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.
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.