If a patient’s disease progresses on enzalutamide and then you administer abiraterone, there’s cross-resistance. The same thing happens in the reverse order. In a patient with a response to enzalutamide or abiraterone who then experiences disease progression, the likelihood that this patient with mCRPC will derive meaningful benefit that will be evident to the patient or the physician with the other agent is about 30%.

Enzalutamide and abiraterone have different mechanisms of action. Enzalutamide inhibits the androgen receptor, and abiraterone inhibits androgen synthesis. There is a common resistance mechanism called the androgen receptor (AR) variance, particularly, androgen receptor splice variant 7 (AR-V7). The presence of AR-V7 mediates cross-resistance between the 2 agents. It may render the disease less responsive to either enzalutamide or abiraterone.

Currently we do not have any routine tests for AR-V7 as it was measured in an article published recently. A lot has been done to validate AR-V7 as a mediator of cross-resistance between enzalutamide and abiraterone in large sample sizes in order for it to be able to inform clinical decision-making.

If the patient has already received one of the agents, either enzalutamide or abiraterone, it is unlikely that the other will work. The likelihood of deriving a clinically meaningful benefit from one of the agents after disease progression on the other is about 10% to 20%.

In the Netherlands, my experience with enzalutamide is in the second-line setting, after docetaxel. I have no personal experience with abiraterone. However, from the data out there, I believe that the likelihood of obtaining clinically meaningful benefit with abiraterone in a patient with mCRPC with initial response to enzalutamide followed by disease progression is virtually zero.

The current data that we have indicate that some patients may experience a PSA response that is not clinically meaningful on enzalutamide after abiraterone but not the other way round. So if a patient experiences disease progression on enzalutamide at one point, this patient is unlikely to derive any benefit from abiraterone. I believe this occurrence is related to the aversion against chemotherapy, but it may also have to do with financial considerations. I do not expect a benefit from crossing over from enzalutamide to abiraterone.

Though the administration of enzalutamide after disease progression on abiraterone may be beneficial, the benefit will be brief and will not be clinically meaningful.

For a patient with mCRPC with an initial response and then disease progression on enzalutamide, the likelihood that this patient will derive a clinically meaningful benefit with abiraterone is about 20% to 30%. I believe the same will apply in the reverse order of sequencing the 2 agents.

For a patient with mCRPC with an initial response and then disease progression on enzalutamide, the likelihood that this patient will derive a clinically meaningful benefit with abiraterone is about 10% to 15%. The same type of benefit is expected if the agents are sequenced in the reverse order.

If a patient with mCRPC develops progressive disease on either enzalutamide or abiraterone, the chances of response with the other are not impressive. The likelihood that a patient will derive a clinically meaningful benefit with the other is about 5% to 10%.

I have administered enzalutamide to few patients and have not yet used abiraterone. From the published data, however, I believe the response to abiraterone or enzalutamide in a patient who has already progressed on treatment with the other agent is about 20%.

If the patient has already received either one of the agents, the likelihood of deriving a clinically meaningful benefit from the other agent after disease progression on one is about 20% to 30%. Importantly, if the patient has the AR-V7 mutation, there will be no benefit of treating with the other agent after disease progression on the first.

There’s a reason why there may be a difference. Data from MD Anderson demonstrate that there’s an upregulation of testosterone synthetic enzymes at disease progression on enzalutamide, so one would think that abiraterone would have a chance of working. In contrast, we know that some beta hydroxysteroid mutations go along with abiraterone resistance, and then perhaps treating with enzalutamide, which is a receptor antagonist, in a situation in which you have high testosterone levels, may actually work. I believe we need a prospective trial of these resistant markers to understand what is going on.

The likelihood that a patient with mCRPC will derive a clinically meaningful benefit with abiraterone post disease progression on enzalutamide is about 10%, and the likelihood of benefit with enzalutamide after disease progression on abiraterone is about 25%.

It’s asymmetric. The available data together with my clinical experience are better with enzalutamide as opposed to abiraterone post enzalutamide. I’m puzzled by that. I believe the mechanisms of resistance to abiraterone and enzalutamide may be a little bit different, but the actual mechanisms are unknown. There is some interesting work on the 3-beta hydroxysteroid dehydrogenase enzyme, Dr N Sharifi showing that different alleles of the enzyme are detected at different levels. This may be something that may factor in to resistance more to abiraterone than to enzalutamide. However, the exact mechanism is unknown. The bottom line is that we are still trying to understand the mechanism of resistance in CRPC.

The clinical data indicate a little higher resistance to abiraterone post enzalutamide than for enzalutamide post abiraterone.

A series of single-institution studies have been reported, mostly retrospective. From these studies, it appears that whichever of the 2 drugs goes first, the second drug doesn’t have as long of a response. It seems to be anywhere from 4 to 7 months, based on the metrics of PSA and new lesions, in addition to some symptomatology.

A few more studies have suggested that the duration of response is better if abiraterone is administered before enzalutamide. These are based on small, single-institution studies. We need larger Phase III trials to investigate this.

The response rate if any of the agents is administered first is about 85%. However, when one is administered after the other, the response rate falls to about 50% to 60%.