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Alicia Morgans: Hi, I'm so excited to be here with Dr. Ravi Madan, who's a genitourinary medical oncologist at the National Cancer Institute. Thank you so much for being here with me today.

Ravi Madan: Thank you.

Alicia Morgans: Wonderful. Ravi, you gave a really fantastic discussion at the poster discussion session for prostate cancer at ASCO 2023. This was all really focused on patient reported outcomes and I'd love to hear your take on this whole group of posters that you talked about and give us a sense of what you discussed.

Ravi Madan: Yeah, I think obviously talking to you about quality of life is interesting because that's your field and really not mine. And that was actually an important part of my perspective and disclaimer is that I come at this as a clinician who prioritizes quality of life, but not necessarily someone who lives and breathes this stuff.

But there was three abstracts. Two were really very similar and then actually an abstract from you and your team at Dana-Farber that I thought in some ways was the most interesting. This was a presentation by the lead author was Dr. Sentana Lledo from Dana-Farber. And you guys looked at CHAARTED, which we all know CHAARTED from 2014 when it improved survival with docetaxel and ADT versus ADT alone. But you guys did quality of life every three months.

And what he was able to highlight from the data was that using the FACT-P, the three month quality of life assessment actually turned out to be pretty important. What you guys did was you broke it down by quartiles and the best quartile seemed to have no real benefit from treatment intensification with docetaxel. I think it was about 70 month survival, regardless of whether you got chemotherapy or not, it was ADT or docetaxel. But when you looked at the lesser quartile, there was an improvement of about 29 months with ADT alone. But if they got docetaxel in that lesser quartile, it was closer to 50 months. About a 20 month improvement.

You guys were very modest in, I think in your conclusions where you said, "Maybe this helps us look at treatment intensification in castration sensitive prostate cancer." I actually think there's a bigger story here because whether it's clinic or trials, we use crude measures like performance status, or pain levels, which is often arbitrarily diagnosed or determined. But you really open the door here to use very much more complex and vetted instruments to really identify perhaps patients that require greater care. I think it's really interesting. I think it'd really built this into a lot more trials.

Alicia Morgans: Wonderful. Well thank you so much for those kind words. And I think we use things like volume status too, and sometimes we can augment that power with some of this quality of life data.

Ravi Madan: And actually I forgot to mention, but the volume status that didn't impact this. This was irrespective of volume status, which again speaks to the added dimension that this has provided.

Alicia Morgans: Yeah. And thank you for your comments there and I look forward to... I'll put you on as a reviewer for the paper when it's out.

Ravi Madan: Sure.

Alicia Morgans: But great, and hopefully we can continue some of this work because I think many of these trials that we have, even older trials like CHAARTED, have a wealth of data in quality of life data and patient reported outcome instruments that have been collected that we really haven't explored to the extent that they may provide some of these insights.

Ravi Madan: And going through the data must be just a very difficult task.

Alicia Morgans: It is, but if this is what you do, it's just like biomarker data, right? You dig through it because you know that there might be gold at the end.

Ravi Madan: I think there was here.

Alicia Morgans: Well, and thank you for that. You also looked at two other abstracts though, and these are complex because there's a lot of controversy in the field about some of these intensification strategies that really combine the androgen receptor signaling inhibitors and PARP inhibitors and just a lot swirling around in the field around these studies. Let us know what were the two other abstracts and how did you break those down?

Ravi Madan: The other two abstracts were the TALAPRO trial, TALAPRO-2, which combines enzalutamide with talazoparib, versus enzalutamide alone in first line metastatic castration resistant prostate cancer, MCRPC. And in that trial they used the EORTC instrument, quality of life instrument, and they didn't really see any substantial changes looking at bowel function, or urinary symptoms, or sexual function. There was no meaningful differences in the results there.

When they looked at more symptom based or quality of life in that regard, there were differences that favored the enzalutamide and placebo group, but they were not thought to be clinically meaningful because it didn't really have the magnitude of decline that you would really require, which is a 10 point decline, I think for that to be considered significant clinically.

What they did look at though, and which was a little more interesting was this deterioration of quality of life over time. And what they saw was that it was roughly equivalent until about the 22 month mark, and then there seemed to be a separation. And they were conditional on how they phrased it appropriately, but they thought that potentially that was the benefit of preserving progression-free survival that much longer. And perhaps that's where the quality of life benefit was reflected. And I think that that was interesting.

And then the second abstract really was this, the PROpel trial, which as you know is abiraterone with olaparib, versus abiraterone alone. And also in first line MCRPC. I should also take a step back and say that these patients were globally not selected for mutation status. And that's part of the discussion points that come up a lot frequently in this. But in this trial, it took on added relevance this week because the FDA just approved the combination of abiraterone and olaparib for BRCA mutated first line MCRPC.

In that context, we looked at this data from Andy Armstrong from Duke, and they looked at actually several parameters including quality of life. They looked at time to pain progression and abiraterone was very effective in first lamp MCRPC. There were very few events, not a big difference. They looked at the brief pain index. Again, similar findings, not a big difference. Another point they looked at was skeletal related events along those lines, again, abiraterone is very effective. Very few events, no difference.

They did see a big difference in an endpoint that I have some questions about, and that's time to chemotherapy. They reported that I think it was a 32 versus 24 month improvement, and it was actually very substantially perhaps driven by the mutated patients to where it was like 15 months in the control arm but not reached in the patients got abiraterone and olaparib. I wonder a little bit about how meaningful this particular endpoint or perspective is in this particular disease state at this particular time.

The one thing I wonder about with the time to the chemotherapy again, is how much of it is driven by the BRCA mutated patients? Because that's going to be important. But the other thing I think is also important along the same lines in that same population is in 2023 in the United States, if you get abiraterone first line, you can get a PARP inhibitor second line. Your second line option, unlike most of the patients on the trial, isn't chemotherapy. It's not really that relevant I don't think in America in 2023.

And the final thing, it's maybe more just a nuance, but I think it should be controlled for somehow. And that is, we know PARP inhibitors induce myelosuppression. How much of this delay was just patients giving their patients' bone marrows time to recover before they're like, "All right, now you're okay to get chemo, we give you a few months." The big takeaway is really how, from my perspective in terms of looking at all of that is how does that impact clinical practice? And I think that it really brings up the broader perspective of the potential role of patient reported outcome in clinical trials.

And I found an article which I quoted, and it basically highlighted something that made sense to me and resonated with what I believe, now at least. And that is the role of patient reported outcomes, and you can affirm this or not, but is on some level is to identify toxicities that are, despite the deliberate nature of trials, often overlooked in trials, and it basically allows things that are not being recognized to be captured and therefore provide an added dimension of understanding of treatments impact on patients.

As a clinician, my sense would be that in the optimal situation, is a patient reported outcome would be in a situation where you have two therapies that either seem to have no toxicity or relatively equivalent toxicity. And then basically the patient reported outcome data gives you that added dimension to break the tie. But if you look at the toxicity from these two trials, the addition of the PARP inhibitor is quite extensive. And we know this from having used PARPs. And I'll just give one example, and I was shocked when I saw it today just because it's a big number. But in the TALAPRO-2 trial, the data presented today in that cohort, the grade three plus toxicities were 66% versus 33%.

It really brings up a question which I don't really have the answer for as to how that really impacts practice, but it's something we'll have to wrestle with. And that is when you have clear objective toxicity differences, how do you really factor in the patient reported outcome? And maybe that's something I can ask you as an expert.

Alicia Morgans: Yeah. That's such a great question and I love the quote that you brought up because the fact that we under identify toxicities that patients may feel, particularly those subjective toxicities is a problem, but is something that we can start to correct with patient reported outcomes. The other side of that is that there are things that we capture on our CTCAE as being grade one, grade two, that make us anxious or are things that give us some pause or at least some seconds of brain power that patients may not feel or care about. And I think is in some ways helps us to balance the under capture and the over capture into what really matters to patients, which is just another dimension of all of the information that we have to put together.

But I think that when it comes to grade three toxicities, these are things that in most cases will impact patients in some way because oftentimes this requires a blood transfusion, or hospitalization, or emergency department, or some intervention that at least requires a conversation with the patient, or perhaps another test, or perhaps some intervention.

And what I wonder, and this is not a criticism of these trials in any way, but what we need to think about as a field is particularly in settings where we are adding toxicity in these different ways, are we capturing these patient reported outcomes frequently enough? Because if the survey asks in the last seven days, or some of them may say in the last 14, or some might say in the last 30, is that the duration of time that's really important? Or are we missing a large chunk of time between the assessments where things could be happening and we're just not asking patients?

And it's not to say that we should ask patients every week what's going on. That would be so much data as to be overload and the patients would stop answering. But there might be windows of time where patients are having events where essentially patient reported outcome type events, complications, blood transfusions, hospitalizations, but we aren't asking them about their quality of life at those time points. We're asking them at a time point where maybe they're better and they're coming into clinic. There may be some under capture or some under reporting in some of our assessments just based on the timing of these surveys. And nothing is perfect, but that might be something for us to think about as we go forward.

Ravi Madan: The other thing that is not naive to this field coming into this presentation I found was it's very complex flow diagram from I think seminal work back in like 1995 from a JAMA article, I'm blanking on the two authors who wrote it, and I showed it in my presentation. It highlights the complexity that goes into it. I think clinicians like myself think of quality of life and we just think it's the patient, it's the drug, and there's some sort of equation and that's what's reflected here, but there's so much more. And I think there's a lot of socioeconomic things that come in.

But I also think that, I don't envy the obstacles you have in your research because it's complicated as I think about this and that is how do you factor in what's driving the answer to the question? How much of it is the perception of where they would be if they weren't on any therapy? And I'm just going to tough it out through the symptoms and I'm just happy that I'm okay, or maybe my PSA is going down and anything's worth that. And it's so complex to tease out what's the driving motivation for the different answers that you get on those questionnaires.

Alicia Morgans: Absolutely. And you can't always assess that. Those are a bunch of unmeasured things. Patient optimism may come into play, the lack of, or the very good support system that they have, whether they have anxiety or depression underlying all of this, whether there might be a little bit of unidentified dementia or mild cognitive impairment. All of these things, and many, many others can come into play. Any of us could have a good day or a bad day. And if we complete the same PROM on one of those days, even if there's a complete stability of our quality of life overall, it may be drastically different on the two days that we answer the questions.

Ravi Madan: Yeah.

Alicia Morgans: Really interesting questions and I'm sure it will give me many sleepless nights to come.

Ravi Madan: But I think it highlights the great aspects of these three abstracts because sometimes the best research doesn't have all the answers, but it just leads to better questions.

Alicia Morgans: Wonderful. Well thank you. That's a wonderful thing to say. And if you had to sum this up and what a wonderful discussion you gave and really certainly making me think twice and more deeply about a lot of this work, what would your message be to listeners?

Ravi Madan: Again, I think patient reported outcomes are things that maybe we can use more like you did in your trial with CHAARTED to better understand and maybe understand or stratify patients on trials.

And then I think that, I don't know that I have a way to summarize the dilemma that we have now. And that is how do we weigh the toxicity that we have potentially from these combinations of PARP inhibitors and antiandrogens with how do we rationalize that with the patient reported outcome data? And I think the toxicity, like you said, given the grades and the disparities, I think to a lot of clinicians that might actually speak a little bit more than the patient reported outcomes, but it's going to be a tough calculus and we might have to just take it patient by patient and really think this through.

Alicia Morgans: And that's what we do day-to-day in clinic anyway. A little bit more information, many more questions, and ongoing conversations with our patients are probably where we'll end up and...

Ravi Madan: Better care and better outcomes.

Alicia Morgans: And better care and better outcomes. And I really appreciate the time that you took to think through all of these abstracts and posters. And thank you for your time today.

Ravi Madan: No, thank you for inviting me to talk with you.