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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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Biochemical Recurrence

In March, we’re talking about biochemical recurrence.

Dr. Snuffy Myers frames the issue for us below.

Not a member? Join us to read conversations with Drs. Daniel George, Pedro Barata, Julio Aguirre-Ghiso, and Rahul Aggarwal.

Pp_March_2018_V4_N7

This issue focuses on treatment issues for men with an increasing PSA after prostatectomy or prostate radiation. In this introduction, I will review some basic concepts that should help you follow the discussion more easily.

If surgery has successfully removed the prostate gland, the only source of PSA will be surviving cancer cells. After radiation, there can be normal prostate cells in addition to cancer cells. However, prostate cancer cells differ from normal prostate cells because the cancer cells are able to grow in a particular manner. Cancer cells grow by doubling: 1 cell becomes 2; 2 become 4; 4 become 8. Cancer cells do this at a constant rate.

For example, if the cancer cells double every year, then on subsequent years, the number of cancer cells would be 1, 2, 4, 8, 16, 32, 64, 128, 256, and so on. As a general rule, it takes 15 doublings to go from 1 cancer cell to a mass 1 centimeter across. At 1 centimeter, cancer masses generally become detectable by CT scan. As a rough rule of thumb, it takes another 15 doublings to reach a lethal cancer burden.

The implication is that half of the cancer growth occurs below the level of detectability.

Unlike most cancers, our ability to follow prostate cancer is not limited to imaging tools like the

CT or bone scans. We have PSA as a biochemical marker that can be used to follow the cancer. The PSA is a much more sensitive indicator of cancer presence than both CT or bone scan and can indicate the presence of recurrent cancer months to years earlier.

In most patients, the PSA level is roughly proportional to the size of the cancer mass: if the cancer doubles in size, the PSA will double. Thus, the PSA doubling time is thought to provide an estimate of the cancer doubling time. PSA doubling times faster than 3 months usually indicate rapidly growing disease associated with short survival unless treated aggressively. PSA doubling times slower than 9 months usually indicate much less aggressive cancers. PSA doubling times greater than two years are associated with prostate cancers that can take a decade or more to cause metastases detected by the scans.

As a result, it is common to see men after surgery or radiation who have an increasing PSA, but no other evidence of disease. In those patients, PSA doubling time represents the only well established tool to determine the aggressiveness of the cancer and how soon metastatic cancer might manifest itself.

PSA, however, provides no information about the location of the cancer. Is it present in bone, lymph node, liver, or lung? The recent advances in PET scans mean that the cancer can now be detected while it is much smaller than would be the case with CT or bone scan. However, clinical trials have yet to prove this early detection improves the outcome of treatment.

Finally, there is the problem of late relapses. After surgery, patients can have an undetectable PSA for years—even more than a decade— and then recur. What was going on during that silent interval and what changed to trigger recurrent cancer? This phenomenon is called cancer dormancy and is also reviewed in this issue.

Charles E. Myers, Jr., MD


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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. Mary-Ellen Taplin On Zytiga, Xtandi + Erleada

Dr. Mary-Ellen Taplin is the Director of Clinical Research at the Lank Center for Genitourinary Oncology at Dana-Farber Institute. Prostatepedia spoke with her about the impact Zytiga (abiraterone), Xtandi (enzalutamide), and Erleada (apalutamide) have had on how we treat prostate cancer patients.

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Why did you become a doctor?

Dr. Mary-Ellen Taplin: I was drawn to medicine because I really like the science behind cell biology and cell growth. I was attracted to oncology because I like being able to think about how to attack unbridled cell growth. Oncology is about understanding mechanisms of response and resistance. My goal is to give patients the highest level of care through application of basic discovery and not just go with the same status quo. For me, it was the intellectual pursuit of cell biology that then connected with oncology and oncology patients.

Have you had any particular patients over the years whose cases have changed either how you see your own role as a doctor or how you practice medicine?

Dr. Taplin: I treat all my patients as if they were family. I try to go to where they are, provide support, and be a healer. I give them the best go at the best quality of life and length of life that they can have.

Can you talk to us a bit about how Zytiga (abiraterone), Xtandi (enzalutamide), and Erleada (apalutamide) have changed the treatment landscape for men with prostate cancer?

Dr. Taplin: First, in castrate-resistant cancer, these agents have provided patients with fairly well-tolerated oral therapies that work well in most people, at least for a significant period of time. It’s never long enough, but for a year or two, they work well.

Prior to these agents, all we had was ketoconazole, which works similarly to Zytiga (abiraterone) but is less targeted and has a lot of side effects. Ketoconazole wasn’t approved specifically for prostate cancer and wasn’t an optimal drug. We also had chemotherapy. Patients’ lifestyles are always more hindered by having to come in for IV chemotherapy every three weeks compared to taking oral medications.

These newer drugs not only provide effective therapy, but also provide therapy that is more conducive to keeping patients in their regular lifestyles.

Secondly, with newer data that has since evolved, these agents have also been found to improve outcomes for patients when used earlier, like in patients with non-metastatic castrate-resistant prostate cancer, in the case of Erleada (apalutamide), and for hormone-sensitive metastatic disease, in the case of Zytiga (abiraterone).

So, firstly: men with castrate resistant metastatic prostate cancer have more tolerable options, an improved life expectancy, reduced cancer related symptoms on many levels, reduced intensive pain, reduced need for narcotics, and reduced need for early chemotherapy. All things that go along with improving people’s quality of life while treating them.

And then secondly, moving these agents up earlier in disease progression has provided benefits to earlier stage patients. There are a lot of ongoing investigations looking at using these drugs earlier in conjunction with radiation and even prostatectomy. The field is not done with trying to optimize the timing and improving outcomes for patients with these particular clinical tools.

Which combinations are being explored, and which might be the most promising in the long run?

Dr. Taplin: To date, there are no combinations that have been proven effective in any sequential therapy in castrate-resistant prostate cancer (CRPC), but combinations are important and should be evaluated. There is strong biologic rationale to combine Xtandi (enzalutamide) with a CPY-17 inhibitor (abiraterone), Xtandi (enzalutamide) and a PD-1 inhibitor, or Xtandi (enzalutamide) or Erleada (apalutamide) with a PI3 kinase pathway inhibitor.

These are important combinations to explore. But in prostate cancer, at least in the 28 years that I’ve been practicing, despite many trials, not one combination regimen has been approved in CRPC. It’s tough to build a combination therapy in prostate cancer for unclear reasons. That doesn’t mean we shouldn’t explore them, but it means it’s unclear how effective combination therapy will be, at least in the short term.

There is a Phase III Alliance trial looking at Xtandi (enzalutamide) and Zytiga (abiraterone) together in patients with castrate-resistant prostate cancer. Dr. Mike Morris is the Principal Investigator. The biologic rationale is strong to explore more intense androgen receptor pathway inhibition with the combination of a second-generation AR antagonist with a ligand antagonist like Zytiga (abiraterone).

The preclinical rationale is promising, but to date, combination therapy in prostate cancer has been an unfulfilled dream.

What are the side effects like for each of these agents?

Dr. Taplin: There are differences, but they all cause some degree of fatigue, muscle wasting, and hypertension. With Zytiga (abiraterone) we have to watch for low potassium and elevated liver enzymes. We don’t see those things with Xtandi (enzalutamide) or Erleada (apalutamide). In a subset of patients, there is some cognitive clouding, some reduced concentration even to the point of confusion with Xtandi (enzalutamide), though rarely with Zytiga (abiraterone). Erleada (apalutamide) can rarely cause hypothyroidism, which is specific to that drug, so it needs to be monitored.

In general, patients need to have laboratory and blood pressure monitoring on a regular basis, every 2-8 weeks depending on the patient and the individual risks.

At present most patients are castrate resistant when they start on these drugs, so they’ve already had years of adjusting to medical castration. These patients have usually adjusted to the typical side effects that you see with medical castration when you start them on Lupron (leuprolide) or similar LHRH agonists/antagonists and have been more or less familiar with side effects such as hot flashes and weight gain for years.

A lot of patients talk about the high price of these medications. Do you have any thoughts about that?

Dr. Taplin: It’s a big problem. The copays are anywhere from $0 to $4,000 if you have coverage. Then there are the people who don’t have any coverage. This is the nature of Big Pharma in the United States and because the United States bears the burden of research and development of these products for the rest of the world. They’re expensive, and as a society, we have not prioritized dealing with the costs. Sometimes what we would consider even a small copay for a particular patient is too much for them. They’re faced with paying their phone bill or getting their medication.

It’s been well documented that, especially in the elderly, these expensive medications lead to people not taking their medication correctly, trying to stretch them out, skipping days or reducing doses, or not taking them all together. It’s a little different for cancer medication than, say, for blood pressure medicine. Cancer patients are more motivated to take the medication, but probably, they do not often take it correctly to try to make it last longer.

Family members sometimes share the burden. The patient can’t afford the drug, so family members try to patch together the funding. It can be a family problem as well as an individual problem.

I don’t know what the answer is, but it’s definitely true that, as we develop more oral therapies in prostate cancer, patients could be on very expensive sequential oral therapies for many years. For instance, a patient may go from bicalutamide to Zytiga (abiraterone) to Xtandi (enzalutamide) to Lynparza (olaparib). Three out of those four are expensive oral therapies. You’re not just talking about big copays for a year—because Zytiga is only going to work for a year—but sequential copays. These patients are probably going to be on these oral drugs for many years.

Does that ever factor into your choice of which agents to use in which patient?

Dr. Taplin: If we had more choice, it would. Most insurance companies require, at least in castrate-resistant prostate cancer, that you use Zytiga (abiraterone) first because, though still expensive, it is less expensive than enzalutamide. You don’t have a choice as a physician because the insurance companies decide what will be covered. Zytiga (abiraterone) is less expensive than Xtandi (enzalutamide) by almost 50 percent. I’ve stopped doing appeals to insurance companies for these drugs because insurance denials are rarely over turned.

Do you have any thoughts for men who’ve been prescribed any of these agents?

Dr. Taplin: Get guidance from the physician who is prescribing them so that you understand the common potential side effects. Take them as prescribed. If there is toxicity, discuss with your doctors the potential for a dose reduction. Even though there’s the FDA-recommended dose, often these medicines work well at lower doses. You might have less toxicity or feel better, say, on 750 mg instead of 1,000 mg of Zytiga (abiraterone) or 120 mg instead of 160 mg of Xtandi (enzalutamide). Don’t do that on your own, but it’s something that could be discussed with your doctor.

Another important message to get out to patients on these medications is the importance of keeping strong and of regular exercise. Find exercise and activities that you like. Get a trainer. Join a YMCA. Do the LIVESTRONG program. Commit to some sort of strengthening activity to keep your muscles. That will reduce side effects over time and be helpful. Of course, diet is important. A good heart-healthy diet is a good prostate cancer patient diet as well. Exercise and diet are often neglected by patients and physicians but are really important tools for patients on second generation hormone inhibiting drugs.

Diet and exercise can put patients in a better place so that they don’t have a fall or other toxicity problems. If you get a prescription for Xtandi (enzalutamide), you should also get a prescription to go to the gym four times a week. You need more than just a walk to the mailbox and back or to go grocery shopping. You don’t have to be an Olympic athlete, but doing some type of strength training will help build muscle, or at least reduce the reduction in muscle tone that a lot of these men suffer from.

Join is to read the rest of our October conversations about Zytiga (abiraterone), Xtandi (enzalutamide) and Erleada (apalutamide).


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Switching from One Chemo Drug to Another

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

This is not what we found.

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

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

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

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

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

Does it matter which you get first?

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

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

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

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

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

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

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

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

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

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

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

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