Brigida Maiorano: Thank you for the invitation.
Kristine Lacuna: Absolutely. We're excited to have you. So I'd like to just kind of get started with how you came up with the study design, a little bit about the background, and how you came to kind of choosing the items that you decided to investigate in this Q-TWIST study.
Brigida Maiorano: Yes. We know that the ARASENS phase-three trial demonstrated a survival benefit when darolutamide was added to docetaxel plus ADT in the metastatic hormone-sensitive prostate cancer. We know there is an improvement in overall survival with a reduction of the risk of death of around 32% with the darolutamide triplet compared to the doublet of docetaxel plus ADT. However, there could be some concerns around about adverse events and toxicity. And there are many attempts also to try to find the patients which most likely will benefit from the intensification strategy to try to maximize the efficacy while minimizing potentially unnecessary adverse events.
Kristine Lacuna: Right.
Brigida Maiorano: In this sense, the Q-TWIST analysis came up to evaluate not only the overall survival of patients, but a quality-adjusted survival. So the possibility to measure not only how long our patients live, but also how is the quality of life, how they spend this time living.
Kristine Lacuna: Absolutely. And I think that that's an important piece of information, especially because in the last 10, 15 years, we've seen a lot of different agents come through doublet therapies, triplet therapies where we are seeing an overall survival benefit, but what does that survival really mean for the patient at hand? And so I'd love to kind of hear more about the design and the different arms that you looked at or the different kind of factors that you looked at, the TWIST, the time to relapse, the time to toxicity. Would you be able to talk about kind of that design?
Brigida Maiorano: Yes. Basically the Q-TWIST analysis compares the variation in efficacy and safety between the treatment arms, assuming that patients can progress through a different set of some measurable health states. These are represented by the TOX, which is the time spent with toxicity. The TWIST, which is the time spent without severe toxicity and the REL, which is the time spent in relapse or disease progression, basically a sort of difference between the overall survival and the progression-free survival.
Kristine Lacuna: Right.
Brigida Maiorano: So the Q-TWIST was adjusted according to the follow-up of the study and 53 months restricted mean was used to analyze these different time periods. The Q-TWIST was like the weighted sum of the different time spent in the health states comparing the darolutamide arm with the placebo arm within the ARASENS trial. Data were retrieved from the ARASENS trial and were the quality of life questionnaires, the Grade 3 and 4 adverse events and your survival and the time to mCRPC. The variation in Q-TWIST, so the difference in Q-TWIST was also calculated between the two treatment arms.
Kristine Lacuna: Right. And what did you guys find?
Brigida Maiorano: We found that interestingly and very significantly, these patients had a 6.3-month gain in the Q-TWIST, which was basically driven by an increase in the TWIST time and a decrease in relapse time in the darolutamide arm compared with the placebo arm. So the population was balanced because this was patients coming from the phase-three ARASENS trial.
Kristine Lacuna: Right.
Brigida Maiorano: We find that even if there was a similar incidence of Grade 3 and 4 adverse events between the two treatment arms, in the darolutamide arm, there were fewer mCRPC events and a longer overall survival. Finally, we found that these patients can live and can gain a Q-TWIST of 16% more, which is very positive because the Q-TWIST analyses that have previously been published in literature were considered positive with a gain of 10 to 13%. And we found a gain of 16%. So our patient, very clinically meaningful, can live longer and can live with a better quality of life compared to those not taking darolutamide but only docetaxel plus ADT.
Kristine Lacuna: No, I think that's really important information, especially for these patients who we have different treatments available with overall survival efficacy. And so it sounds like you see an increase in TWIST, a decrease in relapse. I did see that there was maybe a slight increase in toxicity. Would you be able to talk a little bit about that? I mean, it makes sense if you're adding an additional therapy, but kind of delve into that data a bit.
Brigida Maiorano: Oh yes, because this is like a quality-adjusted survival. We know that a patient can develop an adverse event during this treatment, but the importance, and I think the added value of Q-TWIST analysis, is that we can measure how much these adverse events can impact a patient's quality of life.
Kristine Lacuna: Absolutely.
Brigida Maiorano: I think that this is an interesting analysis, and this is the first time that it is produced in the prostate cancer field. It is used in the bladder cancer, pancreatic cancer, breast cancer, but this was the first analysis, especially in the metastatic hormone-sensitive prostate cancer setting. The added value is that we can talk in a more objective way of quality of life, not only as a subjective perception by the patients within the limitation of the quality of life questionnaires that we face in our clinical practice and also in the clinical trials. But we can relate with the statistical adjustment and a precise statistical method to grade three or four adverse events and survival within the study to render the analysis of quality of life to make it more objective than before. So I think this is the added value of the Q-TWIST analysis.
Kristine Lacuna: Yes, this is the first time I'm certainly seeing it in prostate, but I do think that it is worthwhile, especially because there's a lot of subjectivity when we're talking about quality of life, and to have a more objective sense of how to do things, I think, is very important, especially for our patients who, again, have a lot of treatment options that we can offer. And from a clinician standpoint, we kind of have to think about the balance of treating their disease and making sure that we are choosing the treatment that will be most beneficial for controlling their disease while also thinking about the patient in front of us and making sure that their quality is not compromised. The last thing I'd like to talk about is, when ARASENS was designed, I'm sure as you know, the standard of care at the time was ADT plus docetaxel. And so the way that the study was designed was that it was asking the question, "What is the significance of adding darolutamide to what was the standard of care doublet therapy at that time, ADT plus docetaxel?" And so how would you interpret the data that you're seeing or extrapolate the data that you're seeing in this Q-TWIST study to patients who were seeing in clinic today? Where we're faced with the decision of either adding chemotherapy to a backbone of doublet therapy ADT plus ARSI, which is not the question that ARASENS asked.
Brigida Maiorano: Yeah, we know that this is a big limitation. We have no direct comparison between the two main intensification strategies. So the triplet of darolutamide plus ADT plus docetaxel and the AR doublets. We should try to generate such kind of direct comparisons. So the Q-TWIST is, I think, very applicable also to our clinical practice because we know that these patients can have an improvement in their quality of life because when you have a patient with metastatic hormone-sensitive prostate cancer, the symptoms and also the quality of life depends not only on the toxicity profile of the treatment that we give to the patient but also on the disease itself. So they have symptoms related to the disease. And I think that if you start the treatment, your quality of life can improve if the disease starts to be treated and to be reduced. And also your quality of life depends on these symptoms. So I think that this can be applied in our clinical practice because we observe these improvement in symptoms and quality of life in our patients. So this analysis could be useful to also try to balance our perception between the efficacy and safety of treatment and design also, and include also our patient when the treatment decision-making is done.
Kristine Lacuna: Absolutely. And I think that some of the cooperative group trials are trying to answer that question going forward, but we won't have that data for several years. And so I think that it's important to see that data, but right now I think I commend you and your team for having this Q-TWIST data, because at least we have some information to extrapolate from for our patients and meaningful data where we are seeing improvement in quality of life. And so, any final words, any kind of future directions in terms of this study or applying Q-TWIST to other types of studies that you're doing?
Brigida Maiorano: Yeah, I think that this analysis is very huge. I found this analysis particularly interesting. So I was very happy when we were able to realize this kind of study. I think that the quality of life data and the possibility to have a more objective interpretation of safety, tolerability, and even the patient's perception about quality of life could be very useful in the future, also to try to differentiate between the treatment options and how to personalize treatment strategies. So I believe in a future with biomarker analysis, of course. Maybe direct comparison just to find the right treatment for every patient, but also more attention to quality of life besides the efficacy, which of course is very important. So in the future, we should give to our patient more life, but also more quality of life or more life with quality.
Kristine Lacuna: And I think that that's a perfect ending and an important patient-centric sentence that you said. And I commend you and congratulate you for this wonderful abstract and poster and looking forward to hearing more from your team.
Brigida Maiorano: Thank you very much.
Kristine Lacuna: Thank you.