Abiraterone Acetate Plus Prednisone in Black and White Men with Metastatic Castrate-Resistant Prostate Cancer, Journal Club - Christopher Wallis & Zachary Klaassen
July 19, 2021
In this UroToday Journal Club, Christopher Wallis and Zachary Klaassen discuss a retrospective analysis of randomized trials that suggest that Black men with metastatic castration-resistant prostate cancer (mCRPC) have longer survival than White men, a prospective study of abiraterone acetate plus prednisone to explore outcomes by race. The goal of this study was to first demonstrate the feasibility of enrolling a study population enriched with black men, as well as to report outcomes by race and perform some correlative studies. This was a non-comparative, open-label, multi-center pilot study, and men were included if they had castration-resistant prostate cancer with metastatic disease on the basis of CT and bone scan imaging. This is the first interventional trial in metastatic CRPC to pre-specify parallel patient treatment groups by self-identified race and to evaluate clinical efficacy and safety outcomes perspectively by race. Dr. Klaassen highlights that although this study was not designed to compare outcomes by race, black men did have higher rates of PSA decline and longer time to PSA progression.
Biographies:
Christopher J.D. Wallis, MD, Ph.D., Instructor in Urology, Vanderbilt University Medical Center, Nashville, Tennessee
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., Instructor in Urology, Vanderbilt University Medical Center, Nashville, Tennessee
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. Today we are discussing a recent publication entitled, A prospective trial of abiraterone acetate plus prednisone in black and white men with metastatic castrate-resistant prostate cancer. I'm Chris Wallis, a Fellow in Urologic Oncology at Vanderbilt, and with me today is Zach Klaassen, Assistant Professor in The Division of Urology at The Medical College of Georgia.
This is the citation for this recent publication, in The Journal of Cancer led by Dr. George. Racial disparities in prostate cancer have been well-recognized for many years and notably among all the cancer types. And disparities in both incidence and outcomes on the basis of race are among the greatest for patients with prostate cancer. Access to care certainly contributes to much of these disparities and biological differences are somewhat more controversial.
However, when we look at the response to treatment across a variety of different treatment approaches, we see that race is not really a predictor. So, on the left, we see an initial publication that looked at the impact of race and survival in men with mCRPC and you can see that the black and white lines are essentially superimposed in the middle JCO publication, focusing on patients treated with docetaxel, and finally on the right, a recent publication from the PROCEED registry, looking at patients who received sipuleucel-T and here we can actually see that African American men fared better than the Caucasian members of this cohort.
In advanced prostate cancer, we see that death from diseases is common and nearly always goes through the castration-resistant disease space. We've had numerous new drug approvals in this indication over the last 10 or 15 years and, relevant to this study we're discussing today, we see the approvals of abiraterone, initially post-taxane-based chemotherapy in 2011 and subsequently pre-taxane-based chemotherapy in 2012. The mechanism of action, as most will know of abiraterone, is as a CYP inhibitor. So, this acts for androgen biosynthesis inhibition and, as a result of its mechanism of action, is co-administered with prednisone.
These are the two studies that led to the approval. Here, we can see the use of abiraterone in men following docetaxel chemotherapy and a significant survival benefit compared to placebo, and then in the pre-chemo setting in COUGAR-302, again we see a significant improvement in survival. The hypothesis, the authors sought to test that black men may be more responsive to novel hormonal-based therapy in prostate cancer. Unfortunately, in the COUGAR-302 study, black men comprised only 3.5% of the study cohort and so subgroup analyses that are meaningful were unable to be performed. However, in their own institutional analysis, the authors performed a retrospective study, which showed that responses between black and white men were similar when treated with abiraterone and so those are in the PSA responses and overall survival. Thus, for this study, the authors sought then to take a prospective multi-center trial of abiraterone with prednisone in 100 men with mCRPC and intentionally accrued 50 black men and 50 white men, according to their self-identified race.
This study's goal was to first demonstrate the feasibility of enrolling a study population enriched with black men, as well as to report outcomes by race and perform some correlative studies. So this was a non-comparative, open-label, multi-center pilot study, and men were included if they had castration-resistant prostate cancer with metastatic disease on the basis of CT and bone scan imaging. They had to have a suppressed testosterone as well as acceptable hematologic renal and liver function and were excluded if they had uncontrolled hypertension or uncontrolled diabetes. The primary endpoint was radiographic progression-free survival and secondary endpoints included a variety of PSA-based metrics, as well as bone flare, safety and tolerability, and overall survival. In addition, in keeping with a goal to assess correlative markers, genotyping was performed with general DNA from 88 patients and genotyping was performed using the Illumina Infinium Multi-Ethnic Global Bead Chip.
The authors estimated that the median radiographic progression-free survival would be 16.5 months, so they then used this to drive their study sample of 50 patients per group, as you can see here. The authors used the Kaplan-Meier technique to assess time to event outcomes and the binomial distribution to calculate confidence intervals for the proportion of patients with each threshold of PSA decline. In terms of the genetic analysis, they used Cox models to identify SNPs that were associated with time to progression.
At this point in time, I will hand it over to Zach to take us through the results of this study.
Zachary Klaassen: Thanks, Chris.
So, this is the CONSORT diagram for this study and you can see here they screened 119 patients. There were 61 that were white and 57 that were black and those that were treated and included in the analysis, included 50 in each of the arms.
These are the baseline characteristics at enrollment. You can see on the right is all men, in the middle is black and white men, which we will discuss briefly. You can see that the median age was slightly older in black men at 69 years versus 67.8 in white men, time from diagnosis to enrollment, a median of 3.75 years for black men and 4.12 years for white men. The most common Gleason score at diagnosis was 8-10 for both groups in terms of 56% for black men and 56% for white men. The lymph node classification was most commonly N0, with 44% for black men and 52% for white men.
The extent of metastases was M0 for the majority of patients, 52% for black men, and 54% for white men. The Karnofsky performance status was most commonly 90-100, with 80% for black men, and 88% for white men. In terms of sites of metastases, bone-only, 44% for black, 38% for white, lymph node-only, 16% for black and 20% for white, and visceral metastases, 14% for black and 14% for white men. The median PSA was higher in white men at 22.3 compared to 17.7 for black men. And in terms of prior treatment, radiation therapy, 58% for white men and 48% for black men, prior prostatectomy, 34% for black men and 46% for white men, and prior docetaxel, 16% for black men and 22% for white men.
This table looks at common baseline comorbidities and this is to highlight that the comorbidity profile was higher in black men prior hypertension, at 88% compared to 68% for white men, prior hypercholesterolemia, 42% for black men, and 30% for white men, obesity, 50% for black men and 44% for white men, and prior diabetes was 42% for black men and only 10% for white men.
This is the Kaplan-Meier curve looking at radiographic progression-free survival, which is essentially the same between these two cohorts, 16.6 months for black men and 16.8 months for white men.
This looks at the time to PSA progression, and this actually was longer for black men at 16.6 months, compared to 11.5 months for white men.
This table looks at the proportion of PSA decline from baseline and to summarize this table, you can see that this favored black men in all of these categories, specifically decline in PSA greater than 30%, at 82% for black men, and 78% for white men, decline at PSA greater than 90%, 48% for black men and 38% for white men, and looking at PSA less than 0.1, 18% for black men at 8% for white men.
This Kaplan-Meier curve looks at overall survival, nearly identical between these groups, 35.9 months for black men and 35.7 months for white men.
Looking at the adverse event profile, on the far right is what we will focus on, which is the grade three and four adverse events, most commonly was hypertension, at 24% for black men and 16% for white men. And also looking towards the bottom of the table, there was more hyperglycemia at 10% in black men and 4% in white men as well as more hypokalemia at 12% in black men and 4% of white men.
This table summarizes single-nucleotide polymorphisms associated with time to PSA progression. In the middle are the hazard ratios, and on the left are the genes, and you can see that the mutation in ACAA2 had a hazard ratio of 19.9 for PSA progression. Other ones with a significant impact included TM4SF20, with a hazard ratio of 9.95, and SPHKAP, with a hazard ratio of 7.68.
So several discussion points from this study. This is the first interventional trial in metastatic CRPC to pre-specify parallel patient treatment groups by self-identified race and to evaluate clinical efficacy and safety outcomes perspectively by race. Although this study was not designed to compare outcomes by race, black men did have higher rates of PSA decline and longer time to PSA progression. Furthermore, the longer-term outcomes of radiographic progression-free survival and overall survival were similar by race. This leads to encouraging data to support the intentional broadening of eligibility criteria to improve the inclusion of disproportionately affected black men with metastatic CRPC in prospective trials.
So in conclusion, this study demonstrated the feasibility of prospective race-based studies, inclusive of a high percentage of black men. With proper representation in treatment trials, more insights into how black patients tolerate and respond to therapy based on genetic and cultural factors may be gained. Ultimately, larger prospective randomized studies, proportionately inclusive of black men will be necessary to investigate fully the biological determinants associated with ancestry and outcomes.
Thank you very much. We hope you enjoyed this UroToday Journal Club.
Christopher Wallis: Hello and thank you for joining us for this UroToday Journal Club. Today we are discussing a recent publication entitled, A prospective trial of abiraterone acetate plus prednisone in black and white men with metastatic castrate-resistant prostate cancer. I'm Chris Wallis, a Fellow in Urologic Oncology at Vanderbilt, and with me today is Zach Klaassen, Assistant Professor in The Division of Urology at The Medical College of Georgia.
This is the citation for this recent publication, in The Journal of Cancer led by Dr. George. Racial disparities in prostate cancer have been well-recognized for many years and notably among all the cancer types. And disparities in both incidence and outcomes on the basis of race are among the greatest for patients with prostate cancer. Access to care certainly contributes to much of these disparities and biological differences are somewhat more controversial.
However, when we look at the response to treatment across a variety of different treatment approaches, we see that race is not really a predictor. So, on the left, we see an initial publication that looked at the impact of race and survival in men with mCRPC and you can see that the black and white lines are essentially superimposed in the middle JCO publication, focusing on patients treated with docetaxel, and finally on the right, a recent publication from the PROCEED registry, looking at patients who received sipuleucel-T and here we can actually see that African American men fared better than the Caucasian members of this cohort.
In advanced prostate cancer, we see that death from diseases is common and nearly always goes through the castration-resistant disease space. We've had numerous new drug approvals in this indication over the last 10 or 15 years and, relevant to this study we're discussing today, we see the approvals of abiraterone, initially post-taxane-based chemotherapy in 2011 and subsequently pre-taxane-based chemotherapy in 2012. The mechanism of action, as most will know of abiraterone, is as a CYP inhibitor. So, this acts for androgen biosynthesis inhibition and, as a result of its mechanism of action, is co-administered with prednisone.
These are the two studies that led to the approval. Here, we can see the use of abiraterone in men following docetaxel chemotherapy and a significant survival benefit compared to placebo, and then in the pre-chemo setting in COUGAR-302, again we see a significant improvement in survival. The hypothesis, the authors sought to test that black men may be more responsive to novel hormonal-based therapy in prostate cancer. Unfortunately, in the COUGAR-302 study, black men comprised only 3.5% of the study cohort and so subgroup analyses that are meaningful were unable to be performed. However, in their own institutional analysis, the authors performed a retrospective study, which showed that responses between black and white men were similar when treated with abiraterone and so those are in the PSA responses and overall survival. Thus, for this study, the authors sought then to take a prospective multi-center trial of abiraterone with prednisone in 100 men with mCRPC and intentionally accrued 50 black men and 50 white men, according to their self-identified race.
This study's goal was to first demonstrate the feasibility of enrolling a study population enriched with black men, as well as to report outcomes by race and perform some correlative studies. So this was a non-comparative, open-label, multi-center pilot study, and men were included if they had castration-resistant prostate cancer with metastatic disease on the basis of CT and bone scan imaging. They had to have a suppressed testosterone as well as acceptable hematologic renal and liver function and were excluded if they had uncontrolled hypertension or uncontrolled diabetes. The primary endpoint was radiographic progression-free survival and secondary endpoints included a variety of PSA-based metrics, as well as bone flare, safety and tolerability, and overall survival. In addition, in keeping with a goal to assess correlative markers, genotyping was performed with general DNA from 88 patients and genotyping was performed using the Illumina Infinium Multi-Ethnic Global Bead Chip.
The authors estimated that the median radiographic progression-free survival would be 16.5 months, so they then used this to drive their study sample of 50 patients per group, as you can see here. The authors used the Kaplan-Meier technique to assess time to event outcomes and the binomial distribution to calculate confidence intervals for the proportion of patients with each threshold of PSA decline. In terms of the genetic analysis, they used Cox models to identify SNPs that were associated with time to progression.
At this point in time, I will hand it over to Zach to take us through the results of this study.
Zachary Klaassen: Thanks, Chris.
So, this is the CONSORT diagram for this study and you can see here they screened 119 patients. There were 61 that were white and 57 that were black and those that were treated and included in the analysis, included 50 in each of the arms.
These are the baseline characteristics at enrollment. You can see on the right is all men, in the middle is black and white men, which we will discuss briefly. You can see that the median age was slightly older in black men at 69 years versus 67.8 in white men, time from diagnosis to enrollment, a median of 3.75 years for black men and 4.12 years for white men. The most common Gleason score at diagnosis was 8-10 for both groups in terms of 56% for black men and 56% for white men. The lymph node classification was most commonly N0, with 44% for black men and 52% for white men.
The extent of metastases was M0 for the majority of patients, 52% for black men, and 54% for white men. The Karnofsky performance status was most commonly 90-100, with 80% for black men, and 88% for white men. In terms of sites of metastases, bone-only, 44% for black, 38% for white, lymph node-only, 16% for black and 20% for white, and visceral metastases, 14% for black and 14% for white men. The median PSA was higher in white men at 22.3 compared to 17.7 for black men. And in terms of prior treatment, radiation therapy, 58% for white men and 48% for black men, prior prostatectomy, 34% for black men and 46% for white men, and prior docetaxel, 16% for black men and 22% for white men.
This table looks at common baseline comorbidities and this is to highlight that the comorbidity profile was higher in black men prior hypertension, at 88% compared to 68% for white men, prior hypercholesterolemia, 42% for black men, and 30% for white men, obesity, 50% for black men and 44% for white men, and prior diabetes was 42% for black men and only 10% for white men.
This is the Kaplan-Meier curve looking at radiographic progression-free survival, which is essentially the same between these two cohorts, 16.6 months for black men and 16.8 months for white men.
This looks at the time to PSA progression, and this actually was longer for black men at 16.6 months, compared to 11.5 months for white men.
This table looks at the proportion of PSA decline from baseline and to summarize this table, you can see that this favored black men in all of these categories, specifically decline in PSA greater than 30%, at 82% for black men, and 78% for white men, decline at PSA greater than 90%, 48% for black men and 38% for white men, and looking at PSA less than 0.1, 18% for black men at 8% for white men.
This Kaplan-Meier curve looks at overall survival, nearly identical between these groups, 35.9 months for black men and 35.7 months for white men.
Looking at the adverse event profile, on the far right is what we will focus on, which is the grade three and four adverse events, most commonly was hypertension, at 24% for black men and 16% for white men. And also looking towards the bottom of the table, there was more hyperglycemia at 10% in black men and 4% in white men as well as more hypokalemia at 12% in black men and 4% of white men.
This table summarizes single-nucleotide polymorphisms associated with time to PSA progression. In the middle are the hazard ratios, and on the left are the genes, and you can see that the mutation in ACAA2 had a hazard ratio of 19.9 for PSA progression. Other ones with a significant impact included TM4SF20, with a hazard ratio of 9.95, and SPHKAP, with a hazard ratio of 7.68.
So several discussion points from this study. This is the first interventional trial in metastatic CRPC to pre-specify parallel patient treatment groups by self-identified race and to evaluate clinical efficacy and safety outcomes perspectively by race. Although this study was not designed to compare outcomes by race, black men did have higher rates of PSA decline and longer time to PSA progression. Furthermore, the longer-term outcomes of radiographic progression-free survival and overall survival were similar by race. This leads to encouraging data to support the intentional broadening of eligibility criteria to improve the inclusion of disproportionately affected black men with metastatic CRPC in prospective trials.
So in conclusion, this study demonstrated the feasibility of prospective race-based studies, inclusive of a high percentage of black men. With proper representation in treatment trials, more insights into how black patients tolerate and respond to therapy based on genetic and cultural factors may be gained. Ultimately, larger prospective randomized studies, proportionately inclusive of black men will be necessary to investigate fully the biological determinants associated with ancestry and outcomes.
Thank you very much. We hope you enjoyed this UroToday Journal Club.