AR and PI3K Genomic Profiling in Lutetium-177-PSMA Treatment: A Pathway to Identifying Poor Responders, Journal Club - Rashid Sayyid & Zachary Klaassen
August 2, 2023
Rashid Sayyid and Zach Klaassen review a study concerning AR and PI3K genomic profiling of cell-free DNA to identify poor responders to Lutetium-177-PSMA among mCRPC patients. This therapy is approved for patients whose disease has progressed following prior chemotherapy and androgen receptor signaling inhibitor, based on two Randomized Control Trials (RCTs): VISION and TheraP. These RCTs, however, lack robust biomarkers to predict patient response beyond imaging parameters. The reviewed study aims to address this gap by examining the association of commonly altered genes in baseline circulating tumor DNA samples from Lutetium-PSMA treated patients, including the androgen receptor gene and phosphoinositide 3 kinase signaling. The study, a single center observational cohort, observed 57 mCRPC patients, revealing a significant association between specific antigen receptor alterations and PI3K pathway signaling alterations and inferior outcomes. The findings encourage prospective evaluation of these genomic alterations for patient selection for Lutetium-PMSA treatment.
Biographies:
Rashid Sayyid, MD, MSc, Urologic Oncology Fellow, Division of Urology, University of Toronto, Toronto, Ontario
Zachary Klaassen, MD, MSc, Urologic Oncologist, Assistant Professor Surgery/Urology at the Medical College of Georgia at Augusta University, Georgia Cancer Center, Augusta, GA
Biographies:
Rashid Sayyid, MD, MSc, Urologic Oncology Fellow, Division of Urology, University of Toronto, Toronto, Ontario
Zachary Klaassen, MD, MSc, Urologic Oncologist, Assistant Professor Surgery/Urology at the Medical College of Georgia at Augusta University, Georgia Cancer Center, Augusta, GA
Read the Full Video Transcript
Rashid Sayyid: Hello, everyone. This is Rashid Sayyid. I'm a urologic oncology fellow at the University of Toronto, and along with Zach Klaassen, associate professor and program director at Augusta University, we'll be discussing the recent publication from European Urology Open Science looking at AR and at PI3K, genomic profiling of cell-free DNA and whether it can identify poor responders to Lutetium-177-PSMA among patients who had mCRPC. This article was recently published by Dr. Vanwelkenhuyzen et al in European Urology Open Science.
So, we know that Lutetium-PSMA is an approved treatment regimen for mCRPC patients as of 2022 who've had disease progression following prior treatment with chemotherapy and an androgen receptor signaling inhibitor. And this is based on the results mainly of two RCTs.
So, we have VISION, which is a randomized, open label, phase III RCT that included mCRPC men who had progressed on a prior antigen receptor signaling inhibitor and one to two lines of taxane chemotherapy. Importantly, all patients had PSMA-positive disease on their Gallium-PSMA PET/CT and had no evidence of any PSMA-negative lesions. And patients in this trial are randomized two-to-one to either lutetium plus standard of care or standard of care alone. And this trial met its co-primary endpoints of imaging-based progression-free survival and overall survival, as demonstrated in the Kaplan-Meier curves to the right.
Also, we've had TheraP which is a phase II trial, open label, as well, that included 200 mCRPC men who had disease progression following docetaxel, again prior ARSI was allowed, and all patients also importantly had high Gallium-PSMA-11 expression defined as an SUV max of at least 20, and no sites of FDG-positive/PSMA-negative disease. So, no discordant imaging findings. And patients in this trial were randomized one-to-one to either lutetium, similar to VISION trial versus an active control arm to cabazitaxel, which we know is approved in the third line setting previously.
And while we didn't see any differences significantly for radiographic progression-free survival, we mainly saw them for a PSA response which was better for lutetium. And apologies, we did see a radiographic progression or PSA progression-free survival but no overall survival differences between the two arms. And based on these two trials, lutetium was approved in this setting.
And so we don't, however, today really have any strong biomarkers or predictors of treatment response beyond the imaging parameters that we had discussed previously and were inclusion criteria for entry into these studies. And so we need to further be able to better predict which patients are going to respond to this treatment versus the other, especially given that we have cabazitaxel also proven in this setting. And so the association of genomic events with Lutetium-PSMA therapeutic responses and outcomes is lacking.
And so the study objective was to evaluate the association of commonly altered genes or signaling pathways, defined as occurring in at least in 30% of patients, in the baseline circulating tumor DNA samples from Lutetium-PSMA treated patients and evaluating these results with PSA responses and outcomes. And so specifically for the genomic events, the authors looked at androgen receptor gene, the phosphoinositide 3 kinase signaling, the TP53, and the TMPRSS2-ERG mutations.
And so for the purposes of this study, the authors conducted a single center non-interventional observational cohort study of 57 mCRPC patients from the AZ Groeninge Hospital in Belgium, between January 2020 and October 2022. All patients had received at least one chemotherapy and/or ARSI for mCRPC, which is in keeping with the current indication for this therapy. All patients had Gallium-PSMA or Fluoride-PSMA metastatic uptake on PET/CT and were eligible for treatment with Lu-PSMA.
The authors collected data with regards to clinical pathologic variables, PSA responses, clinical outcomes, and they collected liquid biopsy samples both before and during the lutetium treatment and they performed a comprehensive genomic profiling of the plasma-derived ctDNA. Now the cells-free DNA genomic profiling assay was custom designed for metastatic prostate cancer and it was able to detect all relevant genomic alterations. Treating physicians, importantly, were blinded to ctDNA results during treatment follow-up.
The primary endpoint of this analysis was progression-free survival, which was defined as the time until patients were no longer experiencing clinical benefit per the Prostate Cancer Working Group 3 guidelines. This was a composite outcome of time to events, incorporating biochemical, radiologic, and clinical progression. As a secondary endpoint, the authors also looked at PSA50 response rate.
At this point, I'll turn it over to Zach to go over the results and discussion for this article.
Zach Klaassen: Thanks so much, Rashid.
So, this is the patient characteristics and baseline blood chemistries for this study. As we can see at the top, median age of 70 years. Excellent performance status: roughly three-quarters of patients ECOG 0 to 1. The most common Gleason score was 8 to 10 at 52.6%. And roughly two-thirds of patients were M0 at the time of diagnosis.
When we look at the PSMA-PET/CT findings, 64.9% had lymph node metastases, 91.2 bone metastases, and 45.6% of patients had visceral metastases. And when we look at the key blood chemistries, we see that median PSA at the time of study was 132. Prior radical prostatectomy in about half of patients as well as roughly half of patients having prior radiotherapy.
These are extensively treated patients so we look median prior lines of systemic therapy was four. In terms of prior ARSIs, roughly two-thirds had one regimen, roughly one-third had greater than or equal to two regimens. Again, with regards to chemotherapy, one regimen 26.3% of patients and two-thirds of patients had greater than or equal to two regimens of prior chemotherapy. Of note, some other prior systemic therapies: 38.6% of patients had prior Radium-223 and 10.5% PARP inhibitors.
This is the spider and waterfall plots of PSA responses during lutetium treatment. The spider plot is on the left, the waterfall plot is on the right. And we can see from a summary of these figures that 37.5% of patients had a PSA50 response over the course of treatment.
This is the progression-free survival on Lutetium-PSMA therapy for androgen receptor mutations, amplifications, and genomic structural rearrangements. So, we'll walk through these Kaplan-Meiers from left to right. On the left, we have no mutations or wild type in black, which is consistent with all three of these figures. On the left, the AR-mutated, which is in the yellow line, demonstrated there was no difference in progression-free survival between AR-mutated and wild type patients or tumors.
In the middle, we have again, wild type in black and the AR-amplification mutations, and we see that there's a significant worse progression-free survival among those patients with AR-amplified tumors. And finally, on the right, this is the genomic structural rearrangements. So again, wild type in black and patients with AR genomic structural rearrangements in yellow. A significantly worse progression-free survival for the genomic structural rearrangement patients.
This is the Kaplan-Meier analysis of progression-free survival on the Lutetium-PSMA for androgen receptor signaling. Wild type androgen receptor is in black with a median progression-free survival of 5.4 months. The amplified AR only is the yellow line at 3.8 months and median progression-free survival and genomic structural rearrangements in the blue line, 2.6 month median progression-free survival. And we can see that these differences were statistically significant with a P-value of 0.02.
This is the same looking figure for Lutetium-PSMA treatment with PI3K signaling. Median progression-free survival of the wild type is in the black line at median of 5.3 months. And the altered PI3K, the yellow line, median progression-free survival 2.7 months. Again, statistically significant with a P-value of 0.013.
This is the multi-variable Cox regression analysis of PFS for patients receiving Lutetium-PSMA for antigen receptor signaling. So, this is the variables that were in the model on the left. And what I've highlighted here is that patients with genomic structural rearrangements compared to wild type, or the reference, had significantly worse progression-free survival. Hazard ratio 9.74 and a 95% confidence interval of 2.40 to 39.54.
Similarly, this is the multi-variable regression model for PI3K signaling for progression-free survival. The included variables, again, on the left. And when we look at PI3K-altered patients versus wild type, again, significantly worse progression-free survival. Hazard ratio 3.58, 95% confidence interval of 1.41 to 9.08.
So, by way of discussion, this study demonstrated the prognostic value of baseline ctDNA profiling in the Lutetium-PSMA-treated mCRPC with high ctDNA levels associated with inferior outcomes. Specific antigen receptor or genomic structural rearrangements and amplifications and PI3K pathway signaling alterations were associated with inferior outcomes in this study.
For the antigen receptor amplifications, this finding is in line with the literature. However, this study also demonstrated that the prognostic value of the antigen receptor alterations may be driven by intragenic structural variants which frequently co-occur with a AR gene amplifications in late stage disease.
So, in conclusion, among patients with CRPC who started Lutetium-PSMA therapy, patients with cell-free DNA genetic alterations in the androgen receptor or PI3K pathway genes did not experience lasting benefit from therapy. Although this data is hypothesis-generating, it warrants prospective evaluation of AR and PI3K pathway genomic alterations for patient selection for Lutetium-PMSA treatment, which will be investigated in the ProBio trial.
We thank you very much for your attention. We hope you enjoyed this UroToday journal club discussion.
Rashid Sayyid: Hello, everyone. This is Rashid Sayyid. I'm a urologic oncology fellow at the University of Toronto, and along with Zach Klaassen, associate professor and program director at Augusta University, we'll be discussing the recent publication from European Urology Open Science looking at AR and at PI3K, genomic profiling of cell-free DNA and whether it can identify poor responders to Lutetium-177-PSMA among patients who had mCRPC. This article was recently published by Dr. Vanwelkenhuyzen et al in European Urology Open Science.
So, we know that Lutetium-PSMA is an approved treatment regimen for mCRPC patients as of 2022 who've had disease progression following prior treatment with chemotherapy and an androgen receptor signaling inhibitor. And this is based on the results mainly of two RCTs.
So, we have VISION, which is a randomized, open label, phase III RCT that included mCRPC men who had progressed on a prior antigen receptor signaling inhibitor and one to two lines of taxane chemotherapy. Importantly, all patients had PSMA-positive disease on their Gallium-PSMA PET/CT and had no evidence of any PSMA-negative lesions. And patients in this trial are randomized two-to-one to either lutetium plus standard of care or standard of care alone. And this trial met its co-primary endpoints of imaging-based progression-free survival and overall survival, as demonstrated in the Kaplan-Meier curves to the right.
Also, we've had TheraP which is a phase II trial, open label, as well, that included 200 mCRPC men who had disease progression following docetaxel, again prior ARSI was allowed, and all patients also importantly had high Gallium-PSMA-11 expression defined as an SUV max of at least 20, and no sites of FDG-positive/PSMA-negative disease. So, no discordant imaging findings. And patients in this trial were randomized one-to-one to either lutetium, similar to VISION trial versus an active control arm to cabazitaxel, which we know is approved in the third line setting previously.
And while we didn't see any differences significantly for radiographic progression-free survival, we mainly saw them for a PSA response which was better for lutetium. And apologies, we did see a radiographic progression or PSA progression-free survival but no overall survival differences between the two arms. And based on these two trials, lutetium was approved in this setting.
And so we don't, however, today really have any strong biomarkers or predictors of treatment response beyond the imaging parameters that we had discussed previously and were inclusion criteria for entry into these studies. And so we need to further be able to better predict which patients are going to respond to this treatment versus the other, especially given that we have cabazitaxel also proven in this setting. And so the association of genomic events with Lutetium-PSMA therapeutic responses and outcomes is lacking.
And so the study objective was to evaluate the association of commonly altered genes or signaling pathways, defined as occurring in at least in 30% of patients, in the baseline circulating tumor DNA samples from Lutetium-PSMA treated patients and evaluating these results with PSA responses and outcomes. And so specifically for the genomic events, the authors looked at androgen receptor gene, the phosphoinositide 3 kinase signaling, the TP53, and the TMPRSS2-ERG mutations.
And so for the purposes of this study, the authors conducted a single center non-interventional observational cohort study of 57 mCRPC patients from the AZ Groeninge Hospital in Belgium, between January 2020 and October 2022. All patients had received at least one chemotherapy and/or ARSI for mCRPC, which is in keeping with the current indication for this therapy. All patients had Gallium-PSMA or Fluoride-PSMA metastatic uptake on PET/CT and were eligible for treatment with Lu-PSMA.
The authors collected data with regards to clinical pathologic variables, PSA responses, clinical outcomes, and they collected liquid biopsy samples both before and during the lutetium treatment and they performed a comprehensive genomic profiling of the plasma-derived ctDNA. Now the cells-free DNA genomic profiling assay was custom designed for metastatic prostate cancer and it was able to detect all relevant genomic alterations. Treating physicians, importantly, were blinded to ctDNA results during treatment follow-up.
The primary endpoint of this analysis was progression-free survival, which was defined as the time until patients were no longer experiencing clinical benefit per the Prostate Cancer Working Group 3 guidelines. This was a composite outcome of time to events, incorporating biochemical, radiologic, and clinical progression. As a secondary endpoint, the authors also looked at PSA50 response rate.
At this point, I'll turn it over to Zach to go over the results and discussion for this article.
Zach Klaassen: Thanks so much, Rashid.
So, this is the patient characteristics and baseline blood chemistries for this study. As we can see at the top, median age of 70 years. Excellent performance status: roughly three-quarters of patients ECOG 0 to 1. The most common Gleason score was 8 to 10 at 52.6%. And roughly two-thirds of patients were M0 at the time of diagnosis.
When we look at the PSMA-PET/CT findings, 64.9% had lymph node metastases, 91.2 bone metastases, and 45.6% of patients had visceral metastases. And when we look at the key blood chemistries, we see that median PSA at the time of study was 132. Prior radical prostatectomy in about half of patients as well as roughly half of patients having prior radiotherapy.
These are extensively treated patients so we look median prior lines of systemic therapy was four. In terms of prior ARSIs, roughly two-thirds had one regimen, roughly one-third had greater than or equal to two regimens. Again, with regards to chemotherapy, one regimen 26.3% of patients and two-thirds of patients had greater than or equal to two regimens of prior chemotherapy. Of note, some other prior systemic therapies: 38.6% of patients had prior Radium-223 and 10.5% PARP inhibitors.
This is the spider and waterfall plots of PSA responses during lutetium treatment. The spider plot is on the left, the waterfall plot is on the right. And we can see from a summary of these figures that 37.5% of patients had a PSA50 response over the course of treatment.
This is the progression-free survival on Lutetium-PSMA therapy for androgen receptor mutations, amplifications, and genomic structural rearrangements. So, we'll walk through these Kaplan-Meiers from left to right. On the left, we have no mutations or wild type in black, which is consistent with all three of these figures. On the left, the AR-mutated, which is in the yellow line, demonstrated there was no difference in progression-free survival between AR-mutated and wild type patients or tumors.
In the middle, we have again, wild type in black and the AR-amplification mutations, and we see that there's a significant worse progression-free survival among those patients with AR-amplified tumors. And finally, on the right, this is the genomic structural rearrangements. So again, wild type in black and patients with AR genomic structural rearrangements in yellow. A significantly worse progression-free survival for the genomic structural rearrangement patients.
This is the Kaplan-Meier analysis of progression-free survival on the Lutetium-PSMA for androgen receptor signaling. Wild type androgen receptor is in black with a median progression-free survival of 5.4 months. The amplified AR only is the yellow line at 3.8 months and median progression-free survival and genomic structural rearrangements in the blue line, 2.6 month median progression-free survival. And we can see that these differences were statistically significant with a P-value of 0.02.
This is the same looking figure for Lutetium-PSMA treatment with PI3K signaling. Median progression-free survival of the wild type is in the black line at median of 5.3 months. And the altered PI3K, the yellow line, median progression-free survival 2.7 months. Again, statistically significant with a P-value of 0.013.
This is the multi-variable Cox regression analysis of PFS for patients receiving Lutetium-PSMA for antigen receptor signaling. So, this is the variables that were in the model on the left. And what I've highlighted here is that patients with genomic structural rearrangements compared to wild type, or the reference, had significantly worse progression-free survival. Hazard ratio 9.74 and a 95% confidence interval of 2.40 to 39.54.
Similarly, this is the multi-variable regression model for PI3K signaling for progression-free survival. The included variables, again, on the left. And when we look at PI3K-altered patients versus wild type, again, significantly worse progression-free survival. Hazard ratio 3.58, 95% confidence interval of 1.41 to 9.08.
So, by way of discussion, this study demonstrated the prognostic value of baseline ctDNA profiling in the Lutetium-PSMA-treated mCRPC with high ctDNA levels associated with inferior outcomes. Specific antigen receptor or genomic structural rearrangements and amplifications and PI3K pathway signaling alterations were associated with inferior outcomes in this study.
For the antigen receptor amplifications, this finding is in line with the literature. However, this study also demonstrated that the prognostic value of the antigen receptor alterations may be driven by intragenic structural variants which frequently co-occur with a AR gene amplifications in late stage disease.
So, in conclusion, among patients with CRPC who started Lutetium-PSMA therapy, patients with cell-free DNA genetic alterations in the androgen receptor or PI3K pathway genes did not experience lasting benefit from therapy. Although this data is hypothesis-generating, it warrants prospective evaluation of AR and PI3K pathway genomic alterations for patient selection for Lutetium-PMSA treatment, which will be investigated in the ProBio trial.
We thank you very much for your attention. We hope you enjoyed this UroToday journal club discussion.