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Dr. Hashim U. Ahmed on Today’s Focal Therapy For Prostate Cancer

Dr. Ahmed is Professor and Chair of Urology at London’s Imperial College Healthcare.

His research focuses on prostate diagnosis using novel imaging and tissue biomarkers, prostate treatments that reduce the harms of traditional surgery and radiotherapy, and clinical trials and health technology evaluation.

Prostatepedia spoke with him about the current state of focal therapy for prostate cancer.

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What is focal therapy?

Dr. Ahmed: Focal therapy is about targeting the tumor within the prostate with a margin of normal tissue. The tumor is one that we believe that were we to leave it untreated, would progress, grow and spread, and impact the patient’s life at some point. By doing so, we avoid treating the entire prostate. We avoid damaging as much normal little tissue as possible. By damaging as little tissue as possible, we aim to maintain as much function as possible for that particular man, whilst at the same time treating the cancer that would otherwise cause problems in the future.

What are some of the various forms of focal therapy? Focal therapy is an umbrella term, is it not?

Dr. Ahmed: It is an umbrella term. I often joke that there’s almost like a catwalk of treatments that can be used for focal therapy. The traditional ones were cryotherapy, which freezes the tissue, and high intensity focused ultrasound (HIFU), which uses very focused ultrasound waves that heat up the prostate. You can use laser, which also heats up the prostate. You can use electrocution of the cells, which is called irreversible electroporation. There are now some new injectable drugs. You can inject hormone drugs or molecules that are activated by PSA, which then kill the prostate cells once they are injected into the prostate. There’s a lot of activity going on.

What I often say is that all of these different modalities are interesting. It’s good to see that commercial bodies are really interested in this field. That shows that the concept has real legs and everybody sees this as a big future, so that everybody’s crowding into the market. Ultimately, these are all tools, if you like— surgical instruments for me to do my focal therapy. No one tool can be applied to all tumors.

Let me take an example. If you had a big prostate with a tumor high up in the gland, there’s no way HIFU would be able to reach it. The ultrasound wave just can’t get that far. Even if it could, by the time it reached the tumor, there would be so much tissue it went through that it would lose its energy. For that particular tumor, an anterior tumor, something like cryotherapy is probably going to be better for that particular man than HIFU. A posterior tumor near the rectum, but contained in the prostate, probably does really well from HIFU at the moment, but could easily be treated in the future using these injectable drugs, if they’re to be efficacious.

Which form of focal therapy is best really does depend on where the tumor is, how big it is, and how big the man’s prostate is. Are there other characteristics within the prostate, for instance, like calcification, which means you can’t see the tumor? Those calcifications might, potentially, deflect the energy. There are a lot of other considerations, but there are quite a lot of things that you can use. I would say the two that are in pole position at the moment, just because they’ve been around for longer and therefore they have a lot of data, and the two that I use routinely in clinical practice, are HIFU and cryotherapy.

For which men is focal therapy usually an appropriate choice?

Dr. Ahmed: Firstly, focal therapy is a choice for the man who wishes to preserve or minimize his risk of genitourinary side effects like incontinence and erectile dysfunction as much as possible. You could argue that everybody wants that, but there are some men who will just have radical treatment and say to me, “I understand that I have side effects, but I just want it sorted out.” There are other men who prioritize minimizing the genitourinary impact that treatments have.

Focal therapy is also a good choice for men who have one index lesion. In other words, they have one tumor that is clinically significant, but at the same time have either no other tumors or one or two clinically insignificant cancers. In those men, we would target the main, biggest, or highest grade tumor because that is the one, studies have shown, that is likely to grow, progress, and metastasize if it was left on its own. The other, smaller, low-risk lesions are the type of indolent disease that a lot of men in the male population have that doesn’t need immediate treatment. You can monitor those after you’ve knocked out the main tumor, for instance.

You wouldn’t want to just knock out those one or two insignificant cancers while you were in there anyway because of potential side effects?

Dr. Ahmed: One of the reasons is it’s difficult to localize one or two millimeters of low-risk disease. In order to treat those, you’d have to end up treating a block of tissue. By the time you’d treated that block of tissue, or two other blocks of tissue, you’re probably at 70 to 80% of the prostate volume.

And if you do that, you might as well just target the whole thing?

Dr. Ahmed: You might as well just treat the whole thing because you’re going to cause as much damage. These small lesions are often not visible on MRI. They’re found on random, systematic biopsies, and you have no idea exactly where they are.

Another consideration is the characteristics of the lesion itself that we would want to treat. It could be one of two things: intermediate Gleason Grade 7, so 3+4 or 4+3. Or, there’s an increasing recognition that high volume Gleason Grade 6 is also something that is better treated immediately than monitored because that is also likely to progress.

For unfavorable, if you like, low-risk disease and intermediate-risk disease where there is one index lesion you can carry out focal therapy. If you can have intermediate-risk disease, which has two or three significant lesions, you would be better served having radical therapy.

What happens if a man gets focal therapy and later his cancer recurs? Can he go on to other subsequent treatments?

Dr. Ahmed: This is quite an important topic now. We know that following focal cryotherapy, focal HIFU, and some of the newer emerging focal therapy modalities that about 15 to 20% of men will either have residual or recurrent disease in the area that’s already been treated. Most of those men will be eligible to have a repeat session of HIFU or cryotherapy. Certainly in my practice, I tell men there is a one in five chance that we may have to repeat the focal therapy to the same area. Almost invariably, all men see that as just part of the intervention. I would argue having two treatments in a fifth of men is probably part of the treatment.

If they fail two treatments in that area, then they really should go on to have radical therapy, or a change in the type of treatment that you give. If the cancer has resisted 80 to 90 degrees centigrade temperature changes twice, or with cryotherapy minus 50/minus 60 degree centigrade twice, then that is an aggressive tumor. It probably has got a very aggressive blood supply and we need to change tacks.

There is a group of men who develop new lesions in untreated tissue. Some of those men can have another focal therapy, but most of them will go on to have radical therapy because their untreated tissue, if you like, has declared itself as unstable. It has a propensity to develop new tumors, and therefore, it would be better to treat the entire prostate.

About 15 to 20% of men over five to six years need a second focal therapy treatment. Overall, about 5 to 7% of men go on to have radical therapy, despite one or two focal therapy sessions. Now that is five to six-year data; we don’t have ten-year data at the moment, either from HIFU or cryotherapy. The newer modalities don’t even have five to six-year data.

Is it safe to say focal therapy is still an emerging option and that we still don’t have all the data?

Dr. Ahmed: I guess it depends on how you define that level of evidence. If we have to wait ten to fifteen years, then yes. If you argue that we’ve now got good five to ten-year data showing non-inferior cancer control, superior toxicity, or superior side effect profiles after focal therapy, then there are a considerable group of men who will accept the uncertainty of the lack of ten to fifteen-year data. They prioritize genitourinary function and they are not compromising their cancer control, at least at five to six-years median follow-up. And they can still have surgery or radiotherapy afterwards.

In the United Kingdom, in certain centers, focal therapy has been offered side by side with other radical therapies within the National Health Service, as part of the NICE, or National Institute for Clinical and Healthcare Excellence, approvals that we have.

What are some of the other controversies over focal therapy?

Dr. Ahmed: There are a number of controversies. One big controversy is this lack of ten to fifteen-year data. I was in the European Congress a couple of days ago. There was a Pro/Con focal therapy argument. I was pro and the person before me was con. He stood up and said, “We don’t have fifteen to twenty year data.” Five years ago, we didn’t have five-year data. A couple of years ago, it was you don’t have ten-year data. When we first started, they said well you don’t have any one year data on biopsies. This is the first time I’ve heard people stand up and say, well you don’t have fifteen to twenty-year data. It’s slightly amusing. It’s infuriating, as well, because the goalposts keep on changing. The long-term data will come; we’re collecting all the data in registries in the United States, the United Kingdom, and European centers. It’s all very robust data collection. We’re doing trials to see if men will accept randomization between radical and focal therapies. Those trials are tough. Men generally want to choose their therapy rather than allowing themselves to be randomized, but we’ll see.

Then the other controversies are around the areas that we touched on. What happens to the untreated tissue? So far, about 4 to 5% of men over the five to six years of median follow-up that we have in our series of several hundred cases have developed new lesions in untreated tissue. Now, those are probably just tiny bits of Gleason 7 tumors that the biopsy and MRI missed that then subsequently progressed. Some of them will be new lesions, but some of them will be disease that was missed in the first place, which declare themselves later. By ten years, it might be higher. So far it’s quite low.

One of the arguments against focal therapy is that this is a multi-focal disease. The untreated tissue is just going to show up with lots and lots of cancers, but that has not been the case, so that has been quite reassuring. The other controversy is around the point that MRI is not good enough and biopsy is not good enough. But I think both MRI and targeted biopsy are good enough. You can never be 100% in anything. If you look at breast mammography, the data shows that a negative mammogram can miss anywhere between 5 to 30% of breast cancers, yet we still use it as a screening tool. We all accept that nothing in medicine is certain. Then there’s concern about what happens to men who fail focal therapy. Can we remove the prostate, or are these men too scarred. What happens in terms of their cancer control? It’s early days yet, but certainly technically, removing a prostate after focal therapy is easier than removing a prostate after failed radiotherapy. It certainly is more scarred around the treated area, though. Does that mean men shouldn’t have focal therapy?

I would argue not because we’re giving radiotherapy to hundreds of thousands of men. It’s an accepted treatment modality, and if it does fail, it’s tough surgery afterwards. That is, unfortunately, the nature of the beast. When the first treatment fails, secondary treatments are always going to be a little bit more difficult, if not a lot more difficult.

It is difficult to perform that second surgery or men will have more side effects after their surgery?

Dr. Ahmed: The concern is both. If it’s more difficult to perform, then are they likely to suffer more side effects? And, as a result of the surgery being difficult, are we going to get more positive margins? Are they going to fail more often?

These are men whose tumors are going to be very aggressive by nature because, as I said, they resisted extremes of temperature, sometimes twice, and there are still a few cells. So they’re going to be pretty aggressive. The failure rates might be higher in that group, just because of the focal therapy paradigm. Just like radiotherapy, when you get radio-resistant cancers they are generally more aggressive and nastier cancers just by natural selection, if you like.

Do you have any advice for men who are considering focal therapy?

Dr. Ahmed: It’s very important when you are first diagnosed with prostate cancer not to rush into treatment. It’s important to do as much reading as you can and have consultations with urologists and radiation oncologists. If you haven’t been told about focal therapy, ask whether you’re suitable. You might get an answer that says, “Well, it’s not proven.” But if you are keen to explore it, you should definitely have a consultation with somebody who does focal therapy so that they can tell you first whether you are suitable, and secondly, what the outcomes might be in your case. I think every good focal therapist will share the uncertainties, as well as the certainties, around the treatment that they give.

If they’re not sharing those uncertainties, then see somebody else. It’s also very important that they quote their own data. That data, ideally, should be published in the public domain because that is a sign, first of all, that you’re being told the right outcomes for that surgeon or physician. Also, it’s a sign that physician takes their trade seriously and is constantly looking to see how they can improve, as well as sharing their data with their peers.

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Focal Therapy

In April, we’re talking about focal therapies.

Dr. Snuffy Myers comments:

“Interest in focal therapy is fueled by the promise of cancer control with fewer side effects than are seen after radiation or radical prostatectomy. From the patient perspective, this is certainly an attractive option. As a result, we have seen the development of an increasing list of approaches to focal therapy.

There are a number of issues that make critical evaluation of the various focal therapies problematic. First, with the exception of a recent trial that involved laser, randomized clinical trials are absent. There is even a controversy about what is the best control group. The laser trial just mentioned used an active surveillance control group. The second approach would be to randomize against surgery or radiation therapy. The major problem is that such trials have proved nearly impossible to run because of poor accrual. For this reason, I suspect that focal therapies are most likely to find a clinical niche as an alternative or add-on to active surveillance.

Another issue is that we lack trials that randomize between two different focal therapies, so it is difficult to know what approach to recommend for a given patient.

For example, cryosurgery and high intensity focused ultrasound (HIFU) have both been around for many years and have never been directly compared in a clinical trial. In developing focal therapies, it is currently common practice to treat a group of patients with a new technology and then follow those patients over time. Results are reported after 1, 5, and 10 year follow-ups and comparisons made to historical results with radiation or radical prostatectomy.

However, we have long known that such comparisons with historical data are often unreliable. As mentioned above, a better, more time efficient approach would be to test focal therapies as an alternate or add on to active surveillance rather than as an alternate to radical prostatectomy or radiation.”

Join us to read this month’s conversations about focal therapy.


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Dr. Daniel George on PSA Recurrence

Dr. Daniel James George is Professor of Medicine and Professor in Surgery at Duke University.

Prostatepedia spoke with him recently about biochemically recurrent prostate cancer.

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

Dr. Daniel George: As we evolve new therapies and indications for treatment, it’s really interesting how that affects our relationships with patients. As an oncologist, my relationships with patients have become more longitudinal. What I mean by that is: people are living longer than ever. I’m beginning to recognize my treatments in the context of not just the short-term endpoint of how to control my patient’s disease in the next few months but in terms of the ramifications for his life and long-term survival. What does it mean in terms of his functional well-being, not simply now, but in a year from now or five to ten years from now?

In many ways, it comforts patients to hear the perspective, that I see them as a long-term survivor, and that I’m thinking about the implications of our treatments in a long-term perspective. That helps the patient invest in his own life and well-being for the long-term, whether that be diet, exercise, sleep, or all these other behavioral interventions that can really impact their quality of life.

You’re basically saying that prostate cancer is becoming more of a chronic disease.

Dr. George: It has been for some patients, and we’re beginning to recognize it more and more for all patients.

We used to think of short-term goals for some of our most advanced cases of prostate cancer—just in terms of disease control or palliation and not worry about the long-term implications of treatment. While on the other end of the spectrum we would have cases where we don’t have to treat the disease at all or maybe treat it minimally in others. Now I’m recognizing prostate cancer as a chronic disease for everybody, and so everybody needs to think of the long-term implications of treatments.

Likewise, we need to think of the implications of our sequential therapies and their cumulative side effects.

Can you define M0 prostate cancer, or biochemically recurrent prostate cancer, for patients?

Dr. George: This is probably confusing because of its name. We refer to prostate cancer in terms of stage. Stage refers to the extent of the disease. The Gleason Score or grade refers to how it looks under the microscope, its aggressiveness. But stage refers to the progression of this disease. Do they have bone metastases? Do they have distant lymph node metastases or other sites of disease? Or is it localized?

We usually use three categories: the T stage, which is the localized tumor, the N stage, which is the lymph node status, and then the M stage, which is the presence of metastases that are distant from the prostate. M0 refers to patients who have no distant metastasis. Think of M0 in terms of patients who are newly diagnosed with prostate cancer.

Recurrent prostate cancer patients are those who’ve had local therapy, surgery, or radiation, and who now have evidence of disease recurrence by PSA. After these treatments, we know that your PSA should be 0 or very low, and it should stay low. If your PSA rises and continues to rise, that’s an indication of disease recurrence. Yet, in many cases, they’re what we call M0 because, when we stage the patient with a bone scan or a CT scan, we can’t see any evidence of cancer. Many of those patients have what we might otherwise refer to as microscopic metastatic disease, disease that’s just below the level of detection. Some of them could have local recurrence or recurrence just within the pelvis and regional nodes that’s not distant. We now know from recent studies that the majority of those patients are going to relapse with distant metastatic disease. In other words, they have distant metastatic disease, but it’s just below the level of detection.

So, this is a bit of a misnomer because we’re treating them with systemic whole-body treatment therapy now because we recognize the risk of distant metastatic disease for the majority of these patients. We’re beginning to use newer imagining techniques, such as PET scans, that could be more sensitive at picking up this microscopic metastatic disease. That shouldn’t deter us from applying the current data to that patient population.

I think of M0 prostate cancer as being low-volume castrate resistant prostate cancer. When we think of it that way, it makes sense that the drugs we’re using work and work even better in that low-volume population. We should use them because M0 is just an early continuation of that metastatic process.

What are these systemic approaches that patients are likely to receive? What are the implications down the line in terms of side effects, and in terms of the longer longitudinal quality of life issues you mentioned earlier?

Dr. George: This is an important aspect of the care for these patients because we have two studies—and a third will soon be reported—that demonstrate a clinical benefit from using what we have broadly termed secondary hormonal therapies, therapies that we add to primary androgen deprivation (ADT) or testosterone suppression.

Patients for whom testosterone suppression has failed can respond to another hormonal intervention later. These are drugs that target the androgen receptor, the protein that testosterone binds to, and inhibits it from signaling. It shuts off what seems to be the most common mechanism for resistance to testicular testosterone suppression. That is an overexpression or overabundance of this receptor, which makes prostate cancer cells sensitive to low levels of residual testosterone in the body.

Xtandi (enzalutamide) and Erleada (apalutamide), in two separate Phase III studies, have demonstrated a clinically significant benefit: a delay in the time to metastasis. The FDA has accepted this as a meaningful endpoint because of the degree of delay. It was associated with about a two-year delay in the time to metastasis in this population.

Patients who were at high risk for developing metastatic disease were in the control arm and developing metastatic disease within about a year of coming on the study for the placebo arm. For the treatment arms, with Xtandi (enzalutamide) or Erleada (apalutamide), we’re seeing a delay of about two additional years. That means three years until the time of metastasis.

The results suggest that we’ve changed the progression of this disease dramatically. In addition, both studies showed a strong trend in favor of the treatment arm for improved overall survival associated with this delay in metastasis. Even though the data may not be as complete because it takes a longer time to report, we’re seeing this correlation in metastasis-free survival, if you will.

Again, I caution the semantics here because these patients do have metastases; they just can’t be seen yet. But the delay in that radiographic appearance of metastasis is associated with an improved survival.

What’s the approach to finding smaller metastases earlier on with the newer imaging techniques? And if they are very small, do you treat them aggressively with radiation, do you continue using the systemic therapies, or do you use a combination?

Dr. George: There is a mix of presentations of patients. When we image with a novel PET-imaging tracer, we’re going to see more than one site of disease in most patients. We’re going to see multiple lymph nodes, multiple bone metastases, or maybe lymph and bone metastases.

For a subset of about 20 percent of patients, we see this disease limited to only lymph node disease or only one or two bone metastases. We refer to this as oligometastatic disease, which we have yet to biologically define. Clinically, we know that it’s associated with a longer survival.

Oligometastatic prostate cancer raises the question of whether or not these patients could be managed with therapy localized to those sites, therapy that does not necessarily expose them to further systemic therapy. We don’t have a lot of data in the castrate-resistant setting, but in the hormone-naïve setting, there are some data that suggest that there can be a delay in the time to initiating subsequent hormonal therapy by doing that.

There’s a study out of Europe, but the median effect was relatively small, just a few months. It’s not clear that this is going to be a meaningful difference for most patients, but it is something that can be discussed.

A lot of those treatment approaches can be done with minimal intervention, external radiation, ablations, or limited surgery. Those will be options. But in the majority of these patients that we do this molecular imaging for, we’re going to find evidence of more than one site of disease or multiple lesions. This suggests that they need a systemic therapy approach.

It’s reasonable to extrapolate this data because we know from the placebo arm of these studies that these patients went on to develop metastases in their bone scan or CT scan within months, 50 percent of them within a year, and many of them in just a few months of their subsequent scan. The likelihood is, if we’d done the molecular imaging at baseline on these patients,we would have seen it. Yet still, in this population, we’re seeing a treatment effect.

We see the treatment effect regardless of what level of PSA doubling time you have. In patients who have a PSA doubling time of just two or three months, we see a dramatic treatment effect. In patients who have a doubling effect of eight or ten months, we still see a dramatic treatment effect in terms of prolongation in the time to metastasis—fewer events in those cases, but still, we see that treatment effect.

The PSA doubling time is an important parameter that we’re using now, in addition to these imaging stats, to determine who we should treat with these drugs and their prognosis.

Isn’t doubling time an indication of the aggressiveness of the disease?

Dr. George: It is. We knew this earlier in disease prior to hormones. PSA doubling time was very prognostic for time to metastasis and overall survival. It’s been less studied in the castrate-resistant setting, when patients have progressed on primary hormonal therapy, but we’re still seeing it there. In fact, the results are really dramatic.

There were some abstracts at the Genitourinary Cancer Symposium (GU ASCO) around this data. There have been reports from these two Phase III studies with Xtandi (enzalutamide) and Erleada (apalutamide) that demonstrate this. We believe there is a strong correlation between a shorter PSA doubling time—a shorter time to bone metastasis—and shorter overall survival.

Just to put these studies into context, the requirements were that PSA doubling times were less than ten months. If doubling time is a year or longer, these are slow-growing cancers. Even though they’re castrate-resistant, these are patients who will live for many years with no metastasis, so it’s reasonable just to observe their disease. For the studies, the median or 50th percentile PSA doubling time was around four months. That’s really short and aggressive.

That’s why we saw that the average time to metastasis was just about a year in the control arms. It’s important to recognize where your patient is in this continuum because it guides whether we should treat him like we did on the study, or if their disease is too slow growing to justify the treatment.

What other considerations are important for patients who fall into this category?

Dr. George: The important thing for patients to know: not to worry. I know that as a physician, it’s easy to say ‘don’t worry about your rising PSA level,’ but as a patient, it is hard to ignore.

Join us to read the rest of Dr. George’s comments about biochemically recurrent prostate cancer.


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Dr. Maha Hussain On Biochemical Recurrence

Dr. Maha Hussain is the Genevieve Teuton Professor of Medicine in the Division of Hematology, Department of Medicine, and the Deputy Director of the Robert H. Lurie Comprehensive Cancer Center of the Northwestern University Feinberg School of Medicine.

Prostatepedia spoke with her recently about biochemically recurrent prostate cancer.

What is biochemical recurrence?

Dr. Hussain: A biochemical recurrence implies that an individual with prostate cancer who has received therapy now has evidence of disease activity as reflected by their PSA blood test. In the context of negative imaging, the PSA is a flag. It generally indicates a relapse. Generally speaking, when the patient has a rising PSA, they get imaged. If the scans are negative, then this becomes purely biochemical recurrence.

Why is this a disease state that we’re particularly focused on? What are some of the key issues in how we approach treating these men?

Dr. Hussain: There are two settings of biochemical recurrence. One is the non-metastatic hormone sensitive setting. This means a patient has had local therapy with surgery and their prostate was taken out, or they’ve had radiation therapy with or without hormonal treatment, and now they have a PSA that’s going up. This implies there is cancer activity. Generally, imaging is done, and most of the time, conventional imaging such as bone and CAT scan are negative.

While not imminently harmful, non-metastatic hormone sensitive biochemical recurrence has significant psychological implications for the patient because it reminds them that there is cancer activity in their body that’s growing.

With regard to management, salvage radiation plus hormone therapy is the standard of care for patients who developed PSA-only relapse post radical prostatectomy as it reduces risk of mets and improves longevity. While there are options for patients who had radiation therapy plus hormonal therapy, they are not optimal.

For example, while hormone therapy is an option for patients whose PSA started to increase after salvage radiation and hormonal therapy, the totality of the data to date does not suggest significant benefit for early hormone therapy versus waiting until there’s a reason to treat.

This population; non-metastatic hormone sensitive PSA relapse, tends to live quite long, and some may not develop visible mets. The speed by which the PSA starts to go up and how fast it increases—what we call doubling time—can imply earlier versus later development of metastatic disease. Detailed discussion is needed to address options, pros and cons of treatment, and potential options for clinical trials.

The other setting of biochemical recurrence is the non-metastatic but castrate-resistant setting, which differs from the previous setting in that patients were treated with hormone therapy and now their PSA is rising while on therapy; that is the rising PSA is occurring despite the fact that hormone therapy has lowered their testosterone levels to the castration range. This is a different clinical phase of disease where the cancer has shown that it is no longer responsive biologically to the hormonal therapy that they are receiving. We know that, given enough time, cancer will show up. We know also that the speed by which the cancer is growing, as reflected by the PSA rate of increase, has an implication as to how soon the cancer will show up on the scans.

This is an area of an unmet need for decades, until last year when two drugs were FDA-approved for this particular patient population, specifically Erleada (apalutamide) and Xtandi (enzalutamide) based on significantly delaying time to development of metastasis. At this year’s American Society of Clinical Oncology GU (ASCO GU) conference, there was also positive data from another trial with Darolutamide in this disease setting. I believe the drug is in front of the FDA at this moment for review.

These three trials were done in a population of patients who had a worse prognosis as reflected by their fast PSA doubling time—a doubling time of 10 months or less. This is because these patients are likely to show metastases within an average of about two to two and a half years.

The issue is whether there is benefit for people who don’t have that kind of PSA doubling time. What if the doubling time is one or two years? It certainly is an area where we need to think about value to that patient.

For both Erleada (apalutamide) and Xtandi (enzalutamide), the FDA approval did not specify the doubling time requirement. The FDA approved it in all patients who have non-metastatic castrate-resistant disease. Clearly one size does not fit all. It’s critical to make shared decisions between the patient and the treating physician with regard to the value of the treatment, the risks from the cancer, the risks from the treatment, the treatment objectives, and when to initiate therapy.

Some good news about this disease phase is, because it’s invisible cancer, and while this means there’s micrometastatic disease, the patient has some time to think about things and also monitor carefully.

In my experience, probably about 8 to 9 out of 10 patients elect to be on treatment because of the concern over worsening disease and the value based on the clinical trials. There are some patients who feel great, and if they’re not going to have an issue tomorrow, then they want to wait a few months before deciding on treatment. That’s perfectly reasonable.

Isn’t that true for a variety of situations in prostate cancer, that you have time to gather a variety of opinions?

Dr. Hussain: Correct in general, but specially for this disease space because no one is going to die overnight from a PSA that’s not controlled. That’s to put it bluntly. There is that room. Patients should talk with their physician about that and discuss risk-benefit ratios as all therapies have side effects.

For certain patients, those side effects might be more important, especially for those who have significant cardiovascular disease. It becomes important to incorporate risk-benefit and close monitoring, but it doesn’t mean that no treatment should ever be done.

Do you have any other advice for men in this situation?

Dr. Hussain: One thing to remember for men with hormone-sensitive biochemical recurrence who have had salvage therapy or post radiation and hormonal therapy is that if therapy is to be done, it ought to have a good reason. Lowering the PSA alone is not the objective; clinical benefit should be the objective.

There is potential harm from treatment in the absence of proof that giving hormone therapy for a PSA of let’s say 0.5 or 0.6 will have a benefit. One has to balance the risks from the treatment and both physical and monetary risks to the patient and ultimately implement a shared decision.

These conversations with patients can be long and potentially stressful to the patient. Yes, hormone therapy can be given. The issue is not whether it can be given but whether it should be given, and if so, when.

There’s a fair amount of population-based data that suggests there’s no clear advantage, but there’s limited prospective clinical trial data. I would encourage patients to discuss these issues with their physicians, understand the upsides and downsides, and also discuss opportunities for clinical trials. Clinical trials are one space in which we need informative data and partnerships with patients to come up with better answers.

For patients who had radical prostatectomy (surgical removal of the prostate), and then their PSA is going up, their best treatment option is salvage therapy, which involves radiation with hormonal treatment.

Based on the more recent data from Radiation Therapy Oncology Group (RTOG), the radiation involves the prostate bed and the pelvis to include the pelvic lymph nodes with four to six months of hormone treatment. This is something that should be discussed with the care team. Radiation alone is not enough, and certainly the data indicate the combination is better with regard to outcomes. If the patient doesn’t want to do the hormones, that’s fine, but the hormones can reduce risk of progression and potentially add to overall survival.

The other side would be situations where patients have had radiation therapy and have received hormonal treatment as part of their primary treatment. Then they stopped the therapy, and now months or years later, the PSA is rising. That’s a different scenario. The issue is whether to resume hormone therapy or not. That’s when a careful conversation is necessary between patients and their physician because there is no compelling data that say it’s necessary to do the hormone therapy.

So, there are a variety of situations.

Dr. Hussain: Yes and/or access to clinical trials. We know the phases of prostate cancer now. The same disease state now has multiple phases, and it’s becoming complicated. That’s important because this speaks to the importance of personalizing care for the patient at all levels.

We’re becoming more and more personalized about how we categorize the different disease states.

Dr. Hussain: Yes, absolutely, and we do individualize the care. A 50-year-old who comes in with non-metastatic castrate-resistant prostate cancer and no comorbidities has a very different disease than someone who is 85, had a stroke, and is in a wheelchair.

Patients should ask their physicians specifically about the type of biochemical recurrence they have, their expected prognosis based on their PSA doubling time, their risk-benefits ratio, and which scientific information from prospective clinical trials can help guide their decisions. Patients should ask for educational material, and doctors should help patients make a decision that’s not based on being afraid but being informed about the choices, pros, and cons.

Would you give similar recommendations to anyone along any stage of the disease progression?

Dr. Hussain: Absolutely. Informed decisions are critical in every disease setting. But biochemical recurrence is a complicated phase of disease. In the setting of metastatic disease, it’s relatively easy in that there is no question regarding the disease risks. Earlier therapy, before symptoms or before the disease worsens, is better generally. This a disease setting that is likely to cause harm if therapy is delayed significantly.

But with non-metastatic hormone sensitive biochemical relapse, a patient can go for years without having any visible metastasis. It’s more complicated when there’s no imminent danger. At the end of the day, I tell patients with non-metastatic hormone sensitive disease in whom there is no clear data to support benefit from systemic therapy, that this is a gray area where we don’t have compelling data to say that giving hormone treatment is going to give a meaningful benefit. Therefore, one option is we monitor closely with interval PSA checks and periodic imaging. Based on doubling times and trends, what new evidence that comes up, and patient comfort we can watch. Once the patient is informed about the specifics, it is fascinating that the majority tends to be comfortable with watching and about a third are not comfortable with not getting therapy. There is not a one-size-fits-all approach. Personalized shared decision is critical.

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Who Is Dr. James Gulley?

Dr. James Gulley is the Head of the Immunotherapy Section and the Director of the Medical Oncology Service at the National Cancer Institute’s Center for Cancer Research in Bethesda, MD.

Join us to read Dr. Gulley’s comments about prostate cancer vaccine clinical trials.

Why did you become a doctor?

Dr. James Gulley: I think this has to go back to my high school biology teacher. His name was Vernon McNeilus. He was a retired orthopedic surgeon who just found a way to instill inspiration and that sense of curiosity about life. He drove us to really be excited and interested in science and in biology in particular. I had decided that I wanted to do something in science or medicine, but there was no way that I was going to go spend all that time to become a doctor. I’d been in school long enough. One of my friends decided he was going to go into medicine. I said if he can do it, I can certainly do it.

Then it actually evolved even further than that because during my stint in college I got the opportunity to do a summer research program. I decided I liked research, so I applied to MD/PhD programs and got accepted into two. I decided to go to Loma Linda.

What is it about medicine that keeps you interested?

Dr. Gulley: I think the thing that really drives me is how fascinating it is to understand how things work. I’ve always been fascinated in what makes things work. As a little boy I would take things apart trying to figure out what made them work and then put them back together again. If something was broken in the house, my mom would just give it to me and I’d tinker with it and get it to work again.

To me, the ultimate machine is the human body and one serious puzzle is to figure out ways to bring back health from sickness. Not just a puzzle for curiosity’s sake, but because of the effect that cancer can have on families, to uncover ways to effectively treat cancer. I think it’s truly something that I have seen patients who were close to death who have had remarkable and prolonged clinical responses. That, to me, begs the question that if we can do it for some people, then why can’t we do it for all people? That is what I am passionate about.

Are there any patients you’ve had over the years whose cases changed how you see your own role or the art of medicine?

Dr. Gulley: I’ve had several patients that have been exceptional responders; that really has changed how I view things. One of my more recent exceptional responses from this past year is a retired army surgeon who has advanced metastatic castrate resistant prostate cancer. I have been treating him since 2005. He was initially treated with radical prostatectomy. It turned out that he had a high Gleason disease. He had radiation therapy, but he had recurrence of his disease, unfortunately. He was treated with hormonal therapy, with chemotherapy, with Provenge (sipuleucel-T), and Xtandi (enzalutamide).

He came to me last year having had multiple therapies including other experimental immunotherapies. He was clearly not doing well. His PSA was going up very quickly with a doubling time of less than a month. His symptoms were getting substantially worse. He articulated to me that even going to church every week was becoming difficult: one week he was able to sing the songs and the next week he was too tired to sing. Then the next week he was almost too tired to stand up.

We were able to enroll him in a study combining a vaccine with checkpoint inhibition. When we gave him that combination, his PSA dropped dramatically. It has now gone to undetectable. His lesion in his bladder, which was causing local symptoms so that he had to have a chronic indwelling Foley catheter, shrunk away. When we biopsied it there was no evidence of tumor there. He has some lesions that are seen on bone scan, but I’m not sure if that represents viable tumor or not.

He is now over a year out from when he started treatment. His energy level hasn’t been better since before he was diagnosed. He is out doing everything he wants to do. To me that is amazing. It is amazing we can see responses like that.

From a scientific standpoint, of course, I was stunned to see this and wondered could he have micro-satellite instability that leads to lots of mutations. It turned out that he had micro-satellite instability in his cancer, suggesting that the immune system was able to see his cancer much more readily, so all we need to do is allow those immune system cells to be functional with the Opdivo (nivolumab).

We also had one other patient that didn’t have micro-satellite instability with this combination who also had a really nice 90% or so drop in his PSA. It’s not undetectable, but he hasn’t had the immune checkpoint inhibition for well over a year now. He’s just on vaccine alone because he had some bleeding in his urine from the checkpoint inhibitor. To me, having responses like that changes my outlook. It says the immune system, even in patients with prostate cancer, can be harnessed to attack the tumor. We just have to figure out ways that we can make this more applicable to all patients.


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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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