In the first article of this series, Benjamin H. Lowentritt, MD, FACS, gives an overview of micronized abiraterone and its role in the treatment of patients with metastatic castrate-resistant prostate cancer.
For patients with metastatic castration-resistant prostate cancer who require therapy, micronized abiraterone provides many advantages. In this Urology Medical Perspectives series titled “Clinical Use of Micronized Abiraterone for Patients With Prostate Cancer,” Benjamin H. Lowentritt, MD, FACS, a urologist at Chesapeake Urology in Towson, Maryland, offers detailed insights on micronized abiraterone, with a focus on clinical trial data and practical considerations.
Urology Times®: What is the mechanism of action and the rationale for using abiraterone in patients with metastatic castrate-resistant prostate cancer?
Benjamin H. Lowentritt, MD, FACS: The mechanism of action of abiraterone is that it’s a CYP17 inhibitor. CYP17 is the key enzyme in the steroid hormone production set of reactions. By blocking it, you block all the downstream eventual hormones that could be produced. Most notably, when we’re talking about advanced prostate cancer, we’re talking about testosterone. Although traditional androgen deprivation therapy [ADT] blocks most of the testosterone production by the testicles, CYP17 blockade can prevent testosterone production throughout the body in any extragonadal sites, such as the adrenal gland or potentially even the tumor itself.
Urology Times: Can you discuss the clinical trial background information for abiraterone and the efficacy and safety that was seen there?
Benjamin H. Lowentritt, MD, FACS: The early trials on abiraterone included Cougar 301, Cougar 302, and eventually LATITUDE. These 3 trials were looking at the use of abiraterone in patients with castrate-resistant metastatic prostate cancer after chemotherapy, before chemotherapy, and in the metastatic hormone-sensitive space, respectively. The data from these trials were released in the early 2010s through the mid-2010s for LATITUDE and led to the use of abiraterone in the metastatic castrate-resistant space and the metastatic hormone-sensitive space.
Urology Times: Can you talk through micronized abiraterone? What is micronization? What are some of the implications of having a formulation that’s micronized?
Benjamin H. Lowentritt, MD, FACS: Micronized abiraterone is a different formulation of the same compound that essentially becomes like a different delivery mechanism. Micronized, like it sounds, is creating very small, stable particles of abiraterone, in this case anywhere from 0.1 to 0.5 microns, which is anywhere from 10 to 200 times smaller than what you would get from traditional abiraterone. The thought behind that is that by making very, very small particles, you get increased surface area overall, so there’s less of the abiraterone internally and more of it on the surface. That allows for better interaction with the gut and more reliable absorption, so there’s more bioavailability and the ability to use a lower dose.
Urology Times: What are other considerations with the 2 different formulations? For example, do you have to take them at specific times or with food?
Benjamin H. Lowentritt, MD, FACS: Because traditional abiraterone can be increased in its absorption when taken with food, it’s recommended to be taken without food, on a very empty stomach, with nothing at least 2 hours before taking the medicine and no food for 1 hour afterward. This usually leads to people having to take it either in the middle of the night or first thing in the morning and then delaying when they might eat.
One of the advantages of micronized abiraterone is that it doesn’t have that requirement. Because the absorption is a little more predictable and doesn’t have that interaction with food, it can be taken at any given time. In addition, it’s allowed to be given at a different dose. Whereas traditional abiraterone is given at 1000 mg, or 1 g, daily, which is split up into four 250-mg pills, the micronized abiraterone can be given at 500 mg, half the dose, daily. Once again, those split up into four 125-mg pills.
The other big issue with abiraterone is that because we’re blocking not just the testosterone production but also cortisol production, it has to be taken with an oral steroid. Traditional abiraterone was studied with prednisone, and the micronized form was studied with methylprednisolone, given 4 mg twice daily. You still have a steroid requirement, but the ability to take it with food is a difference with the micronized abiraterone.
Urology Times: Can you speak a bit about the clinical trials with micronized abiraterone and some of the outcomes that were seen in that study?
Benjamin H. Lowentritt, MD, FACS: The clinical trial that led to the approval of the micronized form of abiraterone was called the STAAR trial [NCT02737332]. It was looking at the equivalence of 500 mg of micronized abiraterone to 1000 mg of traditional abiraterone. The main outcome studied in the trial was looking at the equivalence of testosterone blockade over 84 days, and it was seen in both the micronized and traditional abiraterone that a testosterone [level] of less than 1 ng/dL was achieved. In addition, a PSA [prostate-specific antigen] reduction of more than 50%, or a PSA-50, was achieved in greater than 65% of both groups.
Urology Times: What’s the future of this? Are there additional data that you would be interested in seeing? Are there other settings that this could be used in? Are there other novel combinations under investigation?
Benjamin H. Lowentritt, MD, FACS: What’s exciting about abiraterone is that we have a lot of familiarity with it, we’ve used it for a long time, and the micronized form of abiraterone continues to have a lot of promise from a safety and predictability standpoint. We’re now seeing abiraterone used in combination with PARP inhibitors. We’re seeing it used in combination with local and regional therapies with radiation along with ADT. And I think it would be very exciting to continue to see data with the micronized form to see if there’s improved tolerability or predictability of response given the absorption advantages. I think that we’re not in any way done with abiraterone. We’ve had it the longest of all of what we call novel hormonal therapies; although at this point, they’re not that novel. These androgen receptor targeted therapies continue to be a key part and are spread throughout the timing of treatment of prostate cancer.
There’s interest in finding the ideal dose of steroids. Can we avoid steroids altogether in some patients? If it’s not being affected, if there’s maybe a different dosing regimen, I think that’s an exciting place to look. And as we get into some of these more targeted therapies, understanding the role of co-mingling the androgen receptor targeted therapies with some of these other biomarker-driven therapies is really exciting, and we’ll continue to see [them] for a number of years.