TALAPRO-2 Study Reveals Efficacy and Tolerability of Talazoparib Combination for Prostate Cancer - Neeraj Agarwal
June 13, 2023
In this conversation, Alicia Morgans and Neeraj Agarwal discuss the TALAPRO-2 trial, a phase three study investigating the effectiveness of combining ADT plus enzalutamide plus talazoparib in treating first line metastatic castrate-resistant prostate cancer. Agarwal presents the study's quality of life data at ASCO 2023, revealing the experimental arm significantly delayed the deterioration of patients' global health status compared to the control. Despite known side effects of PARP inhibitors, no clinically meaningful differences were found between the groups using a pre-specified significance level. Another tool, EORTC QLQ-PR25, evaluated urologic symptoms, gastrointestinal symptoms, and sexual function and found no significant differences between groups. Agarwal asserts that these patient-reported outcomes, alongside the lack of adverse impact on functional and symptom aspects, validate the study's therapeutic approach. Morgans emphasizes the importance of these findings in informing clinical practice.
Biographies:
Neeraj Agarwal, MD, Professor, Presidential Endowed Chair of Cancer Research, Director GU Program, and the Center of Investigational Therapeutics (CIT) at the Huntsman Cancer Institute, University of Utah, Salt Lake City, UT
Alicia Morgans, MD, MPH, Genitourinary Medical Oncologist, Medical Director of Survivorship Program at Dana-Farber Cancer Institute, Boston, MA
Biographies:
Neeraj Agarwal, MD, Professor, Presidential Endowed Chair of Cancer Research, Director GU Program, and the Center of Investigational Therapeutics (CIT) at the Huntsman Cancer Institute, University of Utah, Salt Lake City, UT
Alicia Morgans, MD, MPH, Genitourinary Medical Oncologist, Medical Director of Survivorship Program at Dana-Farber Cancer Institute, Boston, MA
Read the Full Video Transcript
Alicia Morgans: Hi, I'm so excited to be here with Professor Neeraj Agarwal, who's a GU medical oncologist and professor of medicine at the Huntsman Cancer Institute in Salt Lake City, Utah. Thank you so much for being here with me today.
Neeraj Agarwal: Thank you for having me.
Alicia Morgans: Well, wonderful. I'm excited to talk with you about TALAPRO-2 and the quality of life data that was presented at ASCO 2023. So tell me a little bit about the study, about the schematics so we understand the patients and how they were treated. And then I'd love to hear about the quality of life outcomes that you reported on.
Neeraj Agarwal: Very important data. So thanks for the opportunity here. TALAPRO-2 is a phase three trial, which is randomizing patients regardless of homologous three combination repair mutations to the combination of ADT plus enzalutamide plus talazoparib versus ADT plus enzalutamide in first line metastatic castrate-resistant prostate cancer setting.
So I had the opportunity to present these data in the ASCO GU meeting where we showed that the combination of ADT plus enzalutamide plus talazoparib was significantly superior or superior to the combination of ADT plus enzalutamide as far as efficacy is concerned. We showed improved radiographic progression free survival and other meaningful secondary endpoints such as delay in PSA progression, delay in cytotoxic chemotherapy. We also showed a part of quality of life assessment, which showed delay in the deterioration of health related quality of life as reported by the patients. And those data were well received and we showed the presence of efficacy in both HRR positive and HRR negative patients, although I must tell you that the efficacy parameters are much stronger in patients who had homologous recombination repair mutations. So in the ASCO 2023 Annual Meeting, we presented the data on health related quality of life in a more extensive fashion. So basically the whole presentation is about quality of life as reported by the patients.
Alicia Morgans: Wonderful. And what are some of the outcomes and assessments that you talked about?
Neeraj Agarwal: So the first one was using the validated questionnaires, which were prospectively administered to the patients throughout. So this study, just for our viewer's recollection, it was an 800 patient trial in first line MCRPC setting where patients were randomized in a one-to-one fashion. Now for quality of life portion, we had 793 patients who were eligible, who completed their quality of life questionnaires and they were found to be eligible and they were evenly distributed in these two arms of enzalutamide plus versus enzalutamide. And we used a validated questionnaire known as EORTC QLQ-C30. It, as you know, you are a leader in the field. This overall assessment tool assesses the global health status and quality of life of the patient. But in addition to that, it also assess the physical symptoms and also the functional symptoms or functional parameters such as cognitive function, emotional function, and so on.
So I'd like to first talk about the most important aspect of this questionnaire, which was global health status, quality of life as reported by the patients on the trial. And very pleased to report that there was a significant delay in the deterioration of the global health status quality of life as reported by the patients on the experimental arm of enzalutamide plus talazoparib versus enzalutamide plus placebo. But beyond that, I think there are many more endpoints which are meaningful to our patients. So if you look at the functional subscales of the EORTC QLQ-C30, it's a mouthful to say that, but if you look at the functional scales, physical functioning, social functioning, cognitive functioning, emotional functioning, and there was no difference. So there was no adverse impact of talazoparib on any of these functionings and all of them were, there was no difference in these functions.
Going beyond these physical functioning or functionings of scales, If you look at the symptom scales. If you look at fatigue, nausea and vomiting, anorexia, many of them are very well known side effects of PARP inhibitors. There was a trend which favored the placebo arm as far as the side effects are concerned. But if you look at the pre-specified clinical meaningfulness, which was at least a 10 point difference to make sure there was not a difference by chance. So there was a pre-specified significance level, which was defined as clinical meaningfulness. So none of these side effects, nausea, vomiting, anorexia, fatigue, none of them reached to the level of clinical meaningfulness, meaning there was no clinically meaningful difference in between these two arms. And I think that is partly happening because of the anti-tumor effect, which is happening with the talazoparib based on better efficacy. So if patients are living longer with without deterioration in quality of life, just because we are controlling their disease better, that is reflecting on all other functioning or symptom scales.
Alicia Morgans: Absolutely. I think it's so important that you were able to drill down on those specifics as well, and interesting that there wasn't a clinically meaningful difference because as you said, there can be noise created simply by assessing these surveys over time that don't really suggest that there's something that's a noticeable health related quality of life difference between two groups, even if they're numerically different. And that's so important when you're assessing and comparing these scores over time.
Neeraj Agarwal: Especially when patients are coming to the clinic, they're taking this questionnaire, sometimes the same patient, could be less tired or more tired, depending upon how long they have driven to the clinic.
Alicia Morgans: True, true.
Neeraj Agarwal: So all those aspects can affect our patients' perception of quality of life in the clinic. And that's why we thought it was important to have a pre-specified definition of clinical meaningfulness. I would like to bring your attention to another scale we used, which was EORTC QLQ-PR25, which looks at mostly the urologic symptoms, gastrointestinal symptoms, and sexual function. So this is mostly to do with incontinence, for example, or effects of androgen deprivation therapy on all these functions. And we did not see any difference between these two arms. So I think combining the EORTC QLQ-C30 questionnaire and the PR25 questionnaire, when we see these data that our patients are delaying their disease progression and their quality of life is maintained for longer time and we don't see any adverse impact on this functional and symptom aspect, that's very gratifying.
Alicia Morgans: Absolutely, because it is the way that the patient feels in our clinical practice that often dictates how comfortable we as clinicians are with these agents for use with the next patient and the next after that. So from your perspective, were there other findings that help inform how the patients actually tolerated these treatments and how they were able to function or to feel during the treatment, but especially any comparisons between these arms in terms of these important outcomes for patients?
Neeraj Agarwal: So I think given the very comprehensive nature of these tools, which assessed the global health status, quality of life, their functioning in terms of social, cognitive, emotional, physical functioning, their symptom scales, which included nausea, vomiting, anorexia, fatigue, and then the PR35, which included all the other aspects of one's life, which are very important, sexual dysfunction, urologic dysfunction, and so on. And given that there was no difference in these, I think we feel very assured that the combination of talazoparib plus enzalutamide is indeed benefiting is not only more efficacious, but it doesn't affect adversely our patient's quality of life.
Alicia Morgans: And I just want to emphasize that because I think this is a patient reported quality of life. It's from their own perspective. There's not a filter through a clinical team. And in fact, it's really only reporting on the things that the patient feels or experiences, not laboratory abnormalities that may be completely really asymptomatic. And when we look at quality of life and adverse events, I think sometimes we as clinicians focus very much on the adverse events as collected by the CTCAE that maybe there were some mild LFT abnormalities in this particular treatment, or there might be mild neutropenia with that treatment or a mild anemia with this other treatment. All of these, and I emphasize mild, not necessarily noticeable to the patient, but sometimes we feel anxious about these. From your perspective, it sounds like the patient experience, regardless of arm, was actually pretty similar. And perhaps if we can manage the laboratory values, the patients would feel quite comfortable to manage their quality of life, at least with this particular combination.
Neeraj Agarwal: Absolutely. I agree 100% as I always do when you talk about the quality of life assessment scales. But absolutely, I agree with you. It's very reassuring to see our patients reported no worsening of quality of life and no worsening of all this different aspect of one's daily living with the combination therapy.
Alicia Morgans: Wonderful.
Neeraj Agarwal: So I'm so glad, PROs, patient reported outcomes are valued more and more by the different organizations and they are invited for all presentations. And I think this basically tells us how much more careful, how much more cognizant we are about how our patients feel and not what CTCA grading tells us.
Alicia Morgans: Wonderful. Well, thank you so much for sharing your expertise, for working with your team to bring this to ASCO 2023. And thank you so much today for your expertise and your willingness to talk about it. I appreciate your time.
Neeraj Agarwal: Thank you very much.
Alicia Morgans: Hi, I'm so excited to be here with Professor Neeraj Agarwal, who's a GU medical oncologist and professor of medicine at the Huntsman Cancer Institute in Salt Lake City, Utah. Thank you so much for being here with me today.
Neeraj Agarwal: Thank you for having me.
Alicia Morgans: Well, wonderful. I'm excited to talk with you about TALAPRO-2 and the quality of life data that was presented at ASCO 2023. So tell me a little bit about the study, about the schematics so we understand the patients and how they were treated. And then I'd love to hear about the quality of life outcomes that you reported on.
Neeraj Agarwal: Very important data. So thanks for the opportunity here. TALAPRO-2 is a phase three trial, which is randomizing patients regardless of homologous three combination repair mutations to the combination of ADT plus enzalutamide plus talazoparib versus ADT plus enzalutamide in first line metastatic castrate-resistant prostate cancer setting.
So I had the opportunity to present these data in the ASCO GU meeting where we showed that the combination of ADT plus enzalutamide plus talazoparib was significantly superior or superior to the combination of ADT plus enzalutamide as far as efficacy is concerned. We showed improved radiographic progression free survival and other meaningful secondary endpoints such as delay in PSA progression, delay in cytotoxic chemotherapy. We also showed a part of quality of life assessment, which showed delay in the deterioration of health related quality of life as reported by the patients. And those data were well received and we showed the presence of efficacy in both HRR positive and HRR negative patients, although I must tell you that the efficacy parameters are much stronger in patients who had homologous recombination repair mutations. So in the ASCO 2023 Annual Meeting, we presented the data on health related quality of life in a more extensive fashion. So basically the whole presentation is about quality of life as reported by the patients.
Alicia Morgans: Wonderful. And what are some of the outcomes and assessments that you talked about?
Neeraj Agarwal: So the first one was using the validated questionnaires, which were prospectively administered to the patients throughout. So this study, just for our viewer's recollection, it was an 800 patient trial in first line MCRPC setting where patients were randomized in a one-to-one fashion. Now for quality of life portion, we had 793 patients who were eligible, who completed their quality of life questionnaires and they were found to be eligible and they were evenly distributed in these two arms of enzalutamide plus versus enzalutamide. And we used a validated questionnaire known as EORTC QLQ-C30. It, as you know, you are a leader in the field. This overall assessment tool assesses the global health status and quality of life of the patient. But in addition to that, it also assess the physical symptoms and also the functional symptoms or functional parameters such as cognitive function, emotional function, and so on.
So I'd like to first talk about the most important aspect of this questionnaire, which was global health status, quality of life as reported by the patients on the trial. And very pleased to report that there was a significant delay in the deterioration of the global health status quality of life as reported by the patients on the experimental arm of enzalutamide plus talazoparib versus enzalutamide plus placebo. But beyond that, I think there are many more endpoints which are meaningful to our patients. So if you look at the functional subscales of the EORTC QLQ-C30, it's a mouthful to say that, but if you look at the functional scales, physical functioning, social functioning, cognitive functioning, emotional functioning, and there was no difference. So there was no adverse impact of talazoparib on any of these functionings and all of them were, there was no difference in these functions.
Going beyond these physical functioning or functionings of scales, If you look at the symptom scales. If you look at fatigue, nausea and vomiting, anorexia, many of them are very well known side effects of PARP inhibitors. There was a trend which favored the placebo arm as far as the side effects are concerned. But if you look at the pre-specified clinical meaningfulness, which was at least a 10 point difference to make sure there was not a difference by chance. So there was a pre-specified significance level, which was defined as clinical meaningfulness. So none of these side effects, nausea, vomiting, anorexia, fatigue, none of them reached to the level of clinical meaningfulness, meaning there was no clinically meaningful difference in between these two arms. And I think that is partly happening because of the anti-tumor effect, which is happening with the talazoparib based on better efficacy. So if patients are living longer with without deterioration in quality of life, just because we are controlling their disease better, that is reflecting on all other functioning or symptom scales.
Alicia Morgans: Absolutely. I think it's so important that you were able to drill down on those specifics as well, and interesting that there wasn't a clinically meaningful difference because as you said, there can be noise created simply by assessing these surveys over time that don't really suggest that there's something that's a noticeable health related quality of life difference between two groups, even if they're numerically different. And that's so important when you're assessing and comparing these scores over time.
Neeraj Agarwal: Especially when patients are coming to the clinic, they're taking this questionnaire, sometimes the same patient, could be less tired or more tired, depending upon how long they have driven to the clinic.
Alicia Morgans: True, true.
Neeraj Agarwal: So all those aspects can affect our patients' perception of quality of life in the clinic. And that's why we thought it was important to have a pre-specified definition of clinical meaningfulness. I would like to bring your attention to another scale we used, which was EORTC QLQ-PR25, which looks at mostly the urologic symptoms, gastrointestinal symptoms, and sexual function. So this is mostly to do with incontinence, for example, or effects of androgen deprivation therapy on all these functions. And we did not see any difference between these two arms. So I think combining the EORTC QLQ-C30 questionnaire and the PR25 questionnaire, when we see these data that our patients are delaying their disease progression and their quality of life is maintained for longer time and we don't see any adverse impact on this functional and symptom aspect, that's very gratifying.
Alicia Morgans: Absolutely, because it is the way that the patient feels in our clinical practice that often dictates how comfortable we as clinicians are with these agents for use with the next patient and the next after that. So from your perspective, were there other findings that help inform how the patients actually tolerated these treatments and how they were able to function or to feel during the treatment, but especially any comparisons between these arms in terms of these important outcomes for patients?
Neeraj Agarwal: So I think given the very comprehensive nature of these tools, which assessed the global health status, quality of life, their functioning in terms of social, cognitive, emotional, physical functioning, their symptom scales, which included nausea, vomiting, anorexia, fatigue, and then the PR35, which included all the other aspects of one's life, which are very important, sexual dysfunction, urologic dysfunction, and so on. And given that there was no difference in these, I think we feel very assured that the combination of talazoparib plus enzalutamide is indeed benefiting is not only more efficacious, but it doesn't affect adversely our patient's quality of life.
Alicia Morgans: And I just want to emphasize that because I think this is a patient reported quality of life. It's from their own perspective. There's not a filter through a clinical team. And in fact, it's really only reporting on the things that the patient feels or experiences, not laboratory abnormalities that may be completely really asymptomatic. And when we look at quality of life and adverse events, I think sometimes we as clinicians focus very much on the adverse events as collected by the CTCAE that maybe there were some mild LFT abnormalities in this particular treatment, or there might be mild neutropenia with that treatment or a mild anemia with this other treatment. All of these, and I emphasize mild, not necessarily noticeable to the patient, but sometimes we feel anxious about these. From your perspective, it sounds like the patient experience, regardless of arm, was actually pretty similar. And perhaps if we can manage the laboratory values, the patients would feel quite comfortable to manage their quality of life, at least with this particular combination.
Neeraj Agarwal: Absolutely. I agree 100% as I always do when you talk about the quality of life assessment scales. But absolutely, I agree with you. It's very reassuring to see our patients reported no worsening of quality of life and no worsening of all this different aspect of one's daily living with the combination therapy.
Alicia Morgans: Wonderful.
Neeraj Agarwal: So I'm so glad, PROs, patient reported outcomes are valued more and more by the different organizations and they are invited for all presentations. And I think this basically tells us how much more careful, how much more cognizant we are about how our patients feel and not what CTCA grading tells us.
Alicia Morgans: Wonderful. Well, thank you so much for sharing your expertise, for working with your team to bring this to ASCO 2023. And thank you so much today for your expertise and your willingness to talk about it. I appreciate your time.
Neeraj Agarwal: Thank you very much.