VIABLE Phase 3 Trial: Autologous Dendritic Cell-Based Immunotherapy, Docetaxel, and Prednisone vs Placebo in Patients With mCPRC, Journal Club - Christopher Wallis & Zachary Klaassen
December 5, 2022
In this UroToday Journal Club Christopher Wallis and Zach Klaassen highlight a JAMA oncology publication entitled Efficacy and Safety of Autologous Dendritic Cell-Based Immunotherapy, Docetaxel, and Prednisone vs Placebo in Patients With Metastatic Castration-Resistant Prostate Cancer: The VIABLE Phase 3 Randomized Clinical Trial. VIABLE sought to evaluate the efficacy and safety of DCVAC/PCa plus chemotherapy followed by DCVAC/PCa maintenance treatment in patients with metastatic castration-resistant prostate cancer (mCRPC). DCVAC/PCa is an active cellular immunotherapy designed to initiate an immune response against prostate cancer.
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
Christopher Wallis: Hello, and thank you for joining us for this UroToday Journal Club discussion. Today, we're talking about a recent publication entitled, Efficacy and Safety of Autologous Dendritic Cell-Based Immunotherapy, Docetaxel, and Prednisone versus Placebo in Patients With Metastatic Castration-Resistant Prostate Cancer: The VIABLE Phase III Randomized Clinical Trial. I'm Chris Wallis, an assistant professor in the Division of Urology at the University of Toronto, and with me today is Zach Klaassen, an assistant professor in the Division of Urology at the Medical College of Georgia. This is a citation of this recent work led by Dr. Vogelzang and published in JAMA Oncology.
Advanced prostate cancer represents a common cause of cancer death in older men, and nearly all patients developed castration-resistant disease prior to dying of prostate cancer. In the last 20 years or so we've seen dramatic improvements in outcomes for patients with advanced prostate cancer, as a result of the plethora of new treatment options. The first of these, and still arguably a backbone of care, is docetaxel-based chemotherapy.
When we look at improving treatment options, in the last few years, immunotherapy has gained an increasingly large role for many cancer types. Unfortunately, prostate cancer has an immune-desert like phenotype, and probably as a result, immune checkpoint inhibitor trials have been relatively unsuccessful. Cancer immunotherapy may alternatively be delivered with active cellular immunotherapy using tumor antigen-loaded dendritic cells, and these have proved somewhat inconclusive in general. DCVAC/PCa dendritic cells are prepared from patients monocytes collected by leukapheresis, which are subsequently exposed to LNCaP cells that are killed using immunogenic modalities. In phase I and phase II studies, this approach demonstrated tolerability and suggested a favorable overall survival.
As a result, the authors designed the VIABLE study. This is a phase III randomized controlled trial assessing the role of active immunotherapies in dendritic cell-based treatment for late-stage prostate cancer, designed to test the hypothesis that combining docetaxel with a DCVAC/PCa followed by maintenance therapy with DCVAC/PCa would improve overall survival in patients with metastatic castration-resistant disease. The authors performed a multicenter, double-blind, placebo-controlled, parallel-group phase III randomized controlled trial at 177 centers.
They included men 18 years and older with histologically confirmed prostate cancer who had skeletal, soft tissue, or nodal metastases and had evidence of disease progression on ADT with ongoing castration, making them metastatic castration-resistant. They had to have adequate laboratory parameters and ECOG performance status of 0 to 2. Patients were excluded if they had brain or central nervous system metastases, spinal cord compression requiring surgery or radiation, prior chemotherapy, comorbidity that p
Patients were randomized in a 2:1 design using stratified block randomization to receive either DCVAC/PCa with docetaxel and prednisone or placebo with docetaxel and prednisone. Stratification was performed according to geographic region, prior therapies, and ECOG performance status. In terms of the treatment protocol, patients underwent a single session leukapheresis within 14 days of randomization. Chemotherapy was then started with docetaxel 3 to 7 days after this leukapheresis and standard dosing was utilized for up to 10 cycles. Patients then received infusion with the DCVAC/PCa or placebo. This began approximately 5 weeks after leukapheresis and at least 7 days after their second cycle of docetaxel. Up to 15 doses were given in total. This was administered in 2.5 CC aliquots by a subcutaneous injection. One injection was performed into the axilla, and then the second was performed in the contralateral inguinal region, capturing lymph node drainage. The first nine doses were given concurrently with chemotherapy, and the remaining six doses were given as maintenance treatment every 4 weeks.
The primary outcome of the study was overall survival, with a number of secondary endpoints, including radiographic progression-free survival, time to PSA progression, time to first skeletal-related event, time to radiographic progression or skeletal-related events, proportion of patients with skeletal-related events, and safety. Quality of life was included as an exploratory endpoint. Imaging was performed at baseline in every 12 weeks thereafter. Laboratory investigations included CBC and biochemistry every 3 weeks, and urinalyses every 6 weeks during chemotherapy and then every 12 weeks thereafter. Analysis was performed in the efficacy set, including all randomized patients with at least one baseline assessment. Time to event outcomes were assessed using the Kaplan Meier technique and stratified log-rank test, with Cox proportional hazard models used to calculate a hazard ratios. Subgroup analyses were performed according to the stratification factors, and those, recapped, are the region, prior therapies, and performance status, and post-hoc analyses were done according to the number of cycles of DCVAC/PCa administered.
I'm now going to hand it over to Zach to walk us through the results of this VIABLE phase III randomized control trial.
Zachary Klaassen: Thanks so much for the introduction, Chris. This is the CONSORT diagram for the VIABLE trial. We can see that there was 1,182 patients that were randomized, including 787 to the DCVAC/PCa plus chemotherapy arm and 395 to the placebo plus chemotherapy arm. Importantly, here, you can see that 746 patients started leukapheresis, but only 610 started DCVAC/PCa. Ultimately, we see that there was 454 that completed chemotherapy in the DCVAC/PCa chemotherapy arm and 220 that completed chemotherapy in the randomized to placebo plus chemotherapy arm. The efficacy analysis for the DCVAC/PCa arm included 787 patients and 749 in the safety analysis, and in the placebo plus chemotherapy arm, 395 in the efficacy analysis and 379 in the safety analysis.
This is the characteristics of the patients at baseline in the efficacy analysis. You can see here on the right is the placebo group, and to the left of that is the DCVAC/PCa group. Median age was 68 in the DCVAC/PCa group and 69 in the placebo. We see that the majority of these patients were white, at 93% in the DCVAC/PCa group, and 90.6% in the placebo group. Moving down to the region of randomization, nearly 82% of these patients were outside of the US, just over 60% of these patients had an ECOG performance status of 0. Most commonly, we see, actually, a pretty even breakdown between Gleason 8 to 10 and less than 8 for both of these groups. And in terms of time from prostate cancer diagnosis to randomization, it was roughly 4 years for each of these groups. Finally, in terms of patients with measurable disease at screening, nearly 50% of these patients in each of the allocated groups.
These Kaplan-Meier curves for the next several slides will show several of the outcomes. We can see the placebo arm will be in orange and the DCVAC/PCa arm will be in gray. This looks at overall survival in the efficacy analysis. We see a median overall survival for DCVAC/PCa of 23.9 months, in the placebo arm of 24.3 months, with this hazard ratio of 1.04 and a 95% confidence interval of 0.90 to 1.21. This looks at the Kaplan-Meier estimate of overall survival in patients that had not received abiraterone and/or enzalutamide. Again, no benefit to the treatment arm, with a median overall survival of 26.7 months in DCVAC/PCa arm and 25.7 months in the placebo arm, with a hazard ratio of 0.94 and a 95% confidence in interval of 0.78 to 1.13.
These are the secondary endpoints in the efficacy analysis. To summarize this table, there was no benefit for the DCVAC/PCa arm. With regards to radiographic progression-free survival, hazard ratio of 0.99, time to PSA progression, hazard ratio of 1.08, time to first skeletal-related event, hazard ratio of 0.92, and time to radiographic progression or skeletal-related event, hazard ratio of 0.90. With regards to the proportion of patients with skeletal-related events, it was 0.05 in the DCVAC/PCa arm and 0.07 in the placebo arm, with a relative risk, not significant, of 0.85, 95% confidence interval 0.53 to 1.36.
With regards to adverse events in the safety analysis, any treatment-emergent adverse events was 90% in the DCVAC/PCa arm and 97.4% in the placebo arm. To summarize the remaining of these adverse events, we see, actually, slightly higher adverse events in the placebo arm compared to the intervention arm, specifically with regards to treatment-emergent adverse related events at 12.7 versus 9.2%, chemotherapy-related adverse events, 88.7 versus 80%, and skeletal-related events, 6.6% versus 5.5%.
Several important discussion points from this trial. The hypothesis for the VIABLE phase III study in patients with mCRPC was that DCVAC/PCa pulsed with LNCaP would deliver PCa antigens for effective in vivo T-cell activation to mount an immune response against the tumor. However, as we saw on the previous slides, in this study, the DCVAC/PCa plus docetaxel did not improve overall survival. Additionally, there was no difference between study groups observed for any of the secondary endpoints. Importantly, because DCVAC/PCa prostate cancer could not be produced for 119 patients, their inclusion in the efficacy analysis may have adversely influenced efficacy outcomes. However, the authors did run a per-protocol analysis, and this included patients that received greater than eight doses of DCVAC/PCa or placebo. And again, overall survival was not significantly different, at 29.7 months in the intervention arm and 26.7 months in the placebo arm, with a hazard was a ratio of 0.91 and a 95% confidence interval of 0.75 to 1.11. Notably, DCVAC/PCa was well tolerated, as the majority of adverse events were secondary to chemotherapy.
In conclusion, in this phase III randomized trial, results showed that DCVAC prostate cancer combined with the docetaxel plus prednisone and continued as maintenance treatment did not extend overall survival in these patients with metastatic CRPC. Nevertheless, DCVAC/PCa was well tolerated, with the majority of treatment-emergent adverse events being related to chemotherapy rather than the intervention, thus providing evidence for its safety.
We thank you very much attention and we hope you enjoyed this UroToday Journal Club discussion of the VIABLE phase III study.
Christopher Wallis: Hello, and thank you for joining us for this UroToday Journal Club discussion. Today, we're talking about a recent publication entitled, Efficacy and Safety of Autologous Dendritic Cell-Based Immunotherapy, Docetaxel, and Prednisone versus Placebo in Patients With Metastatic Castration-Resistant Prostate Cancer: The VIABLE Phase III Randomized Clinical Trial. I'm Chris Wallis, an assistant professor in the Division of Urology at the University of Toronto, and with me today is Zach Klaassen, an assistant professor in the Division of Urology at the Medical College of Georgia. This is a citation of this recent work led by Dr. Vogelzang and published in JAMA Oncology.
Advanced prostate cancer represents a common cause of cancer death in older men, and nearly all patients developed castration-resistant disease prior to dying of prostate cancer. In the last 20 years or so we've seen dramatic improvements in outcomes for patients with advanced prostate cancer, as a result of the plethora of new treatment options. The first of these, and still arguably a backbone of care, is docetaxel-based chemotherapy.
When we look at improving treatment options, in the last few years, immunotherapy has gained an increasingly large role for many cancer types. Unfortunately, prostate cancer has an immune-desert like phenotype, and probably as a result, immune checkpoint inhibitor trials have been relatively unsuccessful. Cancer immunotherapy may alternatively be delivered with active cellular immunotherapy using tumor antigen-loaded dendritic cells, and these have proved somewhat inconclusive in general. DCVAC/PCa dendritic cells are prepared from patients monocytes collected by leukapheresis, which are subsequently exposed to LNCaP cells that are killed using immunogenic modalities. In phase I and phase II studies, this approach demonstrated tolerability and suggested a favorable overall survival.
As a result, the authors designed the VIABLE study. This is a phase III randomized controlled trial assessing the role of active immunotherapies in dendritic cell-based treatment for late-stage prostate cancer, designed to test the hypothesis that combining docetaxel with a DCVAC/PCa followed by maintenance therapy with DCVAC/PCa would improve overall survival in patients with metastatic castration-resistant disease. The authors performed a multicenter, double-blind, placebo-controlled, parallel-group phase III randomized controlled trial at 177 centers.
They included men 18 years and older with histologically confirmed prostate cancer who had skeletal, soft tissue, or nodal metastases and had evidence of disease progression on ADT with ongoing castration, making them metastatic castration-resistant. They had to have adequate laboratory parameters and ECOG performance status of 0 to 2. Patients were excluded if they had brain or central nervous system metastases, spinal cord compression requiring surgery or radiation, prior chemotherapy, comorbidity that p
Patients were randomized in a 2:1 design using stratified block randomization to receive either DCVAC/PCa with docetaxel and prednisone or placebo with docetaxel and prednisone. Stratification was performed according to geographic region, prior therapies, and ECOG performance status. In terms of the treatment protocol, patients underwent a single session leukapheresis within 14 days of randomization. Chemotherapy was then started with docetaxel 3 to 7 days after this leukapheresis and standard dosing was utilized for up to 10 cycles. Patients then received infusion with the DCVAC/PCa or placebo. This began approximately 5 weeks after leukapheresis and at least 7 days after their second cycle of docetaxel. Up to 15 doses were given in total. This was administered in 2.5 CC aliquots by a subcutaneous injection. One injection was performed into the axilla, and then the second was performed in the contralateral inguinal region, capturing lymph node drainage. The first nine doses were given concurrently with chemotherapy, and the remaining six doses were given as maintenance treatment every 4 weeks.
The primary outcome of the study was overall survival, with a number of secondary endpoints, including radiographic progression-free survival, time to PSA progression, time to first skeletal-related event, time to radiographic progression or skeletal-related events, proportion of patients with skeletal-related events, and safety. Quality of life was included as an exploratory endpoint. Imaging was performed at baseline in every 12 weeks thereafter. Laboratory investigations included CBC and biochemistry every 3 weeks, and urinalyses every 6 weeks during chemotherapy and then every 12 weeks thereafter. Analysis was performed in the efficacy set, including all randomized patients with at least one baseline assessment. Time to event outcomes were assessed using the Kaplan Meier technique and stratified log-rank test, with Cox proportional hazard models used to calculate a hazard ratios. Subgroup analyses were performed according to the stratification factors, and those, recapped, are the region, prior therapies, and performance status, and post-hoc analyses were done according to the number of cycles of DCVAC/PCa administered.
I'm now going to hand it over to Zach to walk us through the results of this VIABLE phase III randomized control trial.
Zachary Klaassen: Thanks so much for the introduction, Chris. This is the CONSORT diagram for the VIABLE trial. We can see that there was 1,182 patients that were randomized, including 787 to the DCVAC/PCa plus chemotherapy arm and 395 to the placebo plus chemotherapy arm. Importantly, here, you can see that 746 patients started leukapheresis, but only 610 started DCVAC/PCa. Ultimately, we see that there was 454 that completed chemotherapy in the DCVAC/PCa chemotherapy arm and 220 that completed chemotherapy in the randomized to placebo plus chemotherapy arm. The efficacy analysis for the DCVAC/PCa arm included 787 patients and 749 in the safety analysis, and in the placebo plus chemotherapy arm, 395 in the efficacy analysis and 379 in the safety analysis.
This is the characteristics of the patients at baseline in the efficacy analysis. You can see here on the right is the placebo group, and to the left of that is the DCVAC/PCa group. Median age was 68 in the DCVAC/PCa group and 69 in the placebo. We see that the majority of these patients were white, at 93% in the DCVAC/PCa group, and 90.6% in the placebo group. Moving down to the region of randomization, nearly 82% of these patients were outside of the US, just over 60% of these patients had an ECOG performance status of 0. Most commonly, we see, actually, a pretty even breakdown between Gleason 8 to 10 and less than 8 for both of these groups. And in terms of time from prostate cancer diagnosis to randomization, it was roughly 4 years for each of these groups. Finally, in terms of patients with measurable disease at screening, nearly 50% of these patients in each of the allocated groups.
These Kaplan-Meier curves for the next several slides will show several of the outcomes. We can see the placebo arm will be in orange and the DCVAC/PCa arm will be in gray. This looks at overall survival in the efficacy analysis. We see a median overall survival for DCVAC/PCa of 23.9 months, in the placebo arm of 24.3 months, with this hazard ratio of 1.04 and a 95% confidence interval of 0.90 to 1.21. This looks at the Kaplan-Meier estimate of overall survival in patients that had not received abiraterone and/or enzalutamide. Again, no benefit to the treatment arm, with a median overall survival of 26.7 months in DCVAC/PCa arm and 25.7 months in the placebo arm, with a hazard ratio of 0.94 and a 95% confidence in interval of 0.78 to 1.13.
These are the secondary endpoints in the efficacy analysis. To summarize this table, there was no benefit for the DCVAC/PCa arm. With regards to radiographic progression-free survival, hazard ratio of 0.99, time to PSA progression, hazard ratio of 1.08, time to first skeletal-related event, hazard ratio of 0.92, and time to radiographic progression or skeletal-related event, hazard ratio of 0.90. With regards to the proportion of patients with skeletal-related events, it was 0.05 in the DCVAC/PCa arm and 0.07 in the placebo arm, with a relative risk, not significant, of 0.85, 95% confidence interval 0.53 to 1.36.
With regards to adverse events in the safety analysis, any treatment-emergent adverse events was 90% in the DCVAC/PCa arm and 97.4% in the placebo arm. To summarize the remaining of these adverse events, we see, actually, slightly higher adverse events in the placebo arm compared to the intervention arm, specifically with regards to treatment-emergent adverse related events at 12.7 versus 9.2%, chemotherapy-related adverse events, 88.7 versus 80%, and skeletal-related events, 6.6% versus 5.5%.
Several important discussion points from this trial. The hypothesis for the VIABLE phase III study in patients with mCRPC was that DCVAC/PCa pulsed with LNCaP would deliver PCa antigens for effective in vivo T-cell activation to mount an immune response against the tumor. However, as we saw on the previous slides, in this study, the DCVAC/PCa plus docetaxel did not improve overall survival. Additionally, there was no difference between study groups observed for any of the secondary endpoints. Importantly, because DCVAC/PCa prostate cancer could not be produced for 119 patients, their inclusion in the efficacy analysis may have adversely influenced efficacy outcomes. However, the authors did run a per-protocol analysis, and this included patients that received greater than eight doses of DCVAC/PCa or placebo. And again, overall survival was not significantly different, at 29.7 months in the intervention arm and 26.7 months in the placebo arm, with a hazard was a ratio of 0.91 and a 95% confidence interval of 0.75 to 1.11. Notably, DCVAC/PCa was well tolerated, as the majority of adverse events were secondary to chemotherapy.
In conclusion, in this phase III randomized trial, results showed that DCVAC prostate cancer combined with the docetaxel plus prednisone and continued as maintenance treatment did not extend overall survival in these patients with metastatic CRPC. Nevertheless, DCVAC/PCa was well tolerated, with the majority of treatment-emergent adverse events being related to chemotherapy rather than the intervention, thus providing evidence for its safety.
We thank you very much attention and we hope you enjoyed this UroToday Journal Club discussion of the VIABLE phase III study.