Expert Perspectives: Androgen-Deprivation Therapy in Prostate Cancer

Targeted Oncologyinterviewed Cy Stein, MD, PhD, Arthur & Rosalie Kaplan Chair in Medical Oncology and deputy director of Clinical Research at City of Hope National Medical Center, and a member of the NCCN guideline panel for prostate cancer.

Targeted Oncology: Is there optimal sequencing for androgen-deprivation therapy (ADT)?

Dr. Stein:There is probably no such thing as optimal sequencing from what we currently know about treatment; we have no proof of what it would be as yet. In fact, one clinician’s course of treatment may be as good as another’s. What is there still to learn about this? In short, everything. My thought, however, is that even when we know more, we will discover that there is still no fixed sequence. Treatment is likely to continue to be very individualized, because patients--and the disease itself--are heterogeneous. A lot of art will remain in the care of these patients. Some disease is indolent and some is very aggressive. Some of our older patients are able to tolerate very little and have well defined views about quality of life for their remaining years. Younger men often feel differently and are eager to try new approaches.

What are some of the drug sequences physicians are currently using?

For metastatic disease, the antiandrogen bicalutamide can be prescribed. Some doctors in academic centers will then give the immunotherapy sipuleucel-T, but that’s more difficult for community oncologists for reasons of cost, insurance coverage, and administration. Many doctors now prescribe the CYP17 inhibitor abiraterone, while others start with androgen receptor inhibitor enzalutamide, even though it doesn’t have FDA approval yet in the pre-chemo space. Despite this, some insurers will still say yes to it.

There is arbitrariness to some of these decisions. Do we employ these new agents pre-chemotherapy or post-chemotherapy? Most of us believe, for example, that if an agent is active post-chemo, then it’s active pre-chemo as well. Abiraterone is a little tougher to give than enzalutamide. If the patient is diabetic, it can be a problem because it must be given with the steroid prednisone, and abiraterone also can cause electrolyte imbalances and exacerbate liver problems. While enzalutamide is less toxic, it is not without issues, including altered mental status and seizures in rare cases, and some fatigue as well.

So it’s something of a toss-up with these two new agents. Studies have shown that enzalutamide is not that effective after abiraterone, and vice versa. There are still other options. After ADT, doctors will often recommend chemotherapy. If docetaxel fails, clinicians can go with abiraterone or enzalutamide, or radium-223, or the chemotherapy cabazitaxel. The variability between individuals is so huge, there’s no set plan.

Do any drug combinations that include ADT look promising?

Many of these combinations are still in trials, which include several with abiraterone and enzalutamide. It’s too early to tell what is effective. There is a trial of LHRH agonist Lupron (leuprolide acetate) plus bicalutamide versus Lupron plus enzalutamide. There is also enzalutamide combined with abiraterone. While we sometimes think we know what the answers to these trials will be, we have learned to discount that kind of thinking, as we’ve been burned before. We need solid evidence.

What guides decision-making in prescribing ADT?

That is a very difficult question. There are no hard-and-fast rules when you start this therapy, although there are some general guidelines. If the disease is progressing rapidly, the indications are to change therapy. But this doesn’t happen in many patients. Often, we don’t see symptoms, but rather just an increase in PSA. But what does a small increase in PSA mean? Do we treat a number?

The answer is no. In fact, it’s not the number that matters so much as the rate of increase. If PSA doubles in 5 or 6 months, then we might try enzalutamide or abiraterone. If it doubles in a year or more, we may choose to watch and wait. In terms of prescribing the newer agents, few people have bad reactions, except for patients with health issues such as poor liver function who are taking abiraterone or a seizure disorder if enzalutamide is chosen. The androgen receptor is a bad actor until very late in the disease, so everyone is potentially a candidate for these therapies. With long exposure to abiraterone, enzalutamide will likely be less effective. But you can’t necessarily deny it to a patient based on that, because it may in fact work. So often with prostate cancer, we can’t predict.

What strides are we making in identifying biomarkers that will help predict the efficacy of treatment?

This, too, is difficult to say. There is PSA, but we know that it is not necessarily predictive. A high Gleason score or a high PSA to begin with may be signs of aggressive or advanced disease. But even these high numbers must be considered individually in each patient. In some cases, even a high PSA may not mean that much. For example, a PSA of 20 in one person may be like 1000 in another. There are all kinds of studies out there trying to validate additional biomarkers, but again, the problem is heterogeneity. Too many times the results wash out, despite initial promise.

Are there promising ADTs on the horizon?

There is ARN-509, which acts like bicalutamide on steroids. It seems interesting, but those trials are not advanced enough to say much. We have no sense yet, for example, of overall survival, which is the gold standard. There are some other drugs that are closely related to abiraterone, such as galeterone, a CYP17 inhibitor and androgen receptor antagonist. There is also the CYP17 inhibitor TAK-700, although it recently missed its primary endpoint of increasing overall survival. However, it’s getting to be a crowded space for those drugs, so it’s easy to miss an endpoint. Clinicians will be looking at it in earlier-stage cancer, but it’s too early to tell.

How are these new agents changing clinical practice?