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

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

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

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

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

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

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

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

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

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

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

What can men expect to happen step by- step?

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

What images studies will you be using?

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

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

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

Which tumor biomarkers are you looking at?

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

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

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

What are the eligibility criteria?

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

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Merel Nissenberg On Non-Metastatic Castrate-Resistant Prostate Cancer

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

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

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

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

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

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

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

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Dr. Bertrand Tombal On Making Prostate Cancer A Chronic Disease

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

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

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

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

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

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

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

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

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

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

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

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

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

That’s why these drugs are so important.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

What should patients take away from that?

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

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

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

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

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

Why shouldn’t we use imaging as much?

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

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

Europe is ahead of the United States in that regard.

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

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

Dr. Tombal: Exactly.

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Dr. Bertrand Tombal On Why He Became A Doctor

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

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

Prostatepedia spoke with him about why he became a doctor.

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Why did you become a doctor?

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

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

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

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

Funny. Life takes you on different paths.

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

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

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

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

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

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

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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).

October Prostatepedia: Zytiga (abiraterone), Xtandi (enzalutamide) and Erleada (apalutamide)

Chances are you’ve heard of the prostate cancer drugs Zytiga (abiraterone), Xtandi (enzalutamide) and Erleada (apalutamide) even if you haven’t been prescribed any of the three agents yourself.

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They are among a collection of new drugs introduced in the past 5-10 years that have totally transformed how we treat prostate cancer. Others you may also recognize include Xofigo (radium-223) and Provenge (sipuleucl-T.)

One way of treating prostate cancer is of course to block androgens, which are male hormones. (Prostate cancer feeds on these male sex hormones.) This usually works for a while, but eventually some prostate cancers continue to grow even in very low androgen levels.

We now understand that these particular tumors have become so sensitive to androgens that they only need a very little bit to grow. Androgen levels are therefore higher in a prostate cancer tumor than in a normal prostate.

Newer drugs like Xtandi (enzalutamide) and Erleada (apalutamide) work by blocking these androgens from binding to the androgen receptor more effectively than earlier drugs. Zytiga (abiraterone) works by reducing androgen levels much more effectively than earlier drugs. Originally approved for men with metastases whose prostate cancers are resistant to hormonal therapy only after chemotherapy stopped working, researchers have been diligently exploring whether or not these agents are useful in other settings—i.e. before chemotherapy or in men without metastases.

 

Those explorations have panned out: men with metastatic prostate cancer resistant to hormonal therapy are now prescribed Zytiga (abiraterone) and Xtandi (enzalutamide) as an initial treatment. And men with prostate cancer resistant to hormonal therapy but without metastases are prescribed Erleada (apalutamide). All drugs extend life and extend the amount of time before the cancer appears to be growing on imaging studies.

What isn’t so clear are the implications of the early use of these agents— both in terms of side effects and financial burden on patient, nor why some men appear to become resistant to the drugs after a period of time.

Read the conversations this month carefully and then forward to your doctor. Even if your particular situation doesn’t warrant their use today, educating yourself about them will serve you well: if your doctor ever does suggest you use one of these agents, the two of you can have an informed in-depth discussion about whether they’re right for you.

Join us to read our October conversations.

Zytiga, Xtandi + Erleada

In October, Prostatepedia takes an in-depth look at a relatively new set of prostate cancer drugs—Zytiga (abiraterone), Xtandi (enzalutamide) and Erleada (apalutamide).

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

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The development and FDA approval of the new anti-androgens, Zytiga (abiraterone), Xtandi (enzalutamide) and Erleada (apalutamide), represent a major advance in prostate cancer treatment. This issue provides you with experts’ current views on the use of these agents.

For hormone resistant metastatic prostate cancer, their use is now well established. They can provide an alternative to Taxotere (docetaxel) chemotherapy in patients who have failed initial hormonal therapy. While most patients will eventually experience cancer progression on these agents and need chemotherapy, the delay in initiating chemotherapy prolongs the period they have with better quality of life.

Recent trials have extended the use of these drugs to patients with nonmetastatic hormone resistant disease. These studies have shown that early use of these drugs results in a rather dramatic delay in the appearance of metastatic disease. As a result, early use of these agents is becoming widespread.

However, Dr. Mario Eisenberger does an excellent job of discussing unresolved issues with the early use of these drugs. I agree with him that we need to be concerned about long-term side effects of these drugs as many men are likely to be on them for more than five years. For example, Zytiga (abiraterone) results in a rapid drop in both testosterone and estradiol. As estradiol plays a major role in bone health, it is possible that long-term use of Zytiga (abiraterone) might increase the risk of fractures.

The current trend in clinical trial design is to test drugs in all patients who clinically fit the protocol. Thus, all men with hormone resistant metastatic disease would be tested with Zytiga (abiraterone) or Xtandi (enzalutamide). Dr. Eleni Efstathiou correctly points out that a portion of these patients’ cancers may already have molecular changes that make them likely to respond poorly to these drugs. She is investigating whether testing for these molecular changes will allow clinicians to select patients likely to have a significant and durable response to treatment. This approach makes sense.

As a practical matter, these new drugs are important enough that you, as a patient, want to make sure that the doctor managing your prostate cancer is knowledgeable and experienced in the use of these drugs.

Join us to read this month’s conversations about Zytiga (abiraterone), Xtandi (enzalutamide), and Erleada (apalutamide).