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Neeraj Agarwal: So welcome to UroToday. I'm so pleased to welcome Dr. Alicia Morgans, who is a genitourinary medical oncologist and the Director of the Survivorship Program at the Dana-Farber Cancer Institute. Today, Dr. Morgans will be talking about her presentation at the EAU meeting, where she presented the data on association of baseline PSA levels and clinical outcomes in patients with metastatic hormone sensitive prostate cancer. Alicia, welcome.

Alicia Morgans: Thank you so much, Neeraj. I really appreciate your interest in this topic. So I was so pleased to present at EAU the impact of baseline PSA effect on clinical outcomes in patients with mHSPC. And this is really data from the ARASENS trial. Just to set the level set at the beginning here, this was a phase III trial in which patients with metastatic hormone sensitive prostate cancer were randomized to receive ADT and docetaxel with darolutamide, or ADT and docetaxel on its own.

And we know from that trial that this demonstrated a reduction in the risk of mortality by 32.5% when we had that triplet as compared to the ADT and docetaxel doublet. And of course, this led to the approval of darolutamide in this setting. We also know that this triplet achieved a really deep and durable PSA response, and 67% of patients did achieve a PSA that was considered undetectable, with that level set at less than 0.2 at any time during the treatment follow-up.

And this was only 29% of patients who were treated in the ADT docetaxel control arm. And these patients, of course, had a longer time to PSA progression and other benefits in terms of disease control. This post hoc analysis really tried to understand the way that we could think about patients by assessing their baseline PSA value and try to see if that could help us to predict or to talk with our patients about how well their disease control may be during treatment with the ADT, docetaxel, darolutamide triplet, as compared to a standard chemohormonal treatment.

So we tried to understand the achievement of an undetectable PSA defined as less than 0.2 at predefined landmark time points, as well as time to PSA progression and time to castration resistance. And in order to do this, we really made these quartiles of PSA level, with the low quartile being less than 4.8, the middle quartile ranging from a PSA of 4.8 to 27.55, and then the highest quartile was actually about 50% of the patients. This was quartile three and four put together, and these are patients who had a PSA of greater than 27.55. And this was really set up to be this way because we really wanted to try to understand the breakdowns, particularly in the lower levels there for those first two quartiles, versus patients who still had quite a high PSA at study entry.

So regardless of the baseline PSA, of course we know that more patients treated with darolutamide triplet did have that undetectable PSA level. And here we can see the rates of people achieving an undetectable PSA within the different quartiles. So in the quartile that you can see on the left labeled as low, with a PSA at baseline of less than 4.8, we can see that ultimately about 90% of patients did achieve this at any point during follow-up, whereas patients on the control arm had a high of 60% at any time achieving that undetectable PSA. So clear difference there.

If we look at the middle PSA at baseline group, we can see, again, that split between patients receiving darolutamide in the triplet versus patients receiving chemohormonal therapy. Again, any time, with a PSA response of 74.2% versus 31%. And for those patients who came in with the highest PSAs at baseline, we can see that split still remains quite large—any time achieving that PSA of undetectable in the darolutamide-containing arm of 61.6% versus just under 20% for the chemohormonal arm.

So really, across all of these baseline PSA groups, the patients treated with darolutamide had a much higher rate of achieving that undetectable PSA. And here we can see that those patients who had darolutamide also in the lowest baseline PSA group had the longest time to PSA progression versus those patients who, of course, had the highest baseline PSA. And you can see this really broken down here by baseline PSA. Each color represents the baseline PSA from low to high, with the pinkish-red being those patients with the lowest baseline PSA, the middle being the green color, and the highest PSAs at baseline being that dark blue color. And those patients who received darolutamide in the solid lines having the longest time to PSA progression versus those patients who did not receive darolutamide in the dashed lines, of course, having shorter time to progression.

So we can see that nicely illustrated here. Patients who receive darolutamide and had that lowest baseline PSA also had the longest time to CRPC, versus those patients with higher baseline PSAs. And we can see the breakdown, again, with solid lines being patients exposed to darolutamide, dashed lines being patients receiving chemohormonal therapy, and again, the pink-red color being the patients with the lowest baseline PSA, the middle group being the green, and the dark blue group having the highest baseline PSA. So really, that is held out. The same thing here with time to CRPC.

The safety profile was very similar across all of these PSA ranges, so we didn't really see anything fall out as having a higher rate of adverse events here. So in conclusion, the lower baseline PSA was associated with higher rates of achieving an undetectable PSA during treatment, a longer time to PSA progression, and a longer time to CRPC progression. And of course, as we would expect given this drug is now approved in this setting, treatment with the triplet, including darolutamide, was consistently associated with higher rates of undetectable PSA at any point, longer times to PSA progression versus the chemohormonal arm, and longer time to CRPC progression versus the chemohormonal arm.

And patients benefited at all of these baseline PSA levels, but really, we just saw the highest rates of undetectable PSA and the longest time to progression for patients who started off in a better place. So it shows, I think, that there's efficacy to treatment with darolutamide, and it's important to consider for the appropriate patient when we're using a triplet across a wide range of baseline PSA values. But when we talk to patients, we can say the lower the PSA is going in, the longer time to progression, which is nice to confirm something that we would expect from a clinical perspective. So I will stop sharing my screen and I appreciate your time.

Neeraj Agarwal: Well, that was a great presentation, Alicia. Thank you. So one thing which I noticed was that patients who had higher baseline PSA levels—really more than the highest quartile, more than 27 nanograms per mL—they seem to benefit the most by adding darolutamide.

So I could see—obviously it's hard to statistically come up with so many different subgroup analyses. But just as a clinician, when I look at the picture and showing the difference in the PSA responses, that was highest in the highest quartile by adding darolutamide.

Alicia Morgans: Yes. I would say the same thing. Obviously this is a numerical assessment by our eyes. My eyes say the same thing that yours do, Neeraj. And I think the way that this makes sense to me from a clinical perspective is that these are the patients who have the most aggressive disease. They have the poorest prognosis. This is not associating this with volume of disease or de novo recurrence status, so I can't make conclusions there. But maybe they have more metastatic disease. This makes sense, too, if they have a higher PSA. But when we have more aggressive disease behavior, adding on additional therapies is expected to potentially provide some benefit.

Some clones in that larger disease burden may really benefit from the treatment of this additional therapy. And so I think when we have more that we need to conquer when it comes to disease burden, having this extra treatment—especially one that is as effective an AR pathway inhibitor as darolutamide is—can be really, really meaningful to that patient population.

Neeraj Agarwal: It was great to see that patients with lower PSA levels also benefit in terms of the long responses. As you said very rightly, we know that low baseline PSA levels are associated with better outcomes. But it is nice to see these data being, again, validated in a large prospective phase III trial. And this information is so useful. When we are talking to our patients in the clinic and we have such information available, I feel I would feel comfortable telling them that this treatment is going to help you, regardless of the baseline PSA level. Is that correct?

Alicia Morgans: That is correct. I mean, there's benefit across all of these levels, as you can see. The solid lines that represented the progression were all above the dashed lines representing progression, and the solid lines included all the patients who received darolutamide, whereas the dashed ones obviously were the control chemohormonal arm. So in every case, there was a superior disease control with darolutamide added for these populations.

But what I really find helpful is that when I think about patients in clinic, they often ask me, well, how long am I going to be on this treatment? And we can use the baseline PSA, if we're using this triplet combination, and say, well, on average people were on for this many years. And that helps people in so many ways, obviously for their own personal planning, but also, as they're trying to think about finances—how long am I going to pay for this medication? Maybe it's closer to the end of the year and they're thinking about, well, is it worth it for me to sign up for Medicare pharmacy coverage and that benefit? Yes, probably, because all groups actually stayed on this treatment for quite a long time. But it does give people, I think, just some way to think about, how is this going to proceed, and, on average, how long might I be on this medicine?

Neeraj Agarwal: That's a fantastic point you raised. You pointed out it helps with so many other things beyond talking about radiographic progression-free survival and overall survival—how to manage their lives, how to plan their retirement, how long to work in a job which is paying for their insurance. I think this information is so clinically relevant for many of our patients who are dealing with these questions.

Yeah. Just a very quick question. Did you correlate the baseline PSA level with the disease volume? And I'll tell you why I'm asking this question. It's because most of the busy practitioners out there don't have time to assess the disease volume by four or more bone metastases, by presence or absence of visceral metastases. Sometimes you see that one speck in the liver and you don't know what it is. Is it really a liver metastasis? We don't have the time to do an MRI or a biopsy. So in a PSA level, which is such a simple objective measure, which can tell us about the disease volume or how the given treatment is going to behave—how effective a given treatment is going to be—I think it's a very useful information for both practitioners and patients.

Alicia Morgans: Yeah, I love that point. And although we did not present the data analyzed with that in mind, and these were unadjusted assessments, I am absolutely going to talk with the team, because obviously this is a presentation, but a manuscript is in process. And I think that our team really appreciates that feedback and will certainly try to incorporate it into the manuscript, breaking down in each of these groups by baseline characteristic what is their disease volume. Which obviously in ARASENS also was a subsequent analysis that was reported, because this wasn't captured on the initial eCRFs for this study, because of the time when it was designed, they captured it a little bit differently—M1a, M1b, that kind of thing. But we do have that information now, and so can go back to those patients where this was able to be calculated and try to fill in some of those holes as it relates to baseline PSA. That's a great suggestion. Thank you, Neeraj.

Neeraj Agarwal: Any final message for our audience today?

Alicia Morgans: I think the final message is that darolutamide is really helpful as a member of this triplet therapy regimen. And I think what's so important is that no matter where we start from baseline PSA, it can be helpful in getting to that undetectable PSA level, in prolonging the time to PSA progression, and to prolonging the time to CRPC. But importantly, it may make even the most difference in some of those patients that we worry the most about with those high PSA levels who need that extra push to try to get them over the edge in terms of disease control. And when we can do it in a way without clear extra adverse event in that population, I think it's absolutely worth the conversation and consideration.

Neeraj Agarwal: Hey, congratulations to you and your team for presenting such clinically relevant data, which will affect our decision making in the clinic, which affects our patients' own planning during their lives and how it affects overall prognostication and counseling and treatment selection, I would say.

Alicia Morgans: Thank you so much for your time and for your suggestions, Neeraj. I appreciate it.

Neeraj Agarwal: Thank you.