CRPC: Patient Selection in AR-Directed Therapies

Transcript:Charles J. Ryan, MD: Abiraterone is administered, as the label indicates, in patients that need to take a low dose of prednisone. It’s 5 mg twice daily. This is based on the data that showed that when the prednisone was combined with the abiraterone, the potassium levels were more likely to remain normal. So, there was less hypokalemia and there was less mineralocorticoid toxicity, overall. This is part of the treatment and it is part of the safety. Interestingly, prednisone is really part of the efficacy, as well. Prednisone and steroids have, for decades, been shown to have activity against castration-resistant prostate cancer, and it’s really important to know that in the COU-AA-302 study, abiraterone plus prednisone was compared to prednisone alone. And in the prednisone alone arm, there were about 25% of the patients who experienced a PSA response. And those patients fared reasonably well, for example, when compared to the placebo arm of the enzalutamide studies in which patients were getting a placebo and no active therapy. In many ways, prednisone was an active control in the COU-AA-302 study, but in many ways also, it’s part of the therapeutic combination of abiraterone plus prednisone.

The concurrent use of corticoids is something worth discussing because we now know through the Fizazi paper, for example, that the incidence of corticosteroid-related toxicity is relatively low, and we’re talking about 5%, 6%, 7% for things like hyperglycemia and weight gain, and that is with long-term use. And, so, I think it’s fairly safe to conclude that, for the most part, we’re not seeing dramatic toxicities associated with the corticosteroids. I actually think that the corticosteroids do contribute substantially to the overall safety of abiraterone because it reduces the risk of hypokalemia, and it reduces the risk of some of the other mineralocorticoid side effects. There’s ample evidence to suggest that from a safety perspective, the corticosteroids are a net positive.

Now, on the other hand, there’s decades worth of evidence to suggest that corticosteroids have some clinical benefit in terms of disease control, which may amount to upwards of 25% or so. So, I think of this as a package. The abiraterone and the prednisone go together. The efficacy is likely to be optimized because of the presence of the prednisone. The other thing I’d like to point out is that many patients with castration-resistant prostate cancer, especially those who harbor a high degree of bone burden, do have some baseline pain. They have some morbidity associated with the tumor growing in the bone. And it’s long been known that low doses of corticosteroids are a very good palliative treatment. When I’m thinking about which patients to start on an oral androgen receptor targeted therapy, if I’m seeing a patient who has a modest amount of baseline pain, or minimal pain, or is minimally symptomatic, I might be more likely to include a steroid regimen because they’re going to get some better pain control than they would with other regimens.

And finally, I would also add that the choice of a therapy in castration-resistant prostate cancer is exactly that, a choice. None of the treatments that we have available are completely free of downsides, none of them are completely free of side effects. And so we’re now beginning to see more and more about the side effects of other treatments, and it really becomes a choice of finding the right therapy for the right patient. For example, a patient who has a significant amount of baseline fatigue or a significant or moderate amount of baseline pain, I’m more likely to want to give them a steroid-containing regimen as opposed to enzalutamide, which can worsen fatigue and probably isn’t going to have as much of a palliative effect on the pain.

On the other hand, patients who have baseline edema problems, congestive heart failure, and maybe somebody who has brittle or poorly controlled diabetes, I might want to stay away from the corticosteroids in those patients. So, it’s really about adopting the data that we have on the various therapies to individual patient situations.

Transcript Edited for Clarity