The Value of AR-Targeted Therapy in CRPC



Charles J. Ryan, MD: Abiraterone is an orally available steroidal inhibitor of the CYP17 enzyme compound complex. In inhibiting CYP17, it reduces androgen production. And in many patients who take it, in fact most patients who take it, androgen levels can go down to near 0 or undetectable levels.

Now the mechanism of action in inhibiting CYP17 leaves open the potential for stimulation of the adrenal gland in parts of the adrenal gland that are not inhibited by CYP17, most importantly being mineralocorticoid pathway.

The side effects of abiraterone basically come from that mechanism. Aldosterone excess, or an aldosterone excess syndrome, is the clinical output of that. That can lead to fluid retention and potassium loss, and some of the consequences are the sequelae of fluid retention such as congestive heart failure, peripheral edema, and those types of things. About 7% to 10% of patients may experience a transaminase of an elevation as a consequence of abiraterone therapy, and in doing so would likely have to discontinue the drug or decrease the dose.

The drug is currently indicated with FDA approval in 2 settings in metastatic castration-resistant prostate cancer. First, in patients who have already received docetaxel and have experienced disease progression after docetaxel. It’s also indicated in patients who are asymptomatic, or minimally symptomatic, but chemotherapy naïve and have metastatic castration-resistant prostate cancer. And more recently, it has found great use in the setting of metastatic hormone-sensitive disease based on a large series of studies done in Europe and Canada, which showed a significant survival benefit when abiraterone was added to initial androgen deprivation therapy.

Julie Graff, MD: Enzalutamide is currently FDA approved for men with metastatic castration-resistant prostate cancer. It’s for those men who clearly have tumors on imaging studies and the tumors are no longer responding to castration therapies like LHRH or GnRH agonists or antagonists. Enzalutamide is approved in this space where multiple drugs are approved, such as abiraterone, chemotherapy drugs, radium-223, and sipuleucel-T.

Enzalutamide is an androgen receptor antagonist. It makes it so that testosterone, or any androgen, cannot bind to the androgen receptor. It also blocks the movement of the androgen receptor into the nucleus and the binding of that receptor to DNA. So, it has a 3-fold effect.

Enzalutamide has some risks associated with it. In early studies, particularly the phase I and phase II studies, there were seizures at higher doses of enzalutamide. Currently, we use 160 mg a day, and at 360 mg, 480 mg, and 600 mg, people had seizures. In the phase III study, post-chemotherapy, there were some people who had seizures, particularly those who were at risk for seizures. And in the phase III study, prechemotherapy, there was 1 seizure in the enzalutamide arm and 1 seizure in the placebo arm. So, we’re getting better at selecting patients who are appropriate for this agent.

The other risks are fatigue, which can be quite profound, and it can be a reason to decrease the dose; hypertension, so it’s important to follow up with doctors and get regular blood pressure checks; and cognitive dysfunctions, so the patient’s thinking is just a little bit cloudier than it used to be. So, if I have a patient who’s a high-performing patient—an economist, a writer—I may not use this drug right away out of concern that it might cause thinking disorders. And then, in patients age 75 years and older, it’s associated with falls.

Enzalutamide and abiraterone have some cross resistance, which means a patient whose cancer’s reservedly resistant to the abiraterone could already have resistance to enzalutamide, even though the patient hasn’t tried that medication. Both of these drugs work through the androgen receptor. Enzalutamide blocks that receptor and abiraterone decreases the circulating androgens that combine to that receptor. If that receptor mutates, and it doesn’t bind to testosterone or enzalutamide any more, then either one of them can be defective. And I think Dr. Antonarakis at Johns Hopkins University initially showed that the AR-V7 is very important in this mechanism.

Judd W. Moul, MD: One of the things with all of these drugs, be it abiraterone, enzalutamide, apalutamide or darolutamide, is cross-resistance. Patients clearly respond beautifully to these drugs, but eventually most patients stop responding to these drugs, and that’s been the big challenge in not just prostate cancer but all the major cancers. How do we avoid that resistance? One of the things we can say about apalutamide, in some of their earlier phase I and phase II trials, they looked at patients who had stopped responding to abiraterone.

Abiraterone is a CYP17 inhibitor. It’s also used to treat advanced prostate cancer in this space, but it has a different mechanism of action than apalutamide or enzalutamide. They looked at these patients who had already stopped responding to abiraterone and compared responses to apalutamide versus enzalutamide, and that seemed to suggest that patients on apalutamide might have had a better, longer term response as patients who had stopped responding to abiraterone. So, while enzalutamide and apalutamide are similar, there may be some subtle differences that allow some patients to continue to respond to one versus the other.

Enzalutamide and apalutamide are both novel oral antiandrogens. They are both much more potent and effective as compared to the previous generation of drugs such as flutamide, nilutamide, and bicalutamide. Having said that, they’re also very similar in the sense that they’re very potent. They result in significant disease response over some of the previous generation oral antiandrogens. Both enzalutamide and apalutamide do appear to cross the blood-brain barrier. Both of them appear to be very safe. Apalutamide has so far not been associated with any seizures and the fall risk with apalutamide, with my take on the literature, is a little bit less than that with enzalutamide.

The other concern with these drugs, both apalutamide and enzalutamide, is that there is a risk of fatigue. And if we look at both of these phase III trials, anywhere from 30% to 70% of patients will report some fatigue. For most patients it’s manageable, and they do not have to discontinue the drug. But in the practical sense, managing fatigue is one of the biggest challenges of this class of drugs.

At Duke where I work, we have some trials going on where we’re combining these drugs with a formal exercise program, to try to determine if we can help manage fatigue in these patients by putting them on a formal exercise program. There are also some studies ongoing with diet to see what we can do to try to improve fatigue levels in patients who are on these lifesaving drugs.

Transcript Edited for Clarity

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