Talazoparib Monotherapy in Men with DNA Damage Response Alterations (TALAPRO-1) - Celestia Higano
April 1, 2021
Talazoparib, a PARP inhibitor was used in the single-agent phase II TALAPRO study looking at metastatic castration-resistant prostate cancer patients who had a variety of DNA damage response alterations. The patient population in this study was a very heavily pretreated group of patients who had, at least one taxane, as well as one of the AR, directed therapies. In this conversation with Alicia Morgans, MD, MPH, Celestia (Tia) Higano, MD, FACP highlights this study and the planned interim analysis (cut-off Dec 12, 2019) that was presented at the 2021 GU ASCO meeting where encouraging antitumor activity in this docetaxel-pretreated mCRPC patient population with BRCA1/2 alterations were reported.
Biographies:
Celestia S. Higano, MD, FACP, Professor, Division of Medical Oncology, The University of Washington School of Medicine, University of Washington and Fred Hutchinson Cancer Research Center, Seattle, Washington
Alicia Morgans, MD, MPH Associate Professor of Medicine in the Division of Hematology/Oncology at the Northwestern University Feinberg School of Medicine in Chicago, Illinois.
Biographies:
Celestia S. Higano, MD, FACP, Professor, Division of Medical Oncology, The University of Washington School of Medicine, University of Washington and Fred Hutchinson Cancer Research Center, Seattle, Washington
Alicia Morgans, MD, MPH Associate Professor of Medicine in the Division of Hematology/Oncology at the Northwestern University Feinberg School of Medicine in Chicago, Illinois.
Read the Full Video Transcript
Alicia Morgans: Hi. My name is Alicia Morgans, GU medical oncologist and associate professor of medicine at Northwestern University. I'm so excited to have here with me today, a friend and colleague, Dr. Tia Higano, who is a professor and a GU Medical Oncologist. Thank you so much for being here with me today, Dr. Higano.
Tia Higano: It's nice to be with you, Alicia.
Alicia Morgans: Wonderful. So I wanted to talk to you, Tia, about the TALAPRO study, a study that has been reported at GU ASCO 2021, and you participated in this trial. Can you tell us a little bit about it, please?
Tia Higano: Yes. So, talazoparib is the PARP inhibitor that we used in the TALAPRO study. And this was a single-agent phase II study looking at patients who had a variety of DDR mutations, I believe there were 11 different ones that were listed in the protocol. And they had to have measurable soft tissue disease at study entry, and also, this is a very heavily pretreated group of patients who had both, at least one taxane, as well as one of the AR, directed therapies. So, if you think of the other trials that have been reported with PARP inhibitors, olaparib, and rucaparib, this population is more similar to the rucaparib population that was heavily pretreated, whereas olaparib had a combination of, taxane pretreated and taxane naive. So, this was a pretty heavily pretreated group of patients. Similar to the other PARP trials, there is a very strong response, especially in patients with BRCA1/2 mutations, and this has been true across all of the PARP inhibitors. But I think unlike some of the other trials, there were also some reports of activities in patients with ATM mutations in PALB2.
You know, there's sort of two camps out there. Those who think PARPs should not be used in patients with ATM mutations and those who think that, well, maybe they should. And I think this trial tells us that maybe we should keep our minds open for more data, at least in the phase III sets. So again, this is a phase II trial as was the rucaparib trial compared to the olaparib, which was a phase III. The toxicities that we are seeing in this trial were pretty similar to what you see with the other PARPs; anemia, GI symptoms, nausea, decreased appetite, fatigue, asthenia.
The nausea is really, I mean, it's reported of course, but I think in clinical practice, we've learned that if we treat patients with antiemetics like on ondansetron, for example, that they really do quite well. And that even though we report a lot of, that was one of the main top toxicities in the trial on a practical level, I don't think it is as much of an issue for our patients. So, I think, I think the thing we learned from this trial is yes, BRCA 1/2 patients are, much more sensitive than the other DDR mutations, but we are not crossing off ATM yet just because we did see, I think it was almost 11 1/2% overall response rates in the talazoparib trial. So, that is compared to zero in some of the other trials.
And I think the other thing is that there is actually a proposed rationale for that, which is that, amongst the PARP inhibitors, at least in the lab, talazoparib has more so-called PARP trapping abilities. And that may, since ATM is responsible for dealing with the replication of the DNA forks and a mutation there, could lead to a problem. The fact that PARP can really... the PARP inhibitor can really stick there and interfere with that more, might be the rationale for this apparent increase in patients with ATM mutations. So I think, we still have a lot to learn about PARP inhibitors, and I, for one, I'm remaining cautious about whether or not we should eliminate patients with certain DDR mutations from treatment with a PARP inhibitor, whether it's talazoparib or any other one.
Alicia Morgans: So I think that is a great point and it is interesting, and so this was a single-arm phase II. So everybody who came in, and these were all, like you said, "more heavily pretreated patients", "more like the TRITON2 population" who had already had an AR targeted agent and a taxane, they were treated and there was you are right. It's like an 11.8% or almost 12% response rate. And that is a measurable disease response rate in those patients with ATM, which is really interesting. And when we look at the composite rate, which includes a PSA response that goes up even higher in this population, and if talazoparib does have more PARP trapping ability , then perhaps that is the biological way that this drug would be a little bit different. And I think that is really interesting, and exciting, and I'm glad that we are continuing to investigate that because it didn't quite seem to pan out, at least in the initial reports from PROfound, although until PARP B maybe there was some, ATM response that, so and then we don't have approval for those patients for rucaparib based on TRITON, so.
Tia Higano: No.
Alicia Morgans: It is really interesting though.
Tia Higano: Yeah, absolutely. And again, I think we should be cautious going forward and there is a lot of controversies now about why, why did the FDA approve olaparib for all these gene alterations, some of which were not even tested in the trial, whereas rucaparib got the short end of the stick in a way I suppose. But again, I think we are not the only ones learning. I think the FDA will be learning. I think we all have a lot to learn. Certainly, all DDR mutations we know are not the same and there may be other, mutations that are going on that we don't even measure for that might have an effect on whether PARP inhibitors are successful in our patients.
Alicia Morgans: Absolutely. And you know, the other subgroup that your group reported out was PALB2, which seems in, in multiple cohorts to have some maybe intermediate type effect, maybe not necessarily as strong as BRCA2, but in some exploratory analysis, it almost looks as strong as BRCA2 and your analysis here in TALAPRO. It also looked like it had a pretty strong response rate and then it kind of combined response rates. So, PALB2 also appears to be one of those alterations that may sensitize patients.
Tia Higano: Yes, exactly. I think the other thing I didn't mention, which I probably should, is we also had another report at GU ASCO, which was on the quality of life reports from this trial, and actually, it was quite good. I think, in fact, these heavily pretreated patients actually reported an increase in their quality of life measures overall and I think, when you, and that includes by the way pain, which I think is probably one of the most important issues for these patients. So it's not just a numbers response or a shrinkage of measurable disease. It is also actually, something that makes a difference to the patients that they feel themselves.
Alicia Morgans: And I really commend you and the investigators for including that quality of life metrics within a phase II. I can't tell you how many times I've been faced with the feedback that we actually don't need quality of life measures in phase two trials. And I actually disagree on so many levels, but the main level is that it is important, I think always for us to consider our efficacy data in the context of the way that the patient feels and the efficacy data can be strengthened or really shattered by that quality of life data. So I really commend you and I appreciate you, and I appreciate that you are able to interpret this as not just a measurable response, but beneficial to patients, at least in terms of pain control, even perhaps when they are not having a shrinkage of measurable disease. So that is really interesting and exciting. When you are treating patients in the clinic, how do patients tend to feel from your perspective? And you've already said that the adverse events seem relatively manageable in terms of some cytopenias and things like that. Do patients tend to feel pretty well in your opinion?
Tia Higano: Yes. I've been impressed by the fact that first of all, it's like all things, if you warn patients of what to expect, and in this case, we're sort of prophylaxis against nausea or treating it very early and they are already looking out for the symptoms and they have the wherewithal to treat it themselves because you've given them a prescription. I think that goes a long way to helping improve the tolerance of PARPs. And the other thing is, it's in some cases, some of these adverse events do tend to wear off over time. So, I think patients know those things. They can have some control over treating the GI side effects in particular. It's really important.
Alicia Morgans: I agree, the medicine only works when it gets into the patient. And so whatever we can do to help that process and help the patient feel well while we're doing it is going to help improve the efficacy of the drug so that, and make your patients feel better, which is important too. So that, all that will make sense. So if you had to sum up what you and the team presented at GU ASCO 2021 in relation to TALAPRO, what would it be?
Tia Higano: I think that the message I would want people to take away is that this was a heavily pretreated group of patients who tolerated the talazoparib fairly well based not only on the AE profile but on the formal pro, pros that were obtained during the trial. There is a spectrum of responses, like we see in other PARPs, particularly with BRCA1, BRCA2, having the highest response rates, but then also PALB2, an ATM, which is a little different from what we've seen from the other PARPs. And yeah, I mean, I think those are the main messages plus, stay tuned because we are going to be seeing and gaining more information about this particular PARP as well as others over time.
Alicia Morgans: Fantastic, and it's always important to have options and particularly options that may have differential benefits be used in different settings, or maybe even for different patients. And I appreciate you and the team for continuing to push this forward. And I hope at some point we will have another option for a PARP inhibitor for our patients and maybe even a better option for some. So thank you so much for your research, for your time today, your expertise. We always appreciate it.
Tia Higano: You're very welcome, Alicia. Thank you.
Alicia Morgans: Hi. My name is Alicia Morgans, GU medical oncologist and associate professor of medicine at Northwestern University. I'm so excited to have here with me today, a friend and colleague, Dr. Tia Higano, who is a professor and a GU Medical Oncologist. Thank you so much for being here with me today, Dr. Higano.
Tia Higano: It's nice to be with you, Alicia.
Alicia Morgans: Wonderful. So I wanted to talk to you, Tia, about the TALAPRO study, a study that has been reported at GU ASCO 2021, and you participated in this trial. Can you tell us a little bit about it, please?
Tia Higano: Yes. So, talazoparib is the PARP inhibitor that we used in the TALAPRO study. And this was a single-agent phase II study looking at patients who had a variety of DDR mutations, I believe there were 11 different ones that were listed in the protocol. And they had to have measurable soft tissue disease at study entry, and also, this is a very heavily pretreated group of patients who had both, at least one taxane, as well as one of the AR, directed therapies. So, if you think of the other trials that have been reported with PARP inhibitors, olaparib, and rucaparib, this population is more similar to the rucaparib population that was heavily pretreated, whereas olaparib had a combination of, taxane pretreated and taxane naive. So, this was a pretty heavily pretreated group of patients. Similar to the other PARP trials, there is a very strong response, especially in patients with BRCA1/2 mutations, and this has been true across all of the PARP inhibitors. But I think unlike some of the other trials, there were also some reports of activities in patients with ATM mutations in PALB2.
You know, there's sort of two camps out there. Those who think PARPs should not be used in patients with ATM mutations and those who think that, well, maybe they should. And I think this trial tells us that maybe we should keep our minds open for more data, at least in the phase III sets. So again, this is a phase II trial as was the rucaparib trial compared to the olaparib, which was a phase III. The toxicities that we are seeing in this trial were pretty similar to what you see with the other PARPs; anemia, GI symptoms, nausea, decreased appetite, fatigue, asthenia.
The nausea is really, I mean, it's reported of course, but I think in clinical practice, we've learned that if we treat patients with antiemetics like on ondansetron, for example, that they really do quite well. And that even though we report a lot of, that was one of the main top toxicities in the trial on a practical level, I don't think it is as much of an issue for our patients. So, I think, I think the thing we learned from this trial is yes, BRCA 1/2 patients are, much more sensitive than the other DDR mutations, but we are not crossing off ATM yet just because we did see, I think it was almost 11 1/2% overall response rates in the talazoparib trial. So, that is compared to zero in some of the other trials.
And I think the other thing is that there is actually a proposed rationale for that, which is that, amongst the PARP inhibitors, at least in the lab, talazoparib has more so-called PARP trapping abilities. And that may, since ATM is responsible for dealing with the replication of the DNA forks and a mutation there, could lead to a problem. The fact that PARP can really... the PARP inhibitor can really stick there and interfere with that more, might be the rationale for this apparent increase in patients with ATM mutations. So I think, we still have a lot to learn about PARP inhibitors, and I, for one, I'm remaining cautious about whether or not we should eliminate patients with certain DDR mutations from treatment with a PARP inhibitor, whether it's talazoparib or any other one.
Alicia Morgans: So I think that is a great point and it is interesting, and so this was a single-arm phase II. So everybody who came in, and these were all, like you said, "more heavily pretreated patients", "more like the TRITON2 population" who had already had an AR targeted agent and a taxane, they were treated and there was you are right. It's like an 11.8% or almost 12% response rate. And that is a measurable disease response rate in those patients with ATM, which is really interesting. And when we look at the composite rate, which includes a PSA response that goes up even higher in this population, and if talazoparib does have more PARP trapping ability , then perhaps that is the biological way that this drug would be a little bit different. And I think that is really interesting, and exciting, and I'm glad that we are continuing to investigate that because it didn't quite seem to pan out, at least in the initial reports from PROfound, although until PARP B maybe there was some, ATM response that, so and then we don't have approval for those patients for rucaparib based on TRITON, so.
Tia Higano: No.
Alicia Morgans: It is really interesting though.
Tia Higano: Yeah, absolutely. And again, I think we should be cautious going forward and there is a lot of controversies now about why, why did the FDA approve olaparib for all these gene alterations, some of which were not even tested in the trial, whereas rucaparib got the short end of the stick in a way I suppose. But again, I think we are not the only ones learning. I think the FDA will be learning. I think we all have a lot to learn. Certainly, all DDR mutations we know are not the same and there may be other, mutations that are going on that we don't even measure for that might have an effect on whether PARP inhibitors are successful in our patients.
Alicia Morgans: Absolutely. And you know, the other subgroup that your group reported out was PALB2, which seems in, in multiple cohorts to have some maybe intermediate type effect, maybe not necessarily as strong as BRCA2, but in some exploratory analysis, it almost looks as strong as BRCA2 and your analysis here in TALAPRO. It also looked like it had a pretty strong response rate and then it kind of combined response rates. So, PALB2 also appears to be one of those alterations that may sensitize patients.
Tia Higano: Yes, exactly. I think the other thing I didn't mention, which I probably should, is we also had another report at GU ASCO, which was on the quality of life reports from this trial, and actually, it was quite good. I think, in fact, these heavily pretreated patients actually reported an increase in their quality of life measures overall and I think, when you, and that includes by the way pain, which I think is probably one of the most important issues for these patients. So it's not just a numbers response or a shrinkage of measurable disease. It is also actually, something that makes a difference to the patients that they feel themselves.
Alicia Morgans: And I really commend you and the investigators for including that quality of life metrics within a phase II. I can't tell you how many times I've been faced with the feedback that we actually don't need quality of life measures in phase two trials. And I actually disagree on so many levels, but the main level is that it is important, I think always for us to consider our efficacy data in the context of the way that the patient feels and the efficacy data can be strengthened or really shattered by that quality of life data. So I really commend you and I appreciate you, and I appreciate that you are able to interpret this as not just a measurable response, but beneficial to patients, at least in terms of pain control, even perhaps when they are not having a shrinkage of measurable disease. So that is really interesting and exciting. When you are treating patients in the clinic, how do patients tend to feel from your perspective? And you've already said that the adverse events seem relatively manageable in terms of some cytopenias and things like that. Do patients tend to feel pretty well in your opinion?
Tia Higano: Yes. I've been impressed by the fact that first of all, it's like all things, if you warn patients of what to expect, and in this case, we're sort of prophylaxis against nausea or treating it very early and they are already looking out for the symptoms and they have the wherewithal to treat it themselves because you've given them a prescription. I think that goes a long way to helping improve the tolerance of PARPs. And the other thing is, it's in some cases, some of these adverse events do tend to wear off over time. So, I think patients know those things. They can have some control over treating the GI side effects in particular. It's really important.
Alicia Morgans: I agree, the medicine only works when it gets into the patient. And so whatever we can do to help that process and help the patient feel well while we're doing it is going to help improve the efficacy of the drug so that, and make your patients feel better, which is important too. So that, all that will make sense. So if you had to sum up what you and the team presented at GU ASCO 2021 in relation to TALAPRO, what would it be?
Tia Higano: I think that the message I would want people to take away is that this was a heavily pretreated group of patients who tolerated the talazoparib fairly well based not only on the AE profile but on the formal pro, pros that were obtained during the trial. There is a spectrum of responses, like we see in other PARPs, particularly with BRCA1, BRCA2, having the highest response rates, but then also PALB2, an ATM, which is a little different from what we've seen from the other PARPs. And yeah, I mean, I think those are the main messages plus, stay tuned because we are going to be seeing and gaining more information about this particular PARP as well as others over time.
Alicia Morgans: Fantastic, and it's always important to have options and particularly options that may have differential benefits be used in different settings, or maybe even for different patients. And I appreciate you and the team for continuing to push this forward. And I hope at some point we will have another option for a PARP inhibitor for our patients and maybe even a better option for some. So thank you so much for your research, for your time today, your expertise. We always appreciate it.
Tia Higano: You're very welcome, Alicia. Thank you.