Additional Insights: Novel Agents in Prostate Cancer

EXPERT PERSPECTIVE VIRTUAL TUMOR BOARD

Leanne Schimke, CRNP, CUNP:Androgen receptor [AR]-targeted therapy has really changed the whole landscape of prostate cancer. Now we’re looking at the nonmetastatic patient and we’re watching their PSA [prostate-specific antigen] doubling times, because all of the new drugs were approved based on a 10-month PSA doubling time or less. We know, when we look at the research, that this is when things really start to progress in our patients. If they have a 2-year doubling time, it’s probably a pretty slow cancer. But when it gets to 10 months or less, that’s when we need to intervene. And by intervening at this time, we’ve increased their metastasis-free survival. This is huge in prostate cancer because we know when they become metastatic, that does decrease their length of life.

We are increasing the use of these agents. It is a small window, so we have to watch a man’s doubling time very closely. They can go from being a year doubling time down to 10 months very quickly; or even a 2-year doubling time, and all of a sudden they start speeding up. And there’s a small window between being nonmetastatic and then, all of a sudden, having a metastatic lesion.

The modes of action for apalutamide, enzalutamide, and darolutamide—they’re all pretty similar. They’re all androgen receptor inhibitors. They all block the DNA androgen receptor. They all block it going into the nucleus of the cell. The 1 difference is darolutamide does have a bit less blood—brain barrier penetration, so we think that may have some result on adverse effects. And also, darolutamide is a progesterone antagonist, in vitro. We’re not sure how that’s going to relate to real life, but that’s the mode of action of each of them at this point.

They all have slightly different warnings and contraindications. Enzalutamide, for example, has been around the longest. We have a lot more experience with it, and we have noted postmarketing adverse effects too. Enzalutamide is associated with a risk of seizures. It’s a small risk, about 2%. But those patients who have a history of any traumatic brain injury, TIAs [transient ischemic attacks], CVAs [cerebrovascular accidents], Alzheimer disease, any loss of consciousness within the last 6 months, any medications that may increase their seizure risk, should not be put on enzalutamide.

Apalutamide also has a small seizure risk, so the same contraindications go for that. Darolutamide, because of less blood—brain barrier penetration, has no contraindication of seizures at this point.

The other risk that we have with both apalutamide and enzalutamide is ischemic heart disease. We have seen an increase in the possibility of that. So if a man has pre-diagnosed MI [myocardial infarction], unstable angina, heart problems, you have to watch them much more closely and you may want to choose a different mechanism.

Darolutamide is associated with more heart failure than the other 2. So there’s a bit of a difference there. With enzalutamide, they have had some marketing reports of posterior reversible encephalopathy syndrome, also known as PRES. And this is where they get seizures, headaches. They can get lethargic, and they can actually develop blindness. This is something that we’ve seen with other drugs. It’s not just seen with enzalutamide, alone, but there have been some reports of that; so we do think about that also.

With apalutamide and enzalutamide, there is an increased risk of falls—about 12%—and fractures. Again, we think this is because the drug gets into the brain a bit easier. Darolutamide is not associated with increased risk of falls and fractures in the studies that have been done. Those are some of the things that we look at when with the different drugs as we determine which one we’re going to use.

In regard to the drug interactions, they all are CYP3A4 pathways. But they also have some other pathways in there. So it’s very complex, between the 3 different drugs, as to which other medications you have to worry about interactions with. So we do rely on our pharmacologists, and also our drug interaction checker, because it’s hard to know all of the drugs that they could interact with.

Transcript edited for clarity.