn’t want to be a pediatrician anymore. I wanted to be a urologist. And that’s how I started as a urologist.

Funny. Life takes you on different paths.

Dr. Tombal: I like that urology is a broad specialty. You treat cancer patients and incontinence patients. You engage in a lot of private emotional things, so I liked it from day one. After two years, I did my PhD thesis on prostate cancer, which took about four years in the end, and that’s when I got interested in prostate cancer.

Have you had any particular patients whose cases have changed how you either see your own specific role as a doctor or how you view the art of medicine?

Dr. Tombal: After completing my PhD thesis in 1998 in Brussels, I got an appointment at Johns Hopkins, where I finished my PhD. My former boss recognized that I liked to treat prostate cancer, but he preferred surgery, so he had me take care of the advanced cancer. I took care of advanced prostate and bladder cancers, which was not really a multidisciplinary approach at that time because there was no Taxotere (docetaxel) yet. Medical oncologists were not involved at all. We had a handful of old, hormonal treatments like estramustine phosphate (estrogen) or dexamethasone. That’s how I got interested in this. The bottom line is that I would follow many of my patients until death.

In 2000, supportive and palliative care were not yet developed. As a urologist, you would take care of guys usually in their 70s, and that’s where I started to speak with them and learn about interesting things, such as the relative importance of overall survival as compared to quality of life. That was meaningful. I learned from a few patients that, at some point, the only advantage you have as a doctor is that your patient has started the last round or two. You know he will die from the disease. You don’t know when, but you know it’s not that good. I learned that it’s important to have discussions and ask lots of questions. Where do you want to go? What is important for you? Do you have a point you want to reach? What are you ready to accept?

It’s always been extremely important that we don’t impose the treatment sequence at the very end. There is always a point beyond which we should discuss with the patient the philosophy of the treatment and what we expect. In the end, we have to make the choice together. To me, it’s always been extremely important having that kind of conversation, so many of these patients gave me this philosophical approach.

I still believe that managing castrate resistant prostate cancer is more about philosophical choices than scientific evidence. That’s why my background, having seen many patients before these drugs existed, is so important to me.

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