Personalizing ADT: A Modern Approach to High Risk Prostate Cancers

[Dr. Rana McKay]
Yes, absolutely. I think, androgen deprivation therapy has been the backbone of systemic treatment for patients with prostate cancer for decades, has been, and will likely continue to be, just given the addiction of prostate cancer to the androgen receptor and androgen receptor signaling pathway. I think there's definitely been an evolution over the last several decades in how we facilitate a medical decline in testosterone levels with a therapeutic intent to treat prostate cancer.

Historically, before we had GnRH analogs, we just used good old bilateral orchiectomy to treat patients. There is still a role for that, even in the modern era, if you will, if we think about the cost of care and in people who are going to be on indefinite ADT without any reason to discontinue therapy. It still plays a role in the modern era for a select number of patients and certainly, as we think about underserved regions of the world where there's a lack of access to drugs and treatments.

I think as we think about the GnRH analogs, I think there's been an evolution. Classically, we think of GnRH agonists that have been the backbone of treatment. If we go back to normal physiology, typically the LH and FSH are released in a, let's say, pulsatile fashion, if you will, when there's a continuous stimulation of the pituitary hypothalamus access, it results in complete shutdown of the access. Pulsatile therapy versus continuous therapy.

That's basically how we achieve suppressed T levels with the GnRH agonists. Then the antagonists have come around, which instead of work first to turn on the access before they turn it off, then immediately suppress [testosterone levels]. More recently we've seen androgen receptor pathway inhibitors hit the market. There's many of them out there that further suppress or block androgen signaling that have really entered into the landscape. I think we've seen an evolution from surgery to injectable analogs to now next-generation potent oral agents.

[Dr. Aditya Bagrodia]
Totally. I think as advanced prostate cancer management has gotten more complex, really digging into side effects, mitigating those side effects, explaining those side effects has gotten more important. Early on as a urology trainee, it was like, "All right, we're going to start you on Lupron." The counseling might have been, "You might have some hot flashes. Okay, we'll see you in six months with a PSA and a testosterone." I'd like to think that it's a bit more advanced than that.

Maybe you alluded to it. Obviously, this is prostate cancer. It is addicted to testosterone. We've got to get those testosterone levels down to castrate. Can you just talk a little bit about maybe we start with disease states, early disease states, all the way to advanced disease states? When you think about this, how do you think about when ADT might be appropriate?

[Dr. Rana McKay]
Yes, absolutely. It's a very good question. I think in the localized setting for individuals that are undergoing surgery, at the present time, there's no role for perioperative therapy, though there are clinical trials that are looking at investigating that, but currently no role. I think for people that are undergoing radiation, there absolutely is a role for ADT, and the duration and intensity varies dependent on the risk of the patient.
In the context of intermediate-risk disease, six months of a GnRH analog would be sufficient. For patients with high-risk disease, two years of therapy. For patients with very high-risk disease defined as a PSA of greater than 40, at least an 8, 9, 10 disease or T3 disease, having 2 out of 3 of those factors, they're getting the addition of abiraterone to ADT. That's treatment in the definitive setting with a curative intent, and we know that there are some patients that go on to relapse following definitive treatment.

For those individuals that relapse post-surgery, there certainly is a role for ADT combined with radiation, and particularly it's largely dependent on what's the PSA level at the time of radiation, and also what's the patient's risk factors coming in to the radiation therapy, whether they should or shouldn't undergo ADT. Then for those individuals that have a relapse post-definitive treatment, post-salvage radiation, post-definitive radiation, they're not really a candidate for any more pelvic-directed therapy, we're treating with intermittent ADT in the BCR setting.

Again, the potency of treatment is largely dependent on risk of disease. For patients with a rapid PSA doubling time, we're generally now leaning towards double therapy with ADT plus an ARSi, particularly enzalutamide, which has been tested in this setting for intermittent duration, so one year of therapy and then off treatment. Then in the metastatic disease setting, that's where we're really thinking about more continuous therapy with more lifelong hormonal therapy, though I think that many are beginning to challenge that paradigm a little bit, but more lifelong therapy, and particularly for those individuals with high-risk disease or de novo metastatic disease, adding an additional ARSi.

I think the one caveat to everything that I've just stated is PSMA PET imaging has really wreaked havoc in our defining of different stages of prostate cancer. We're identifying disease earlier, we're identifying low volume metastatic disease, and some thought around intermittent therapy for people with metastatic disease by PSMA PET imaging, but conventional imaging negative and not wetting those patients to lifelong ADT, though that's still also being tested. That's the spectrum, I think, across the way the intensity and the potency and the duration has really largely been driven by the patient risk factors.

[Dr. Aditya Bagrodia]
I think that really perfectly captures that ADT has a role potentially across the disease spectrum. Maybe just one question - primary ADT - is there a unique patient these days that might still be an option?

[Dr. Rana McKay]
For just ADT alone without an ARSi, just straight up by itself?

[Dr. Aditya Bagrodia]
Localized prostate cancer, really not a candidate for surgery radiation. Are there patients that you might be considering primary agency for?

[Dr. Rana McKay]
I think that's a very good question. I think at the end of the day it depends on the patient's symptoms, their goals of care, their quality of life. I think if there's somebody that maybe has high-risk localized disease, the treatment's going to be resultant in a lot of morbidity from surgery or morbidity from radiation, but they're high risk enough that you really don't want them to develop metastases and there could be the potential that they would develop metastases in their lifetime. You can certainly think about doing ADT in that context, but I think it's very personalized depending on the patient's comorbidities and also what their goals of care are.