Safety and Activity of Alpha-Emitting Ac-225-PSMA-617 Radioligand Therapy in mCRPC That Has Progressed After Lu-177-PSMA, Journal Club – Christopher Wallis & Zachary Klaassen
October 6, 2022
Christopher Wallis and Zachary Klaassen discuss a publication on the activity and adverse effects of Actinium-225 therapy, in advanced metastatic castrate resistant prostate cancer (mCRPC) patients, after the failure of their Lutetium-177 treatment. Dr. Wallis begins by discussing the topic of theranostics, and the difference between the beta-emitter, 177-Lutetium, and the alpha-emitter, 225-Actinium. As this discussion evolves into more of a discussion about the specific trial results, Dr. Klaassen discusses how this trial has a heavily pre-treated patient population, as they are all advanced mCRPC patients. Following the introduction of specific PSA response data, an interesting trend is shown which shows patients who had no response to Lutetium treatment having a strong response to the Actinium treatment. Dr. Klaassen concludes this journal club by discussing a need for weighing the risks factors of this treatment, and the need for a future trial investigating Actinium-PSMA therapy in different prostate cancer disease states.
Biographies:
Christopher J.D. Wallis, MD, Ph.D., Assistant Professor in the Division of Urology at the University of Toronto.
Zachary Klaassen, MD, MSc, Urologic Oncologist, Assistant Professor Surgery/Urology at the Medical College of Georgia at Augusta University, Georgia Cancer Center
Biographies:
Christopher J.D. Wallis, MD, Ph.D., Assistant Professor in the Division of Urology at the University of Toronto.
Zachary Klaassen, MD, MSc, Urologic Oncologist, Assistant Professor Surgery/Urology at the Medical College of Georgia at Augusta University, Georgia Cancer Center
Read the Full Video Transcript
Chris Wallis: Hello, and thank you for joining us in today's journal club. Today, we're discussing a recent publication titled, Activity and Adverse Events of Actinium-225-PSMA-617 in Advanced Metastatic Castration-resistant Prostate Cancer After Failure of Lutetium-177-PSMA. I'm Chris Wallis, a Fellow in Urologic Oncology at Vanderbilt. With me today is Zach Klaassen, an Assistant Professor in the Division of Urology at the Medical College of Georgia.
This is the citation for this recent publication in European Urology.
Theranostics is the principle that we can combine therapy and diagnostics, and there are a whole variety of ways that this is done, but the current focus in prostate cancer looks at the use of targeted radiotherapy and radioisotopes.
So we currently are predominantly using PSMA theranostics, targeting the transmembrane zinc metalloprotease PSMA. This is heavily over-expressed in prostate cancer and allows us to target it for both diagnostic and therapeutic purposes.
PSMA radionuclides can be used and the most commonly used one is 177-Lutetium-PSMA, which is a beta-emitter with limited tissue penetration and low-level gamma emission. And two forms of this are 177-Lutetium-PSMA 617 and PSMA-I&T.
And so this has been studied predominantly in metastatic castrate-resistant prostate cancer, but there are early studies earlier in this disease space. So the first study in advanced prostate cancer that I want to point out is the Lu-PSMA trial, which is a single-arm study of Lutetium demonstrating relatively favorable PSA response rates. And this study prompted the randomized TheraP trial, which compared to Cabazitaxel in patients who had already received chemotherapy and advanced androgen-inhibitors demonstrated a significantly higher PSA response rate among those receiving the Lutetium-PSMA. However, long-term responses to Lutetium-PSMA are relatively limited and most patients progressed and will require further therapy.
So as a result, treatment options are currently being explored in ongoing PSMA targeting with theranostic approaches is one approach of interest. And alpha-emitters, like 225-Actinium, have higher energy transfer and different micro-dissymmetry compared to beta-emitters, such as Lutetium. And they may have efficacy even among patients who developed radioresistance to beta-emitters.
So this study seeks to assess the use of Actinium-225 in patients who'd progressed following Lutetium-177. They accrued patients with metastatic castrate-resistant prostate cancer who've received prior treatment with Abiraterone or Enzalutamide with Taxane-based chemotherapy and with 177-Lutetium-PSMA. [inaudible 00:03:03] to have life expectancy of at least six months and you call it performance status a zero to two. In order to prevent discordance, they had to be avid PSMA expression at tumor states, which exceeded our liver baseline levels and the same imaging must be performed within four weeks prior to initiation of treatment.
A variety of other standard criteria were applied including a renal and marrow function and notably the authors required that there was no evidence of obstruction on renal scan or glomerular nephritis to be included.
So following interdisciplinary tumor board review patients received individualized treatment recommendations and counseling. Where it was deemed appropriate, Actinium-225 was administered by intravenous infusion every eight weeks. And each infusion was followed by restaging scans. ADT was continued throughout and treatment was continued until progression of disease or toxicity. They assessed a variety of anti-tumor outcomes, including maximum PSA decline, PSA progression-free survival, clinical progression-free survival, and overall survival.
In addition, they looked at toxicity and quantify this according to CTCAE version five, as well as according to patient-reported quality of life.
This is the treatment schedule highlighting some of what we've already discussed, but following initial screening and lead in patients should receive their first cycle as an inpatient, and then received a follow-up evaluation on their six cycle that are in their six week. They underwent imaging with PSMA-PET CT, and this, these results were then discussed at an interdisciplinary tumor board and the next cycle was continued. If this was deemed suitable, if evidence of progression or toxicity are limited, further Actinium therapy, a change of treatment, was recommended at that point. And then the cycle is repeated in their similar interval.
In terms of analysis, the authors utilized swimmer's plots to visualize individual treatment outcomes and use the Kaplan-Meier method to look at time to event outcomes. At this point in time, I'll hand it over to Zach to take us through the results of this study.
Zach Klaassen: Thanks Chris. So this is the baseline characteristics for this trial. You can see there is 26 patients included with a median age of 72.5 years, a median PSA of 331 and a median ECOG score of one. Not surprisingly, the Gleason score meeting was eight with a range of seven to nine. When we look at the prior systemic treatments, you can see here that the majority of these patients also receive previous Docetaxel, 54% received Cabazitaxel, 88% received Abiratorine, 85% received Enzalutamide, 73% received Abiraterone and Enzalutamide, and 23% received Radium-223. Of course, as mentioned a hundred percent of these patients previously received a Lutetium-PSMA treatment. I'm looking at prior lines of therapy. There was actually five patients that had eight lines of therapy. Two had seven, six patients had six, five had five, six patients had four lines of treatment and two patients at three prior lines of treatment. So clearly a very heavily pretreated population for this study. When looking at the site of metastases, overall 88% of patients had lymph node involvement, 100% had bone involvement, 42% had visceral involvement most commonly in the lung at 23% and in liver at 19%.
These are the results looking at the hematological and non-hematological adverse events after the Actinium treatment. And so the left has baseline parameters for focus on the right, which is treatment-emergent adverse events, and looking at grade four and grade three, we can see that anemia was in 31% grade three and 4% grade four. Leukopenia was 27% grade three, thrombocytopenia was 12% grade three and 8% grade four, and xerostomia was 12% grade two, and no grade three or grade four adverse reactions.
This is a swimmer's plot of the mCRPC treatments. And the summary here, as you can see, as I mentioned, the previous slides is a very heavily pretreated population with each different color box representing a different line of therapy. And you can see that there was about three or four patients that had a treatment and survival of between 75 and a hundred months.
The waterfall plot looks at the maximum PSA decline after Actinium radioligand therapy. And I've highlighted here several points on the right. You can see here that 65% of patients had a PSA decline of greater than 50% and actually 12% of patients had a PSA decline of greater than 90% with only three patients having a PSA increase after the Actinium treatment.
This looks at the waterfall plot of the maximum PSA decline after Actinium radioligand therapy compared to Lutetium radioligand therapy. So the Lutetium is in green. And we'll go through that. You can see here that majority of the patients did have a PSA response. However, there was a handful of patients that actually increased PSA, which were deemed failures. And then in blue for the same patients, you can see the PSA response following the Lutetium. And what's impressive is on this side of the graph here, and all these patients that did not have a response was Lutetium, majority of these had a PSA response after a treatment with Actinium.
These three capital markers look at the PSA progression-free survival, the clinical progression-free survival and overall survival after initiation of Actinium-PSMA radioligand therapy on the left, the PSA progression-free survival was 3.5 months. The median clinical progression-free survival in the middle was 4.1 months. And on the right, the median overall survival was 7.7 months.
This then delineates patients with and without liver metastases looking at the same metrics after Actinium-PSMA treatment. On the left, you can see patients without liver metastases had a PSA progression-free survival of 4.0 months compared to 1.9 months in patients with liver metastases. For clinical progression-free survival without liver metastases, 5.2 months compared to 1.8 months for those with liver metastases. And on the far right overall survival, 10.4 months for patients without liver metastases compared to those with liver metastases have an overall survival of 4.3 months. So certainly a clear delineation when stratified by liver metastases yes or no.
So several discussion points from this study in this heavily pretreated population with a meeting of six prior mCRPC therapies, Actinium-PSMA treatment led to a maximum PSA decline of greater than 50% in 65% of patients. However, the frequency of PSA response and duration of response as measured by PSA progression-free survival, clinical progression-free survival, and overall survival were lower than in the previous reports for Actinium-PSMA treatment in less advanced and pretreated mCRPC patients. In this trial, the maximum PSA decline was a greater than 90% was only 12% compared to 40 to 82% of patients in previous studies. Previously known prognostic factors for other mCRPC therapies do apply to the Actinium-PSMA treatment in terms of as a demonstrator in the previous slides, the liver metastases being a very poor prognostic factor.
So in conclusion, Actinium-PSMA treatment has activity in late mCRPC after Lutetium-PSMA failure. However, the duration of tumor responses was shorter than those observed in earlier disease states. Xerostomia caused by Actinium-PSMA can substantially impact patient quality of life. And patients with liver metastases showed very poor outcomes. And the benefits of Actinium-PSMA in this population should be weighed carefully. And finally prospective trial systematically investing in the role of Actinium-PSMA therapy in different prostate cancer disease states is also needed. Thank you very much. We hope you enjoyed this [inaudible 00:11:46] of today journal club.
Chris Wallis: Hello, and thank you for joining us in today's journal club. Today, we're discussing a recent publication titled, Activity and Adverse Events of Actinium-225-PSMA-617 in Advanced Metastatic Castration-resistant Prostate Cancer After Failure of Lutetium-177-PSMA. I'm Chris Wallis, a Fellow in Urologic Oncology at Vanderbilt. With me today is Zach Klaassen, an Assistant Professor in the Division of Urology at the Medical College of Georgia.
This is the citation for this recent publication in European Urology.
Theranostics is the principle that we can combine therapy and diagnostics, and there are a whole variety of ways that this is done, but the current focus in prostate cancer looks at the use of targeted radiotherapy and radioisotopes.
So we currently are predominantly using PSMA theranostics, targeting the transmembrane zinc metalloprotease PSMA. This is heavily over-expressed in prostate cancer and allows us to target it for both diagnostic and therapeutic purposes.
PSMA radionuclides can be used and the most commonly used one is 177-Lutetium-PSMA, which is a beta-emitter with limited tissue penetration and low-level gamma emission. And two forms of this are 177-Lutetium-PSMA 617 and PSMA-I&T.
And so this has been studied predominantly in metastatic castrate-resistant prostate cancer, but there are early studies earlier in this disease space. So the first study in advanced prostate cancer that I want to point out is the Lu-PSMA trial, which is a single-arm study of Lutetium demonstrating relatively favorable PSA response rates. And this study prompted the randomized TheraP trial, which compared to Cabazitaxel in patients who had already received chemotherapy and advanced androgen-inhibitors demonstrated a significantly higher PSA response rate among those receiving the Lutetium-PSMA. However, long-term responses to Lutetium-PSMA are relatively limited and most patients progressed and will require further therapy.
So as a result, treatment options are currently being explored in ongoing PSMA targeting with theranostic approaches is one approach of interest. And alpha-emitters, like 225-Actinium, have higher energy transfer and different micro-dissymmetry compared to beta-emitters, such as Lutetium. And they may have efficacy even among patients who developed radioresistance to beta-emitters.
So this study seeks to assess the use of Actinium-225 in patients who'd progressed following Lutetium-177. They accrued patients with metastatic castrate-resistant prostate cancer who've received prior treatment with Abiraterone or Enzalutamide with Taxane-based chemotherapy and with 177-Lutetium-PSMA. [inaudible 00:03:03] to have life expectancy of at least six months and you call it performance status a zero to two. In order to prevent discordance, they had to be avid PSMA expression at tumor states, which exceeded our liver baseline levels and the same imaging must be performed within four weeks prior to initiation of treatment.
A variety of other standard criteria were applied including a renal and marrow function and notably the authors required that there was no evidence of obstruction on renal scan or glomerular nephritis to be included.
So following interdisciplinary tumor board review patients received individualized treatment recommendations and counseling. Where it was deemed appropriate, Actinium-225 was administered by intravenous infusion every eight weeks. And each infusion was followed by restaging scans. ADT was continued throughout and treatment was continued until progression of disease or toxicity. They assessed a variety of anti-tumor outcomes, including maximum PSA decline, PSA progression-free survival, clinical progression-free survival, and overall survival.
In addition, they looked at toxicity and quantify this according to CTCAE version five, as well as according to patient-reported quality of life.
This is the treatment schedule highlighting some of what we've already discussed, but following initial screening and lead in patients should receive their first cycle as an inpatient, and then received a follow-up evaluation on their six cycle that are in their six week. They underwent imaging with PSMA-PET CT, and this, these results were then discussed at an interdisciplinary tumor board and the next cycle was continued. If this was deemed suitable, if evidence of progression or toxicity are limited, further Actinium therapy, a change of treatment, was recommended at that point. And then the cycle is repeated in their similar interval.
In terms of analysis, the authors utilized swimmer's plots to visualize individual treatment outcomes and use the Kaplan-Meier method to look at time to event outcomes. At this point in time, I'll hand it over to Zach to take us through the results of this study.
Zach Klaassen: Thanks Chris. So this is the baseline characteristics for this trial. You can see there is 26 patients included with a median age of 72.5 years, a median PSA of 331 and a median ECOG score of one. Not surprisingly, the Gleason score meeting was eight with a range of seven to nine. When we look at the prior systemic treatments, you can see here that the majority of these patients also receive previous Docetaxel, 54% received Cabazitaxel, 88% received Abiratorine, 85% received Enzalutamide, 73% received Abiraterone and Enzalutamide, and 23% received Radium-223. Of course, as mentioned a hundred percent of these patients previously received a Lutetium-PSMA treatment. I'm looking at prior lines of therapy. There was actually five patients that had eight lines of therapy. Two had seven, six patients had six, five had five, six patients had four lines of treatment and two patients at three prior lines of treatment. So clearly a very heavily pretreated population for this study. When looking at the site of metastases, overall 88% of patients had lymph node involvement, 100% had bone involvement, 42% had visceral involvement most commonly in the lung at 23% and in liver at 19%.
These are the results looking at the hematological and non-hematological adverse events after the Actinium treatment. And so the left has baseline parameters for focus on the right, which is treatment-emergent adverse events, and looking at grade four and grade three, we can see that anemia was in 31% grade three and 4% grade four. Leukopenia was 27% grade three, thrombocytopenia was 12% grade three and 8% grade four, and xerostomia was 12% grade two, and no grade three or grade four adverse reactions.
This is a swimmer's plot of the mCRPC treatments. And the summary here, as you can see, as I mentioned, the previous slides is a very heavily pretreated population with each different color box representing a different line of therapy. And you can see that there was about three or four patients that had a treatment and survival of between 75 and a hundred months.
The waterfall plot looks at the maximum PSA decline after Actinium radioligand therapy. And I've highlighted here several points on the right. You can see here that 65% of patients had a PSA decline of greater than 50% and actually 12% of patients had a PSA decline of greater than 90% with only three patients having a PSA increase after the Actinium treatment.
This looks at the waterfall plot of the maximum PSA decline after Actinium radioligand therapy compared to Lutetium radioligand therapy. So the Lutetium is in green. And we'll go through that. You can see here that majority of the patients did have a PSA response. However, there was a handful of patients that actually increased PSA, which were deemed failures. And then in blue for the same patients, you can see the PSA response following the Lutetium. And what's impressive is on this side of the graph here, and all these patients that did not have a response was Lutetium, majority of these had a PSA response after a treatment with Actinium.
These three capital markers look at the PSA progression-free survival, the clinical progression-free survival and overall survival after initiation of Actinium-PSMA radioligand therapy on the left, the PSA progression-free survival was 3.5 months. The median clinical progression-free survival in the middle was 4.1 months. And on the right, the median overall survival was 7.7 months.
This then delineates patients with and without liver metastases looking at the same metrics after Actinium-PSMA treatment. On the left, you can see patients without liver metastases had a PSA progression-free survival of 4.0 months compared to 1.9 months in patients with liver metastases. For clinical progression-free survival without liver metastases, 5.2 months compared to 1.8 months for those with liver metastases. And on the far right overall survival, 10.4 months for patients without liver metastases compared to those with liver metastases have an overall survival of 4.3 months. So certainly a clear delineation when stratified by liver metastases yes or no.
So several discussion points from this study in this heavily pretreated population with a meeting of six prior mCRPC therapies, Actinium-PSMA treatment led to a maximum PSA decline of greater than 50% in 65% of patients. However, the frequency of PSA response and duration of response as measured by PSA progression-free survival, clinical progression-free survival, and overall survival were lower than in the previous reports for Actinium-PSMA treatment in less advanced and pretreated mCRPC patients. In this trial, the maximum PSA decline was a greater than 90% was only 12% compared to 40 to 82% of patients in previous studies. Previously known prognostic factors for other mCRPC therapies do apply to the Actinium-PSMA treatment in terms of as a demonstrator in the previous slides, the liver metastases being a very poor prognostic factor.
So in conclusion, Actinium-PSMA treatment has activity in late mCRPC after Lutetium-PSMA failure. However, the duration of tumor responses was shorter than those observed in earlier disease states. Xerostomia caused by Actinium-PSMA can substantially impact patient quality of life. And patients with liver metastases showed very poor outcomes. And the benefits of Actinium-PSMA in this population should be weighed carefully. And finally prospective trial systematically investing in the role of Actinium-PSMA therapy in different prostate cancer disease states is also needed. Thank you very much. We hope you enjoyed this [inaudible 00:11:46] of today journal club.