Exploring Post-Salvage Treatment: Risk Stratification, Therapeutic Options for Non-Metastatic HSPC

A roundtable discussion, moderated by Pedro Barata, MD, of University Hospitals, highlighted the evolving treatment landscape of advanced prostate cancer, including hormone-sensitive prostate cancer (HSPC) and castration-resistant prostate cancer (CRPC). The panelists analyze expanding treatment intensity, the utilization of androgen deprivation therapy (ADT) and androgen receptor pathway inhibitors (ARPIs), and integrating patient-reported outcomes (PROs) in care. Dr. Barata was joined by Andrew Armstrong, MD, MSc, of Duke University School of Medicine; Cora Sternberg, MD, of Weill Cornell Medicine; and Evan Yu, MD, of UW Medicine.

In the first part of this series, the panel discusses treatments in the post-salvage setting and review therapeutic options for patients with non-metastatic HSPC.

View the next segment of this roundtable series: Non-Metastatic HSPC: Evaluating Imaging Strategies, Post-Salvage Treatment Options

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Dr. Barata:
Let’s get started. Perhaps Cora, I’ll start with you. Maybe we’ll begin in the post-salvage setting. For patients with non-metastatic hormone-sensitive disease, we got news earlier this year in regard to the addition of the ARPI enzalutamide to ADT for patients who don’t have an opportunity for a cure, so they underwent surgery or radiation with definitive intent or salvage, and then they have rising PSA; the definitional recurrence can be different and we have that question all the time.

We see those patients who have recurrent disease, and we have to think about what we’re going to do with them. So before we talk about treatment options and how we all think about those patients, maybe I should start with you first.

How do you see those patients as far as risk stratification? Because in my clinics, some of those patients take years for the PSA to double. And it sounds like the right thing to do is actually to hold tight. For other patients, you can tell disease is moving and we have to do things faster. Do you agree with that? Do you have any process that you can walk us through about how you stratify the patients that come to you in this post-salvage setting?

Dr. Sternberg:
I mean, if we have elderly patients who have already had radiation – or prostatectomy and radiation – and their doubling time is very long, we might just observe those patients, depending on their age. The EMBARK study is something that we’ve heard quite a lot about, but that’s a select group of high-risk patients with a doubling time of less than nine months. That’s important to realize who we’re talking about when we talk about the EMBARK study.

That was a very good, perhaps practice-changing study, in which patients with PSA doubling time less than nine months were randomized between ADT alone, enzalutamide alone, or enzalutamide with ADT. And what they found was that patients who received enzalutamide alone or with the combination did better than those who received ADT alone. They administered it for a certain amount of time and then they saw how well they did at a certain amount of time. I believe it was 37 weeks. And if they did well, then they would stop the treatment.

Both the monotherapy enzalutamide and the combination arm had better response rates and did better than the ADT alone, but the combination arm actually stayed off therapy for a longer amount of time once it was stopped. However, the monotherapy arm is very attractive to many people who do not want to go on ADT – but there are differences in quality of life.

One would think that the monotherapy would be much, much easier, but there were quality of life issues even with monotherapy. Gynecomastia was something that we’re not so used to seeing with enzalutamide. So I think if people are going to be on enzalutamide alone, one of the things to think about is perhaps prophylactic breast irradiation. And I think that that’s one of the important things to think about with that.

Dr. Barata:
Thank you for that, I would agree completely. Let’s talk about the EMBARK space, because for the first time, we’ve seen a very active antiandrogen added to ADT give the results you just summarized. So Andrew, maybe let me ask you, you look at the eligibility criteria for EMBARK – Cora mentioned the doubling time and the different PSA interest at entry based on when you’re coming out of radiation or coming out of surgery.

Do you use these two factors when you’re considering subsequent therapy, or do you think of other things? Are you looking at any other factors beyond the eligibility criteria? What are your thoughts to address?

Dr. Armstrong:
That’s a great question. I would say that the doubling time is critical, but it’s not a clean cut at nine months. The faster it is, the worse the prognosis, and the shorter the time to metastasis. The time since your local therapy is an important prognostic factor; a guy who relapses within a year of surgery is going to do worse than a guy who relapses a decade after surgery, so that three-year cutoff is prognostically important and that’s been validated in large natural history studies that go back 20 years.

So the PSA level itself, the median PSA, when metastasis appears on conventional imaging, is somewhere around 20 or 30. A lot of patients don’t realize that, but on PSMA PET imaging, it’s a lot lower so you can pick up metastatic disease based on the PSA.

So the PSA level does play a role at the time when you might pull the trigger to start hormonal therapy or perform a PET scan. A lot of the EMBARK patients probably were PET-positive, if you had that accessible during that time. And the Gleason score is important. Poorly differentiated tumors are more likely to be more aggressive.

The disease factors, host factors, and patient factors are really important because patients bring with them that decision point, their preferences. Intermittent therapy has been a longstanding standard of care for these patients to optimize disease control on one hand and minimize toxicities on the other hand. And so EMBARK builds on that intermittent approach, but with more intensive doublet therapy.

Dr. Barata:
There’s a great summary for us. Evan, Cora alluded to the monotherapy arm. I think that’s one of the unique aspects of EMBARK; it provided a non-constrained arm. I would argue that the testosterone levels for those patients were probably higher, so I’m interested to hear your thoughts about patients who do not want to be constricted. How do you approach that?

Cora alluded to the specific safety profile or adverse events that you do expect, which is different when you’re constraining them than when you’re not. So we’re not as used to that compared to in the metastatic setting. So how do you approach that, and how do you decide between enzalutamide monotherapy or enzalutamide plus ADT for the 37 weeks followed by the break?

Dr. Yu:
Yeah, sure. So I think explaining the situation to the patient is the most important thing. The patient needs to know what he’s getting into. So if you look at the adverse events profiles, if you block the androgen receptor and you don’t give an LHRH therapy, you actually expect testosterone to go up. And as a result, that’s where you get the gynecomastia, the mastalgia, etc.

On the flip side, you can get some quality of life benefits with potentially decreased sexual side effects and decreased hot flashes, which can be beneficial as well. So having that discussion in advance with the patient and making sure that they know what they’re getting into is the most important thing there. I think the real key question here, however, is when do you pull the trigger to do it?

That requires a lot of fine nuance in this disease state because there’s a lot of heterogeneity. There are patients, as you mentioned, that have a great prognosis. Not only will they not need doublet therapy or insulin by monotherapy, they may need no therapy or they maybe could even just do traditional intermittent androgen deprivation therapy.

Prior research showed that intermittent androgen deprivation therapy was not inferior to continuous therapy with a median survival of almost a decade and median time to castration resistance of almost a decade. So as Cora alluded to, taking age into account, taking comorbidities into account, taking a patient desires in an account, counseling on all the adverse events, that’s how you’re going to decide.

I don’t know that the PSA doubling time of nine months is the end all be all. Maybe it should be six months, maybe three months. Three months is a no brainer for me.

If I have a patient with a PSA doubling time that’s three months or less, their prognosis is very similar to somebody who has metastatic disease by conventional imaging. That’s somebody where I feel like, “Yes, I need to do the EMBARK method,” but if their PSA doubling times longer, it’s an active discussion, not just about the adverse events of monotherapy versus doublet therapy of androgen deprivation with insulin, but do we even treat and when do we treat?

Dr. Sternberg:
I agree.

Dr. Yu:
So it’s got to be individualized because there’s a lot of heterogeneity in regards to outcomes and prognosis there. Just as we want to have great outcomes for our patients and delay bad outcomes from cancer, we also don’t want to overtreat and affect quality of life negatively.

Dr. Barata:
Right. For sure. That’s a fantastic point that you’re making there.