Exploring Prostate Cancer Data from GU ASCO 2023: Triplet Therapy and PARP Inhibitors in Focus - Cora Sternberg
March 1, 2023
Cora Sternberg joins Alicia Morgans to review prostate cancer session data presented from GU ASCO 2023. Dr. Sternberg begins by discussing the ARASENS study, which explored the efficacy and safety of triplet therapy with darolutamide, chemotherapy, and ADT compared to chemotherapy and ADT alone in metastatic hormone-sensitive prostate cancer patients. The study analyzed the outcomes based on disease volume and risk. They found that triplet therapy provided clear benefits to patients, challenging the notion that it should only be given to those with synchronous metastases. They also discussed the updates on PARP inhibitors, particularly talazoparib and enzalutamide combination therapy, and the need for more data to determine the optimal patient population for these inhibitors. The conversation highlighted the importance of individualized treatment decisions, considering factors such as age, prior exposures, and genomic profiles. They acknowledged the need for further research to address sequencing, long-term side effects, and cost-effectiveness. Overall, they emphasized the ongoing efforts to refine treatment approaches and optimize patient outcomes in prostate cancer.
Biographies:
Cora Sternberg MD, FACP Professor of Medicine and Clinical Director of the Israel Englander Institute for Precision Medicine, Weill Cornell Medicine, New York.
Alicia Morgans, MD, MPH, Genitourinary Medical Oncologist, Medical Director of Survivorship Program at Dana-Farber Cancer Institute, Boston, Massachusetts
Biographies:
Cora Sternberg MD, FACP Professor of Medicine and Clinical Director of the Israel Englander Institute for Precision Medicine, Weill Cornell Medicine, New York.
Alicia Morgans, MD, MPH, Genitourinary Medical Oncologist, Medical Director of Survivorship Program at Dana-Farber Cancer Institute, Boston, Massachusetts
Related Content:
ASCO GU 2023: Efficacy and Safety of Darolutamide in Combination with ADT and Docetaxel by Disease Volume and Disease Risk in the Phase 3 ARASENS Study
ASCO GU 2023: Final Overall Survival in PROpel: Abiraterone and Olaparib Versus Abiraterone and Placebo as First-Line Therapy for mCRPC
ASCO GU 2023: TALAPRO-2: Phase 3 Study of Talazoparib + Enzalutamide Versus Placebo + ENZA as First-Line Treatment in Patients with mCRPC
ASCO GU 2023: PARP Inhibitors in Metastatic Castration Resistant Prostate Cancer (mCRPC): TRITON3 and TALAPRO-2
ASCO GU 2023: Efficacy and Safety of Darolutamide in Combination with ADT and Docetaxel by Disease Volume and Disease Risk in the Phase 3 ARASENS Study
ASCO GU 2023: Final Overall Survival in PROpel: Abiraterone and Olaparib Versus Abiraterone and Placebo as First-Line Therapy for mCRPC
ASCO GU 2023: TALAPRO-2: Phase 3 Study of Talazoparib + Enzalutamide Versus Placebo + ENZA as First-Line Treatment in Patients with mCRPC
ASCO GU 2023: PARP Inhibitors in Metastatic Castration Resistant Prostate Cancer (mCRPC): TRITON3 and TALAPRO-2
Read the Full Video Transcript
Alicia Morgans: Hi. I'm so excited to be here with Professor Cora Sternberg. Thank you so much for talking with me today.
Cora Sternberg: My pleasure.
Alicia Morgans: Wonderful. So I wanted to review some data from GU ASCO 2023 with you. Really some very heavy hitting work has been presented, and one of the most interesting pieces was the ARASENS data, looking at the data that we've seen before, but broken down to help inform us on how patients might do by high and low volume status and also by high and low risk status. So can you tell us a little bit about this?
Cora Sternberg: So today we heard Maha Hussein present the ARASENS study, which has been already presented at prior meetings and has been published. And it's a very interesting study in which triplet therapy with chemotherapy and darolutamide and ADT is compared to chemotherapy and ADT without the darolutamide. What we saw in the past was a clear benefit for patients who received the triplet therapy, but when we looked at the patients in prior studies, it seemed that the majority of patients were patients who presented with synchronous metastasis, widely metastatic disease, initially more than 80% of them not metachronous metastases that slowly showed up. So there was always a question of do we need this triplet therapy for everyone? Do we need the patients for the high risk patients as defined in the CHAARTED trial by patients with visceral metastases and more than four bone metastases outside of the axial skeleton?
And what about the high and low risk patients as defined by Fizazi in his trial, in the LATITUDE trial, where they looked at Gleason score, maybe even picking up a more aggressive group of patients. And what they saw in this trial was that the majority of patients did in fact have high risk, and also had high volume according to CHAARTED. And also some 70% had high risk according to the LATITUDE criteria. But when they looked both at the high volume and at the low volume and they looked at the high risk and the low risk, it seemed that all of the patients across the board did benefit. It wasn't just a benefit for those patients who had a small amount of disease, that came up slowly.
So what we saw from this trial was that giving a triplet therapy is a good thing to do for those patients who can stand triplet therapy. Obviously we're not giving it to patients in their late eighties or patients with a lot of comorbidities, but I think that this was interesting data because it was really thought that we should only be giving it to those patients who were really sick and coming in with synchronous metastases. So I think that that data was pretty interesting today.
Alicia Morgans: I agree. And what I think is so important, at least in my clinical practice, is identifying whether a patient is going to be fit for chemotherapy or not.
Cora Sternberg: Of course.
Alicia Morgans: And if they are, especially in patients with de novo metastatic disease, and a majority of patients in the study had de novo metastatic disease. I really talk to everybody about it. I do let patients have questions and answers and really try to collaborate with them on what they're ultimately choosing. But so many patients in my practice at least seem to be interested in getting that chemotherapy out of the way upfront, which is what this strategy allows them to do and get through with six cycles versus the 10 that they might see in metastatic CRPC. So many of my patients end up getting this combination. And it was interesting and I think validating to see that I'm not sort of miserving or doing the wrong thing for patients who have low risk disease or who have low volume disease. I think that was useful for my practice at least.
Cora Sternberg: I think so too. And I think that if you looked at the curves, especially the ones who were high and low risk, the curves to the time to CRPC was, they were really wide, wider even than the ones looking at high and low volume. So the time to castration resistance disease is definitely longer in those patients who received the triplet therapy both in the high and the low risk patients. So I thought that those data were interesting new data coming out of the ARASENS trial.
Alicia Morgans: Absolutely. So the other big thing that we saw this morning at ASCO GU was really a lot of information about PARPs. And this continues to be a theme at these meetings and we continue to see updated data. Now certainly we saw the TRITON-3 data, we saw the TALAPRO-2 data and we saw some updated data on PROpel. So lots going on. What do you think with all of these studies that were presented with updates?
Cora Sternberg: Last year at the ASCO GU PROpel data was first presented in which they didn't select patients based on their homologous recombination status. And then there was the MAGNITUDE trial in which they did select patients based on homologous recombination status. And many people were arguing pro and con and thinking that perhaps the MAGNITUDE data was done in a better way than PROpel in which they just treated everyone. And today we heard a couple of trials, we heard an update of the PROpel trial in which Noel Clarke presented overall survival improvement in all patients without necessarily selecting for homologous recombination defects. And we heard the TALAPRO-2 trial. I think this also, helps the PROpel data a little bit because that is talazoparib with enzalutamide as compared to enzalutamide alone, again in non-selected patients, again, showing improvements in progression-free survival. So I think that the data are very interesting.
I'm not sure how compelled we are, all of us, yet to use these PARP inhibitors in everyone that don't have BRCA in particular, that don't have homologous recombination defects. And I think that a little more data needs to be done. There is some preclinical data showing that the PARP inhibitors will improve the results with the novel hormonal therapy, but I don't know that we have enough data to use these drugs that are expensive. They're toxic like chemotherapy. They cause neutropenia. They cause thrombocytopenia. In some cases they cause myeloproliferative disorders. They're not so simple drugs. They are pills, but I don't know if they are to be given to everyone yet. We also don't know, since so many people from so many trials are getting upfront abiraterone or enzalutamide with androgen deprivation therapy, when they have CRPC, should we be continue those drugs and then give a PARP inhibitor or should we just give the PARP inhibitor? Nobody's looked at that kind of sequencing because all of these trials have been done in patients with CRPC who've just had ADT alone. So I think we don't know enough about that yet.
Alicia Morgans: So I think it's totally fair to ask these questions. We saw such really compelling data from the TALAPRO-2 study, which is looking at that talazoparib enzalutamide combination. It does look like at least rPFS seems to be longer, again in an all comers population, and after study eight and PROpel now we have this third study suggesting that synergy. I'm so curious about the biology and how that might be different pathways of resistance are being pushed on when we're using these drugs in combination.
But I think it is a completely fair question to say, do we have enough to really treat an all-comers population? And I do wonder about younger patients, patients that want to be more aggressive and having access to the combination potentially for those highly motivated patients who are comfortable being monitored, have access to both drugs. But I think for many of our patients who are older frailer and for many who have already had exposure to an AR targeted agent, it's definitely something that I think is challenging to the field. How exactly do we use this combination in that group of patients, especially when they've already had an exposure.
Cora Sternberg: If we start earlier, and we should start earlier with earlier trials, and patients live longer and they can be on these drugs for longer times, are we going to be seeing more leukemia and more myeloproliferative disorders? Are we going to have more side effects? We're definitely going to have more costs for sure. But I mean is the cost, is the benefit worth it? We need to figure that all out. And we need to figure out what to do with patients who progress on ADT and a novel hormonal therapy such as abiraterone. Do we switch to enzalutamide and now a new PARP inhibitor? Do we switch the PARP? Do we add a PARP inhibitor? Do we just give the PARP inhibitor? I don't think we know what to do yet. I think we have a lot to study.
Alicia Morgans: Yes, we definitely do.
Cora Sternberg: I have a lot of questions.
Alicia Morgans: Many questions. And I think the other data that we saw that TRITON-3 data, this is a group of patients who were really selected for BRCA1, BRCA2, and ATM alterations with mCRPC, who are now receiving rucaparib in this advanced setting versus an alternate AR targeted agent or this
Cora Sternberg: Or chemotherapy.
Alicia Morgans: Or chemotherapy. So interesting here. They could have had exposure to abiraterone in the earlier state and also to docetaxel, I think. I just found that a really interesting control arm, really interesting that they allowed these prior exposures to abiraterone or to docetaxel. And what are your thoughts on this?
Cora Sternberg: And the ATM patients didn't seem to benefit.
Alicia Morgans: They do not seem to benefit.
Cora Sternberg: Only the BRCA patients seem to benefit.
Alicia Morgans: Yeah.
Cora Sternberg: I think we have a lot more to learn about ATM. We have to study more about clonal hematopoiesis and make sure we're not mixing up ATM and know what we're talking about when we talk about ATM as well. So I think that the ATM story seems to keep falling out with rucaparib, but it doesn't always fall out with olaparib. So I'm not a hundred percent sure about that either.
Alicia Morgans: Yes.
Cora Sternberg: So I think we need to learn a lot more about the genomics and the genetics of what we're doing. In the past we just sort of gave chemotherapy to everyone, and now we're trying to be smarter. We're trying to target people. We're doing next generation sequencing, and we should be using that in a smarter way, I hope.
Alicia Morgans: Well, it was just a wonderful meeting, very vigorous discussion and a great conversation here today. I sincerely appreciate your time and your expertise.
Cora Sternberg: Thank you very much.
Alicia Morgans: Hi. I'm so excited to be here with Professor Cora Sternberg. Thank you so much for talking with me today.
Cora Sternberg: My pleasure.
Alicia Morgans: Wonderful. So I wanted to review some data from GU ASCO 2023 with you. Really some very heavy hitting work has been presented, and one of the most interesting pieces was the ARASENS data, looking at the data that we've seen before, but broken down to help inform us on how patients might do by high and low volume status and also by high and low risk status. So can you tell us a little bit about this?
Cora Sternberg: So today we heard Maha Hussein present the ARASENS study, which has been already presented at prior meetings and has been published. And it's a very interesting study in which triplet therapy with chemotherapy and darolutamide and ADT is compared to chemotherapy and ADT without the darolutamide. What we saw in the past was a clear benefit for patients who received the triplet therapy, but when we looked at the patients in prior studies, it seemed that the majority of patients were patients who presented with synchronous metastasis, widely metastatic disease, initially more than 80% of them not metachronous metastases that slowly showed up. So there was always a question of do we need this triplet therapy for everyone? Do we need the patients for the high risk patients as defined in the CHAARTED trial by patients with visceral metastases and more than four bone metastases outside of the axial skeleton?
And what about the high and low risk patients as defined by Fizazi in his trial, in the LATITUDE trial, where they looked at Gleason score, maybe even picking up a more aggressive group of patients. And what they saw in this trial was that the majority of patients did in fact have high risk, and also had high volume according to CHAARTED. And also some 70% had high risk according to the LATITUDE criteria. But when they looked both at the high volume and at the low volume and they looked at the high risk and the low risk, it seemed that all of the patients across the board did benefit. It wasn't just a benefit for those patients who had a small amount of disease, that came up slowly.
So what we saw from this trial was that giving a triplet therapy is a good thing to do for those patients who can stand triplet therapy. Obviously we're not giving it to patients in their late eighties or patients with a lot of comorbidities, but I think that this was interesting data because it was really thought that we should only be giving it to those patients who were really sick and coming in with synchronous metastases. So I think that that data was pretty interesting today.
Alicia Morgans: I agree. And what I think is so important, at least in my clinical practice, is identifying whether a patient is going to be fit for chemotherapy or not.
Cora Sternberg: Of course.
Alicia Morgans: And if they are, especially in patients with de novo metastatic disease, and a majority of patients in the study had de novo metastatic disease. I really talk to everybody about it. I do let patients have questions and answers and really try to collaborate with them on what they're ultimately choosing. But so many patients in my practice at least seem to be interested in getting that chemotherapy out of the way upfront, which is what this strategy allows them to do and get through with six cycles versus the 10 that they might see in metastatic CRPC. So many of my patients end up getting this combination. And it was interesting and I think validating to see that I'm not sort of miserving or doing the wrong thing for patients who have low risk disease or who have low volume disease. I think that was useful for my practice at least.
Cora Sternberg: I think so too. And I think that if you looked at the curves, especially the ones who were high and low risk, the curves to the time to CRPC was, they were really wide, wider even than the ones looking at high and low volume. So the time to castration resistance disease is definitely longer in those patients who received the triplet therapy both in the high and the low risk patients. So I thought that those data were interesting new data coming out of the ARASENS trial.
Alicia Morgans: Absolutely. So the other big thing that we saw this morning at ASCO GU was really a lot of information about PARPs. And this continues to be a theme at these meetings and we continue to see updated data. Now certainly we saw the TRITON-3 data, we saw the TALAPRO-2 data and we saw some updated data on PROpel. So lots going on. What do you think with all of these studies that were presented with updates?
Cora Sternberg: Last year at the ASCO GU PROpel data was first presented in which they didn't select patients based on their homologous recombination status. And then there was the MAGNITUDE trial in which they did select patients based on homologous recombination status. And many people were arguing pro and con and thinking that perhaps the MAGNITUDE data was done in a better way than PROpel in which they just treated everyone. And today we heard a couple of trials, we heard an update of the PROpel trial in which Noel Clarke presented overall survival improvement in all patients without necessarily selecting for homologous recombination defects. And we heard the TALAPRO-2 trial. I think this also, helps the PROpel data a little bit because that is talazoparib with enzalutamide as compared to enzalutamide alone, again in non-selected patients, again, showing improvements in progression-free survival. So I think that the data are very interesting.
I'm not sure how compelled we are, all of us, yet to use these PARP inhibitors in everyone that don't have BRCA in particular, that don't have homologous recombination defects. And I think that a little more data needs to be done. There is some preclinical data showing that the PARP inhibitors will improve the results with the novel hormonal therapy, but I don't know that we have enough data to use these drugs that are expensive. They're toxic like chemotherapy. They cause neutropenia. They cause thrombocytopenia. In some cases they cause myeloproliferative disorders. They're not so simple drugs. They are pills, but I don't know if they are to be given to everyone yet. We also don't know, since so many people from so many trials are getting upfront abiraterone or enzalutamide with androgen deprivation therapy, when they have CRPC, should we be continue those drugs and then give a PARP inhibitor or should we just give the PARP inhibitor? Nobody's looked at that kind of sequencing because all of these trials have been done in patients with CRPC who've just had ADT alone. So I think we don't know enough about that yet.
Alicia Morgans: So I think it's totally fair to ask these questions. We saw such really compelling data from the TALAPRO-2 study, which is looking at that talazoparib enzalutamide combination. It does look like at least rPFS seems to be longer, again in an all comers population, and after study eight and PROpel now we have this third study suggesting that synergy. I'm so curious about the biology and how that might be different pathways of resistance are being pushed on when we're using these drugs in combination.
But I think it is a completely fair question to say, do we have enough to really treat an all-comers population? And I do wonder about younger patients, patients that want to be more aggressive and having access to the combination potentially for those highly motivated patients who are comfortable being monitored, have access to both drugs. But I think for many of our patients who are older frailer and for many who have already had exposure to an AR targeted agent, it's definitely something that I think is challenging to the field. How exactly do we use this combination in that group of patients, especially when they've already had an exposure.
Cora Sternberg: If we start earlier, and we should start earlier with earlier trials, and patients live longer and they can be on these drugs for longer times, are we going to be seeing more leukemia and more myeloproliferative disorders? Are we going to have more side effects? We're definitely going to have more costs for sure. But I mean is the cost, is the benefit worth it? We need to figure that all out. And we need to figure out what to do with patients who progress on ADT and a novel hormonal therapy such as abiraterone. Do we switch to enzalutamide and now a new PARP inhibitor? Do we switch the PARP? Do we add a PARP inhibitor? Do we just give the PARP inhibitor? I don't think we know what to do yet. I think we have a lot to study.
Alicia Morgans: Yes, we definitely do.
Cora Sternberg: I have a lot of questions.
Alicia Morgans: Many questions. And I think the other data that we saw that TRITON-3 data, this is a group of patients who were really selected for BRCA1, BRCA2, and ATM alterations with mCRPC, who are now receiving rucaparib in this advanced setting versus an alternate AR targeted agent or this
Cora Sternberg: Or chemotherapy.
Alicia Morgans: Or chemotherapy. So interesting here. They could have had exposure to abiraterone in the earlier state and also to docetaxel, I think. I just found that a really interesting control arm, really interesting that they allowed these prior exposures to abiraterone or to docetaxel. And what are your thoughts on this?
Cora Sternberg: And the ATM patients didn't seem to benefit.
Alicia Morgans: They do not seem to benefit.
Cora Sternberg: Only the BRCA patients seem to benefit.
Alicia Morgans: Yeah.
Cora Sternberg: I think we have a lot more to learn about ATM. We have to study more about clonal hematopoiesis and make sure we're not mixing up ATM and know what we're talking about when we talk about ATM as well. So I think that the ATM story seems to keep falling out with rucaparib, but it doesn't always fall out with olaparib. So I'm not a hundred percent sure about that either.
Alicia Morgans: Yes.
Cora Sternberg: So I think we need to learn a lot more about the genomics and the genetics of what we're doing. In the past we just sort of gave chemotherapy to everyone, and now we're trying to be smarter. We're trying to target people. We're doing next generation sequencing, and we should be using that in a smarter way, I hope.
Alicia Morgans: Well, it was just a wonderful meeting, very vigorous discussion and a great conversation here today. I sincerely appreciate your time and your expertise.
Cora Sternberg: Thank you very much.