Progression Patterns by Types of Metastatic Spread, PSA, and Clinical Symptoms - Post-Hoc Analyses of ARAMIS - Alicia Morgans
November 15, 2022
Neal Shore interviews Alicia Morgans about her poster presentation on the ARAMIS trial. The ARAMIS trial evaluated darolutamide in non-metastatic castration-resistant prostate cancer (nmCRPC) patients with rising PSA levels and no radiographic evidence of disease. The study found that the combination of ADT and darolutamide extended metastasis-free survival by about two years and increased overall survival compared to ADT and placebo. The study also explored patterns of metastatic progression, revealing that around 28.5% of patients in the placebo arm experienced metastatic progression versus 13.5% in the darolutamide arm. Dr. Morgans also highlights that patient-reported outcomes showed similar or even improved quality of life with intensified therapy, particularly in urinary and bowel domains. The conversation emphasizes the significant survival benefits and quality of life improvements in nmCRPC treatment with darolutamide.
Biographies:
Neal D. Shore, MD, FACS is the Medical Director for the Carolina Urologic Research Center. He practices with Atlantic Urology Clinics in Myrtle Beach, South Carolina
Alicia Morgans, MD, MPH, Genitourinary Medical Oncologist, Medical Director of Survivorship Program at Dana-Farber Cancer Institute, Boston, Massachusetts
Biographies:
Neal D. Shore, MD, FACS is the Medical Director for the Carolina Urologic Research Center. He practices with Atlantic Urology Clinics in Myrtle Beach, South Carolina
Alicia Morgans, MD, MPH, Genitourinary Medical Oncologist, Medical Director of Survivorship Program at Dana-Farber Cancer Institute, Boston, Massachusetts
Read the Full Video Transcript
Neal Shore: Hi everyone. Neal Shore, urologist from GenesisCare. What a great pleasure to have an opportunity to interview Alicia Morgans at the Dana-Farber. Alicia, we're in reverse seating, but this is a great opportunity for me to ask you the question of a really great poster that you presented. You had several really nice posters, but we're going to focus on one today from ASCO 2022 on the ARAMIS trial. Now, the ARAMIS trial, what a great study led to the initial regulatory approval for darolutamide in the nmCRPC patient population. But your work that you presented and your co-authors, this was about patterns of metastatic spread in the treatment arm and in the control ADT placebo arm. What did you find?
Alicia Morgans: Thanks so much, Neal. This was really looking at the ARAMIS study, which of course was patients with non-metastatic castration resistant, prostate cancer, who had a short PSA doubling time, but did have a rising PSA, of course, in the absence of radiographic evidence of disease. And they were treated with ADT plus darolutamide or ADT plus placebo. And the combination of ADT and darolutamide prolonged metastasis free survival by about two years, and prolonged overall survival as compared to ADT and placebo. Really we could never make up for that early intensification, even with subsequent therapies as they were applied to the control arm in this trial. We really undertook this study of patterns of progression to understand whether intensified therapy led to more aggressive disease on the back end, when patients did develop progression of disease. And of course, fewer patients develop metastatic disease in the combination arm, so we were looking at more events in the placebo arm than we were looking at in the treatment arm of the combination.
Ultimately in the placebo arm around 28.5% of patients experienced metastatic progression versus only about 13.5% in the darolutamide treatment arm. I would say that there were a greater number of patients who progressed with bone metastases in the darolutamide arm versus the placebo arm, but more patients progressed numerically at least on the placebo arm and distant lymph nodes than in the darolutamide arm, so slightly different. But also importantly, patients had similar amounts of progression by pain first, which is one of those concerning prognostic signs of patients who were going to have poor outcomes. There was no greater amount of patients who were progressing with pain before PSA in the darolutamide combination arm than in the placebo arm.
This is so important because as we think about pushing patients with continued selection against the androgen receptor, we don't want to find ourselves with patients who have rapidly progressive, more painful disease on the other end that's more difficult to control. And we did not find that in this analysis. And I would argue that the overall survival improvement that we see with the ADT, darolutamide combination also argues against us making some drastic change in the biology of the disease that then puts the patient in a worse setting after progression.
Neal Shore: This is great because I guess what my question for you is, especially in light of the fact that we looked back a few years ago before we had any approved drugs in nmCRPC or what we used to call the M0CRPC, we didn't really offer anything. And we had a whole series of different things. We didn't have any level one evidence until we had these three landmark trials in nmCRPC, ARAMIS being one of them. But a lot of people would say, well, wait a minute, I'm going to start somebody on a drug. Just because to alter their PSA kinetics, you're obviously stating the survival benefit and the delay in MFS. But how do you bring in the data from what you're telling us about now on patterns of metastatic spread, and avoidance of pain, SREs, et cetera? Does that come into your discussion with patients in the clinic now?
Alicia Morgans: Oh, absolutely. I think, these are very important end points as we talk to patients about the benefits of using additional agents versus the cons or the potential pitfalls of doing that. And I think the obvious improvement in overall survival is going to be on most people's lists. But patients also want to know that they're going to feel well. And the adverse events profile of darolutamide treated patients was very similar to that of ADT and placebo alone.
I think there was a slightly higher incidence of fatigue on the CTCAE analysis. But in general, patient reported outcomes reported that patients felt as well or in some domains even better when they had intensified therapy, particularly in the urinary and bowel domains of the EORTC patient reported outcome measure that was used to assess the patient's report of their quality of life. Intensification seemed to be better both in terms of some of those domains, or at least equal in terms of quality of life, which for patients as you know very well, is as important as disease control outcomes for many people.
Neal Shore: Yeah, it's a great point. I remember seeing that data, that even patients who'd had prostatectomies had improvement in urinary and bowel domain in terms of improved symptomatology. A pretty cool and unexpected finding. But I thought that was rather remarkable. Well, that's great. Congratulations on presenting that data, Alicia. Thanks very much.
Alicia Morgans: Thank you.
Neal Shore: Hi everyone. Neal Shore, urologist from GenesisCare. What a great pleasure to have an opportunity to interview Alicia Morgans at the Dana-Farber. Alicia, we're in reverse seating, but this is a great opportunity for me to ask you the question of a really great poster that you presented. You had several really nice posters, but we're going to focus on one today from ASCO 2022 on the ARAMIS trial. Now, the ARAMIS trial, what a great study led to the initial regulatory approval for darolutamide in the nmCRPC patient population. But your work that you presented and your co-authors, this was about patterns of metastatic spread in the treatment arm and in the control ADT placebo arm. What did you find?
Alicia Morgans: Thanks so much, Neal. This was really looking at the ARAMIS study, which of course was patients with non-metastatic castration resistant, prostate cancer, who had a short PSA doubling time, but did have a rising PSA, of course, in the absence of radiographic evidence of disease. And they were treated with ADT plus darolutamide or ADT plus placebo. And the combination of ADT and darolutamide prolonged metastasis free survival by about two years, and prolonged overall survival as compared to ADT and placebo. Really we could never make up for that early intensification, even with subsequent therapies as they were applied to the control arm in this trial. We really undertook this study of patterns of progression to understand whether intensified therapy led to more aggressive disease on the back end, when patients did develop progression of disease. And of course, fewer patients develop metastatic disease in the combination arm, so we were looking at more events in the placebo arm than we were looking at in the treatment arm of the combination.
Ultimately in the placebo arm around 28.5% of patients experienced metastatic progression versus only about 13.5% in the darolutamide treatment arm. I would say that there were a greater number of patients who progressed with bone metastases in the darolutamide arm versus the placebo arm, but more patients progressed numerically at least on the placebo arm and distant lymph nodes than in the darolutamide arm, so slightly different. But also importantly, patients had similar amounts of progression by pain first, which is one of those concerning prognostic signs of patients who were going to have poor outcomes. There was no greater amount of patients who were progressing with pain before PSA in the darolutamide combination arm than in the placebo arm.
This is so important because as we think about pushing patients with continued selection against the androgen receptor, we don't want to find ourselves with patients who have rapidly progressive, more painful disease on the other end that's more difficult to control. And we did not find that in this analysis. And I would argue that the overall survival improvement that we see with the ADT, darolutamide combination also argues against us making some drastic change in the biology of the disease that then puts the patient in a worse setting after progression.
Neal Shore: This is great because I guess what my question for you is, especially in light of the fact that we looked back a few years ago before we had any approved drugs in nmCRPC or what we used to call the M0CRPC, we didn't really offer anything. And we had a whole series of different things. We didn't have any level one evidence until we had these three landmark trials in nmCRPC, ARAMIS being one of them. But a lot of people would say, well, wait a minute, I'm going to start somebody on a drug. Just because to alter their PSA kinetics, you're obviously stating the survival benefit and the delay in MFS. But how do you bring in the data from what you're telling us about now on patterns of metastatic spread, and avoidance of pain, SREs, et cetera? Does that come into your discussion with patients in the clinic now?
Alicia Morgans: Oh, absolutely. I think, these are very important end points as we talk to patients about the benefits of using additional agents versus the cons or the potential pitfalls of doing that. And I think the obvious improvement in overall survival is going to be on most people's lists. But patients also want to know that they're going to feel well. And the adverse events profile of darolutamide treated patients was very similar to that of ADT and placebo alone.
I think there was a slightly higher incidence of fatigue on the CTCAE analysis. But in general, patient reported outcomes reported that patients felt as well or in some domains even better when they had intensified therapy, particularly in the urinary and bowel domains of the EORTC patient reported outcome measure that was used to assess the patient's report of their quality of life. Intensification seemed to be better both in terms of some of those domains, or at least equal in terms of quality of life, which for patients as you know very well, is as important as disease control outcomes for many people.
Neal Shore: Yeah, it's a great point. I remember seeing that data, that even patients who'd had prostatectomies had improvement in urinary and bowel domain in terms of improved symptomatology. A pretty cool and unexpected finding. But I thought that was rather remarkable. Well, that's great. Congratulations on presenting that data, Alicia. Thanks very much.
Alicia Morgans: Thank you.