Pharmaco-ethnicity and Its Impact on Treatment Presentation - Darren MC Poon
September 4, 2019
At the 2019 Advanced Prostate Cancer Consensus Conference (APCCC) Darren Poon gave an overview of prostate cancer in the East-Asian ethnicity. This ethnicity includes China, (including Hong-Kong and Macau), Japan, Mongolia, North Korea, South Korea, and Taiwan. When assessing the taxane related adverse events in Asian prostate cancer patients, compared to the rates described in the major studies, there is clear evidence showing that Asian people have a higher rate of adverse events.
Biography:
Darren MC Poon, FHKCR, Consultant, Honorary Clinical Associate Professor, Department of Clinical Oncology, Prince of Wales Hospital, The Chinese University of Hong Kong, CUHK, Department of Clinical Oncology, Vice President of Hong Kong Society of Uro-Oncology
Read the Full Video Transcript
Darren Poon: Thank you for your kind introduction and thank you for the organizing committee for inviting me to this wonderful meeting. It will be my great pleasure to share with you my humble opinion on this topic regarding the pharmacoethnicity and its impact on treatment for prostate cancer patients, especially for those from Asian populations.
Here are my disclosures.
I was born and I am currently working in Hong Kong, which is part of China. And together with the other major Asian countries including Japan and Korea, we are categorized as East Asian ethnicity. And within this category Han, which is Chinese, Korean, Yamato, which is Japanese, are the major ethnic groups. Historically we might all originate from a common ancestor and share similar genetic features despite diversity, which exists in regard to the culture, history and finance.
When I travel around the world and talk to people that I come from Hong Kong, people usually talk to me about Bruce Lee, a former super movie star. And very interestingly, people usually think about most of the Chinese people will know Kung Fu, and as strong as him. However, in terms of the tolerability to cytotoxic treatments and chemotherapy, we are not as strong as you would imagine.
Previously we have reported our real world experience in using docetaxel in Chinese metastatic prostate cancer patients. Apparently there is a higher incidence of myelosuppression, particularly febrile neutropenia, in our patients compared to Caucasians. And also from the data, real-world data for cabazitaxel in the compassionate program, a similar high incidence of myelosuppression was seen in Asian populations. And this poor myelo tolerance is observed in both mHSPC and mCRPC patients.
Besides, the high susceptibility to docetaxel myelosuppression in the Asian population is not only confined to prostate cancer. In a study involving 120 phase two or three studies, and with the majority were lung and breast cancer patients, and with docetaxel monotherapy Q3 weeks as the treatment arm, it was found that those studies that were conducted in Asia were associated with a higher incidence of grade 3 and 4 neutropenia. And this highlighted the fact that Asian populations, in general, are inherently more prone to docetaxel myelosuppression, irrespective of cancer type.
While the chemo-tolerance in Asian populations are comparatively poor, how about the tolerance to AR agents? Based on our previous reports on the real-world data about abi and enza, apart from a slightly higher rate of hypertension and peripheral oedema with abi, and a slightly higher rate of hypertension and fatigue with enzalutamide, our Chinese mCRCP patient experienced a similar rate of severe adverse events due to dose in the pivotal studies. And in general our patients are quite tolerable to these AR agents, with few of them requiring treatment discontinuations due to the side-effects.
So while we have consistently observed a high incidence, or high risk of myelosuppression with taxane in Asians compared to Caucasians, is there any inter-ethnic difference in terms of drug response, especially with prostate cancer treatments? And based on the registration trial for docetaxel and abiraterone in China, and an analysis that primarily focused on East Asian ethnicity within the PREVAIL trial, our Asian population has a similar [inaudible 00:03:52] of survival benefit compared to the rest of the world, suggesting that the pharmacoethnicity variations is largely limited in drug's toxicity instead of drug's response.
So it's very reasonable to consider the pharmacokinetics of the drugs is important in determining the drug's toxicities. In fact, docetaxel pharmacokinetics has been evaluated since the early nineties. In a pharmacokinetics study that involving nearly 600 patients, docetaxel clearance was found to the major significant predictor for febrile neutropenia. And in the predictor model, a 50% decrease in docetaxel clearance, with result in nearly a three-fold increase in the risk of having febrile neutropenia. So it will be very interesting and important to investigate any underlying inter-ethnic difference in terms of the pharmacokinetics of docetaxel that could explain the high risk of myelosuppression with taxane in Asian population.
However, in a pharmacokinetics study that was conducted in both Caucasian and Japanese, it was found that there is a highly comparable docetaxel clearance between these two populations, suggesting that there is no obvious inter-ethnic difference in docetaxel pharmacokinetics. So, therefore, other factors other than pharmacokinetics may be more important in determining the high risk of myelosuppression in Asian patients.
Body weight? How about body weight? Bodyweight may be an important factor. According to statistics in 2002 obviously there was a remarkable weight difference between Caucasian and Asians. For example, there is around a 20-kilogram difference in mean body weight between an American and a Chinese. And also the weight difference was also observed even between cities in China. In general Asian have similar body weight or smaller body build and as a result the marrow reserve might be limited, and this may be the underlying reason in explaining the high risk of taxane related myelosuppression.
While we are waiting for the data in understanding the inter-ethnic pharmacology, there are several ways to address the high incidence of taxane related hematological complications, particularly the potential life-threatening febrile neutropenia. So for example, we can consider dose or schedule modifications, or the preemptive use of GCSF.
It is a common clinical practice in starting a lower dose of docetaxel in Asia because of the high incidence of myelosuppression that I previously mentioned. In the retrospective study that was conducted by the Japanese colleague, the standard regime, which was considered as 60 milligrams per meter squared every four weeks, was compared to the adaptive regime. And this consisted of three different administrations [inaudible 00:06:43] with a lower dose of docetaxel. And basically the base-line statistics are well balanced between the two different strategies. And you must find that the adaptive regime or dose reduce regime had similar survival, PSA response, and toxicities with the standard regime. And this suggested that the dose reduction, or modification, may be feasible in Asian patients, with a comparable survival outcome to the standard regime.
Apart from dose modification or reduction, switching the schedule from Q3 to Q2 weeks may also be a possible solution in reducing the risk of having hematological complications with taxane. In a randomized phase 3 controlled trial that was published in Lancet Oncology in 2013, 50 milligram per meter squared, Q2 weeks was associated with a better time to treatment failure and also survival. However, because of the potential caveat in the subsequent treatments in both arms, such potential survival benefit with two-weekly schedule might be not definite. But more importantly, the two-weekly schedule is associated with a more favorable toxicity profile and less hematological complications with only 4% of two-weekly schedule versus 14% of three-weekly schedule had febrile neutropenia. So despite such, two-weekly schedule has not been evaluated in Asian population. But because of the more favorable toxicity profile, it will be very attractive to Asian patients.
On behalf of Hong Kong Society of Uro-oncology we have recently reviewed the incidence of taxane related hematological complications in Chinese metastatic prostate cancer patient in Hong Kong. And among 383 patients, 15% of them had developed febrile neutropenia, with a rate slightly higher in mCRCP versus mHSPC patients. Within this cohort, around 29% of them had started with a lower dose of docetaxel, and around 80% of them had the use of preemptive GCSF.
And we have performed a regression analysis of febrile neutropenia at first cycle. Among various clinical parameters including the age, BMI, volume of DCs or dose chemotherapy, the preemptive use of GCSF is significantly associated with a lower risk of having febrile neutropenia after the first cycle of docetaxel. Besides, as expected a poor performance status is associated with a higher risk of having febrile neutropenia.
And because of such local experience, it is now a common clinical practice in Hong Kong, in considering the use of preemptive GCSF for metastatic prostate cancer patient, whom docetaxel is administered. Besides careful patient selection for docetaxel, it is suggested and supported by the consensus statement by the Hong Kong Urological Association and Hong Kong Society of Uro-oncology.
And the bone marrow protective effect with primary GCSF is also seen in patients with cabazitaxel. In this recently published prospective study that evaluates the primary GCSF in every cycle of cabazitaxel, only 9% of the Japanese mCRPC patient had developed febrile neutropenia. And such a rate is substantially low compared to the historical cohort without GCSF.
Nowadays, despite the acknowledgment of the potential ethnic influence on oncological outcomes there remains a lack of ethnic information and over-representation of Caucasian samples across oncological studies. So for example, despite Asian constituting around 60% of human populations, there are few Asian samples in the fundamental cancer research. And less than 10% of clinical trial participants will come from Asia. So there's a clear need in enhancing the non-Caucasian population to participate in a clinical trial in the near future.
Nowadays, we are happy to see more and more international collaborative studies involving multiple ethnics. However, the protocol, or the dose, or the schedule of the drugs is basically identical among different ethnics, with the considerations of the potential variation in pharmacoethnicity. However, if we could identify the potential pharmacokinetic difference between different ethnics at the very early beginning, or if you could identify the potential difference in the disease pattern between different ethnics, perhaps more informative by region or multicenter trial with an ethnic-specific protocol could be contemplated. And a more precise result to each specific region could be obtained.
So in summary, there's a clear inter-ethnic difference in pharmacology, especially cytotoxic toxicity in prostate cancer. Apparently there's a higher risk of taxane related hematological complications in Asian prostate cancer patients. However, there is no obvious inter-ethnic difference in pharmacokinetics, especially with docetaxel. [inaudible 00:11:51] fully explains such phenomenon. The smaller body build and the limited marrow reserve of Asian may be the underlying reasons. In general AR agents are well tolerated in our patients, and our patients enjoy a similar survival benefit with most of the life-prolonging therapy compared with the rest of the world. And in order to alleviate the risk of taxane related hematological complications in Asian prostate cancer patients, dose or schedule modifications of the chemotherapy, or the preemptive use of GCSF might help. Last, but not the least, in the near future pharmacoethnicity should be taken into account in clinical trials and fundamental cancer research.
Lastly, I hope you'll be fascinated with this photo showing you the spectacular view of the other side of Hong Kong, which is seldom known to people. Our home is over there but it's not available in the Airbnb. But anyway, Hong Kong remains one of the most beautiful cities around the world. I warmly welcome you to visit us and please let me know if you come to Hong Kong in the near future. Thank you for your attention.
Darren Poon: Thank you for your kind introduction and thank you for the organizing committee for inviting me to this wonderful meeting. It will be my great pleasure to share with you my humble opinion on this topic regarding the pharmacoethnicity and its impact on treatment for prostate cancer patients, especially for those from Asian populations.
Here are my disclosures.
I was born and I am currently working in Hong Kong, which is part of China. And together with the other major Asian countries including Japan and Korea, we are categorized as East Asian ethnicity. And within this category Han, which is Chinese, Korean, Yamato, which is Japanese, are the major ethnic groups. Historically we might all originate from a common ancestor and share similar genetic features despite diversity, which exists in regard to the culture, history and finance.
When I travel around the world and talk to people that I come from Hong Kong, people usually talk to me about Bruce Lee, a former super movie star. And very interestingly, people usually think about most of the Chinese people will know Kung Fu, and as strong as him. However, in terms of the tolerability to cytotoxic treatments and chemotherapy, we are not as strong as you would imagine.
Previously we have reported our real world experience in using docetaxel in Chinese metastatic prostate cancer patients. Apparently there is a higher incidence of myelosuppression, particularly febrile neutropenia, in our patients compared to Caucasians. And also from the data, real-world data for cabazitaxel in the compassionate program, a similar high incidence of myelosuppression was seen in Asian populations. And this poor myelo tolerance is observed in both mHSPC and mCRPC patients.
Besides, the high susceptibility to docetaxel myelosuppression in the Asian population is not only confined to prostate cancer. In a study involving 120 phase two or three studies, and with the majority were lung and breast cancer patients, and with docetaxel monotherapy Q3 weeks as the treatment arm, it was found that those studies that were conducted in Asia were associated with a higher incidence of grade 3 and 4 neutropenia. And this highlighted the fact that Asian populations, in general, are inherently more prone to docetaxel myelosuppression, irrespective of cancer type.
While the chemo-tolerance in Asian populations are comparatively poor, how about the tolerance to AR agents? Based on our previous reports on the real-world data about abi and enza, apart from a slightly higher rate of hypertension and peripheral oedema with abi, and a slightly higher rate of hypertension and fatigue with enzalutamide, our Chinese mCRCP patient experienced a similar rate of severe adverse events due to dose in the pivotal studies. And in general our patients are quite tolerable to these AR agents, with few of them requiring treatment discontinuations due to the side-effects.
So while we have consistently observed a high incidence, or high risk of myelosuppression with taxane in Asians compared to Caucasians, is there any inter-ethnic difference in terms of drug response, especially with prostate cancer treatments? And based on the registration trial for docetaxel and abiraterone in China, and an analysis that primarily focused on East Asian ethnicity within the PREVAIL trial, our Asian population has a similar [inaudible 00:03:52] of survival benefit compared to the rest of the world, suggesting that the pharmacoethnicity variations is largely limited in drug's toxicity instead of drug's response.
So it's very reasonable to consider the pharmacokinetics of the drugs is important in determining the drug's toxicities. In fact, docetaxel pharmacokinetics has been evaluated since the early nineties. In a pharmacokinetics study that involving nearly 600 patients, docetaxel clearance was found to the major significant predictor for febrile neutropenia. And in the predictor model, a 50% decrease in docetaxel clearance, with result in nearly a three-fold increase in the risk of having febrile neutropenia. So it will be very interesting and important to investigate any underlying inter-ethnic difference in terms of the pharmacokinetics of docetaxel that could explain the high risk of myelosuppression with taxane in Asian population.
However, in a pharmacokinetics study that was conducted in both Caucasian and Japanese, it was found that there is a highly comparable docetaxel clearance between these two populations, suggesting that there is no obvious inter-ethnic difference in docetaxel pharmacokinetics. So, therefore, other factors other than pharmacokinetics may be more important in determining the high risk of myelosuppression in Asian patients.
Body weight? How about body weight? Bodyweight may be an important factor. According to statistics in 2002 obviously there was a remarkable weight difference between Caucasian and Asians. For example, there is around a 20-kilogram difference in mean body weight between an American and a Chinese. And also the weight difference was also observed even between cities in China. In general Asian have similar body weight or smaller body build and as a result the marrow reserve might be limited, and this may be the underlying reason in explaining the high risk of taxane related myelosuppression.
While we are waiting for the data in understanding the inter-ethnic pharmacology, there are several ways to address the high incidence of taxane related hematological complications, particularly the potential life-threatening febrile neutropenia. So for example, we can consider dose or schedule modifications, or the preemptive use of GCSF.
It is a common clinical practice in starting a lower dose of docetaxel in Asia because of the high incidence of myelosuppression that I previously mentioned. In the retrospective study that was conducted by the Japanese colleague, the standard regime, which was considered as 60 milligrams per meter squared every four weeks, was compared to the adaptive regime. And this consisted of three different administrations [inaudible 00:06:43] with a lower dose of docetaxel. And basically the base-line statistics are well balanced between the two different strategies. And you must find that the adaptive regime or dose reduce regime had similar survival, PSA response, and toxicities with the standard regime. And this suggested that the dose reduction, or modification, may be feasible in Asian patients, with a comparable survival outcome to the standard regime.
Apart from dose modification or reduction, switching the schedule from Q3 to Q2 weeks may also be a possible solution in reducing the risk of having hematological complications with taxane. In a randomized phase 3 controlled trial that was published in Lancet Oncology in 2013, 50 milligram per meter squared, Q2 weeks was associated with a better time to treatment failure and also survival. However, because of the potential caveat in the subsequent treatments in both arms, such potential survival benefit with two-weekly schedule might be not definite. But more importantly, the two-weekly schedule is associated with a more favorable toxicity profile and less hematological complications with only 4% of two-weekly schedule versus 14% of three-weekly schedule had febrile neutropenia. So despite such, two-weekly schedule has not been evaluated in Asian population. But because of the more favorable toxicity profile, it will be very attractive to Asian patients.
On behalf of Hong Kong Society of Uro-oncology we have recently reviewed the incidence of taxane related hematological complications in Chinese metastatic prostate cancer patient in Hong Kong. And among 383 patients, 15% of them had developed febrile neutropenia, with a rate slightly higher in mCRCP versus mHSPC patients. Within this cohort, around 29% of them had started with a lower dose of docetaxel, and around 80% of them had the use of preemptive GCSF.
And we have performed a regression analysis of febrile neutropenia at first cycle. Among various clinical parameters including the age, BMI, volume of DCs or dose chemotherapy, the preemptive use of GCSF is significantly associated with a lower risk of having febrile neutropenia after the first cycle of docetaxel. Besides, as expected a poor performance status is associated with a higher risk of having febrile neutropenia.
And because of such local experience, it is now a common clinical practice in Hong Kong, in considering the use of preemptive GCSF for metastatic prostate cancer patient, whom docetaxel is administered. Besides careful patient selection for docetaxel, it is suggested and supported by the consensus statement by the Hong Kong Urological Association and Hong Kong Society of Uro-oncology.
And the bone marrow protective effect with primary GCSF is also seen in patients with cabazitaxel. In this recently published prospective study that evaluates the primary GCSF in every cycle of cabazitaxel, only 9% of the Japanese mCRPC patient had developed febrile neutropenia. And such a rate is substantially low compared to the historical cohort without GCSF.
Nowadays, despite the acknowledgment of the potential ethnic influence on oncological outcomes there remains a lack of ethnic information and over-representation of Caucasian samples across oncological studies. So for example, despite Asian constituting around 60% of human populations, there are few Asian samples in the fundamental cancer research. And less than 10% of clinical trial participants will come from Asia. So there's a clear need in enhancing the non-Caucasian population to participate in a clinical trial in the near future.
Nowadays, we are happy to see more and more international collaborative studies involving multiple ethnics. However, the protocol, or the dose, or the schedule of the drugs is basically identical among different ethnics, with the considerations of the potential variation in pharmacoethnicity. However, if we could identify the potential pharmacokinetic difference between different ethnics at the very early beginning, or if you could identify the potential difference in the disease pattern between different ethnics, perhaps more informative by region or multicenter trial with an ethnic-specific protocol could be contemplated. And a more precise result to each specific region could be obtained.
So in summary, there's a clear inter-ethnic difference in pharmacology, especially cytotoxic toxicity in prostate cancer. Apparently there's a higher risk of taxane related hematological complications in Asian prostate cancer patients. However, there is no obvious inter-ethnic difference in pharmacokinetics, especially with docetaxel. [inaudible 00:11:51] fully explains such phenomenon. The smaller body build and the limited marrow reserve of Asian may be the underlying reasons. In general AR agents are well tolerated in our patients, and our patients enjoy a similar survival benefit with most of the life-prolonging therapy compared with the rest of the world. And in order to alleviate the risk of taxane related hematological complications in Asian prostate cancer patients, dose or schedule modifications of the chemotherapy, or the preemptive use of GCSF might help. Last, but not the least, in the near future pharmacoethnicity should be taken into account in clinical trials and fundamental cancer research.
Lastly, I hope you'll be fascinated with this photo showing you the spectacular view of the other side of Hong Kong, which is seldom known to people. Our home is over there but it's not available in the Airbnb. But anyway, Hong Kong remains one of the most beautiful cities around the world. I warmly welcome you to visit us and please let me know if you come to Hong Kong in the near future. Thank you for your attention.