Delayed Deterioration in Patient Quality of Life, the Impact of Darolutamide on Local Symptoms in the ARAMIS Trial – Neal Shore

September 22, 2021

Alicia Morgans is joined by Neal Shore to discuss his presentation from the 2021 American Urologic Association (AUA) annual meeting on the relationship between PSA response and urinary and bowel adverse events (AEs), time to deterioration in the quality of life, and prostate cancer related invasive procedures in the ARAMIS trial. The authors examined the proportion of darolutamide patients achieving declines in PSA from baseline to week 16 of >90%, 50%–90%, and <50% and correlated these with urinary and bowel AEs.


Neal Shore, MD, FACS, is the Medical Director of 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.

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Alicia Morgans: Hi, my name is Alicia Morgans and I'm a GU Medical Oncologist at Dana-Farber Cancer Institute. I'm so excited to have here with me today, a good friend and colleague, Dr. Neal Shore, who is the Medical Director for the Carolina Urologic Research Center in Myrtle Beach. Thank you so much for being here with me today.

Neal Shore: Thank you, Alicia. A pleasure as always.

Alicia Morgans: Wonderful. So I wanted to talk with you about one of the presentations that you made at AUA this year, and really dig into a new understanding, a deeper understanding of the bowel and urinary symptoms faced by patients on the ARAMIS trial. Can you tell us a little bit about your investigation and what you found?

Neal Shore: Yeah, happy to. Just real quickly, ARAMIS, a large phase three trial in nmCRPC met its primary endpoint of metastasis-free survival with a 2:1 randomization, patients getting daro versus placebo, everybody getting ADT, PSA doubling times less than or equal to 10 months, and the secondary endpoint of overall survival was met. And so that led to its approval, EMA, and FDA for nmCRPC. A good friend and our colleague, Karim Fizazi, has previously presented quality of life scales demonstrating really no difference between the two arms, but what we did in this study and what we did a deeper analysis on, and we are presenting at AUA, is local symptom control. And primarily by that, we looked at the EORTC QLQ-PR25 subscales for both urinary and bowel symptoms and the FACT-P subscales as well. And I think from a urologist standpoint we tend to see equivalency in the overall health reported quality of life. But when we broke it down, what about local voiding symptoms and bowel symptoms?

And we found a hazard ratio of 0.42, favoring the darolutamide arm. And these are the types of things that we saw, urinary frequency, urgency, urinary retention, the need for actual interventions, endoscopic interventions, TURPs, things of that nature, and everything that favored the darolutamide arm in the sub-analyses. So that was really remarkably positive. And so I think that is important, right? Because these patients have intact prostates, many of them, if they haven't had a prostatectomy, but even in those patients, we saw a urinary local control benefit. And when it came to the bowel symptoms, overall the total bowel symptoms were improved, individual aspects of GI symptoms, such as blood in the stool or fecal incontinence was equivalent. But the overall total bowel symptoms were actually better in the daro arm versus the placebo arm.

So the other treatment emerging adverse events that we saw were very consistent, obviously whether there was a benefit or not, in terms of local symptoms. But all consistent with what has been previously reported in ARAMIS. So overall I think this is important. I think many times our colleagues, particularly urologists, may say well why would I start a patient on a drug when they are relatively asymptomatic, with the exception of having testosterone suppression? But this data tells us that in addition to the overall HRQoL, we are seeing improvement in local urinary symptoms and overall total bowel symptoms.

Alicia Morgans: I would agree with you. I remember hearing some initial information about this when Karim presented it and really asked the question, why would this happen if those men really had had a treated prostate before? And it's interesting that even among patients who have had a prostatectomy, certainly, these symptoms seem better. Why do you think that is? And really again, just to emphasize, it is so important from your perspective I'm sure, as much as the patients, right?

Neal Shore: Yeah, no, absolutely. I think it's a great question. I can postulate that maybe their effects, not just on the absence of prostate or an ablated prostate from radiation, although some of the patients, were in a small percentage, were true monotherapy patients, but the majority had had a local intervention. I think there is a potential for the effect of an AR inhibitor on the bladder, on the urethra as well as on the bowel symptoms. So the data were robustly reviewed. I think this is another opportunity to say to a patient. Yes, we are going to see your PSA go down dramatically, in the vast majority of patients. Yes. We are going to delay metastases, radiographic progression, and yes, we are going to improve your survival. But in addition to that, we're going to potentially help your urinary symptoms and even total bowel symptoms.

Alicia Morgans: I think that's great. So as a final message, what would that be?

Neal Shore: I think the final message to our patients with nmCRPC is, this is the ARAMIS trial, really nicely conducted, thanks to the supervision of good friends and colleagues, Karim Fizazi and Matt Smith, level one evidence that two pills twice a day has a really good tolerability safety profile, established MFS and OS endpoint significance. But then also now what we are showing today at 2021 AUA is the improvement in the patients who had daro regarding their urinary symptom interventions, overall urinary symptoms, and total bowel symptoms.

Alicia Morgans: Fantastic. Well, thank you for performing this analysis, of course, and also for discussing your findings and the implications with the group here. Congratulations on your AUA podium presentation. Thank you.

Neal Shore: Thank you.