COMMENTARY

The Changing Landscape of Prostate Cancer Treatment

E. David Crawford, MD

Disclosures

June 17, 2011

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Introduction

Hello. This is E. David Crawford, Professor of Surgery, Urology, and Radiation Oncology and Head of Urologic Oncology at the University of Colorado. Welcome to Medscape Oncology Insights on Prostate Cancer. I would like to talk about a number of exciting developments in advanced and castrate-resistant prostate cancer that are changing the landscape of how we deal with patients at this stage of the disease.

The Landscape of Prostate Cancer Treatment

In the past year, a number of new and innovative therapies have been approved. These include abiraterone acetate, denosumab, cabazitaxel, and sipuleucel-T. The approval of these drugs has changed the landscape of how we manage advanced and castrate-resistant prostate cancer. They have generated a lot of hope, excitement, and also a lot of questions about how we sequence these agents, possibly how we put these drugs together in new combinations, and the hope of developing prostate cancer in these advanced stages into a chronic disease. They have also given us the opportunity to look at the future and new drugs that are coming around that are very similar to these, or additive to these drugs.

Let's talk a little bit about the landscape. In general, when patients have had advanced prostate cancer, that was untreated with hormone therapy, we have had hormone therapy. Primarily, we have had LHRH [luteinizing hormone-releasing hormone] compounds and antiandrogens. Then, when patients failed that, there wasn't really a lot of hope. Over the years, numerous trials have been conducted with chemotherapy. Only in the past decade or so, has excitement been generated by the use of paclitaxel chemotherapy. When patients failed paclitaxel chemotherapy, there was not a lot to offer as second-line therapy. That's what has changed in the last year. We have 2 new drugs that are going to be second-line therapy, including abiraterone acetate and cabazitaxel, which is already approved. These drugs may also be sequenced earlier in the disease.

Targeting the Bone

We also know that prostate cancer likes to spread to bone and has some unique characteristics in bone. Hormone therapy affects bone and causes osteoporosis, and we know that increases the risk for fractures. We also know that when this cancer is in the bone, it can result in skeletal-related events. This has been the focus of a lot of research in the last decade, particularly with using drugs that have an effect on bone. Recently, RANK [receptor activator of nuclear factor kappa-B] ligand inhibitors, such as denosumab, which has an effect on bone, have been developed. A number of studies have been conducted with this drug, (several of them presented recently at meetings, including ASCO®), showing that denosumab has an effect on delaying metastases in patients who are on hormone therapy and also on reducing skeletal-related events, much like what was shown years ago with the bisphosphonate zoledronic acid. We have bone as a target right now.

Testosterone Is the Key

We have also learned over the years that testosterone is the key component to prostate cancer, and only recently have compounds been developed that can lower or annihilate testosterone, so to speak, getting it down to micronanogram levels. This is where drugs like abiraterone acetate come in. In the most advanced refractory stages of prostate cancer, when patients are failing docetaxel and other chemotherapies, the shown survival benefit is 4+ months. Along with that has been the development of new taxanes, such as cabazitaxel, which also improve survival rate.

Excitement is developing because we now have second-line therapies, and people are even talking about third-line therapies. Along with these drugs, analogs of drugs like these are being developed that are similar to abiraterone and to the taxanes. The question is how do we sequence these drugs? Some excitement exists around these new developments. Do they play a role earlier in the disease in patients who might be hormonally naive? Should we consider looking at drugs like abiraterone, using the RANK ligand inhibitors and chemotherapy? A whole lot of questions come up, and this is the basis for studies that we are going to see in the future in prostate cancer on how to sequence these therapies.

More Tricks in Our Bag

We know that the companies and cooperative groups are studying these drugs in different arenas right now. For instance, abiraterone is being looked at in patients who are hormone refractory and who are not receiving chemotherapy. Ongoing studies are sequencing this therapy earlier, along with hormonal therapy and chemotherapy. Recently, some studies have been looking at combining hormone therapy and chemotherapy in adjuvant and neoadjuvant settings. We have come from a disease state in prostate cancer where we had basically a "couple of tricks in our bag," so to speak, a couple of hormone therapies. There were a lot of variations on how we provided these therapies, from orchiectomy to estrogens to LHRH compounds. Another new drug that was approved in the last couple of years is an LHRH antagonist, a drug called degarelix, which has some potential advantages over our current LHRH compounds.

Now, we can look at sequencing some of these other drugs earlier in the disease. We have gone from just having hormone therapy and chemotherapy, basically with just docetaxel (although mitoxantrone and prednisone have been used), to the point where we now have other agents to look at in these 2 areas of hormonal therapy -- newer hormonal therapies that lower testosterone even further. That's a subject about which a number of presentations took place at our American Urological Association recently, and also at the ASCO® -- testosterone and levels of testosterone and what defines the ideal level of testosterone. We now know that even in patients whom we thought were castrate, you can lower testosterone still further. Where does testosterone come from if a patient is castrate? It probably comes from 2 areas: one is the adrenal gland and the other is the tumor itself, which can turn itself on by producing testosterone. This offers some excitement to be able to factor this knowledge early in sequencing.

Antiandrogens and Alpha Emitters

I have often said that the best treatment for advanced prostate cancer would be an antiandrogen that works. I have conducted studies with others using antiandrogens, and these agents have some activity, but it is weak. They are not complete blockers. A couple of new drugs are generating excitement, including MDV3100, which might be called a "super antiandrogen." This drug can potentially have a real impact in prostate cancer throughout the advanced stages. It is also being studied. We'll keep our ears to the ground and expect to hear something about that soon.

Lastly, there are many other agents, probably 80 or more drugs, in development for prostate cancer, and interest once more in radiopharmaceuticals. Over the years, we have had samarium and strontium to treat bone, but there are drawbacks and concerns about their effects on bone marrow. Now, there are some new drugs called alpha emitters that don't have the penetration of the beta emitters that we have had in the past. One of these drugs, radium 223, is being studied in Europe right now and is maturing and may enter into the sequence.

If No Cure, a Chronic Disease?

What we have is a lot of excitement; a lot of new hope. We have a landscape that was pretty simple before. It was hormone therapy and chemotherapy, and it is now being innovatively charged with new ways to integrate therapies, which is exciting. There is a subtle hope that -- like in other cancers -- we can convert prostate cancer in its advanced stages into more of a chronic disease. The future is bright. We are going to see a lot more developments as time goes on in the next couple of years that will change the landscape in prostate cancer. This is E. David Crawford, and thank you for joining me for this edition of Medscape Oncology Insights.

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