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Foreword An interim analysis of the PROpel study published by ASCO GU2022 shows that olaparib combined with abiraterone is the first and only first-line population-based comparison of abiraterone in metastatic castration-resistant prostate cancer (mCRPC).
Long monotherapy has significant benefits in radiographic progression-free survival (rPFS), time to sequential therapy (TSFT) and other efficacy indicators, and although the data are immature, combination therapy has significant benefits in overall survival (OS) and secondary therapy.
Time to progression (PFS2) has also shown a trend of benefit
.
So in addition to the excellent efficacy, what is the safety of olaparib combined with abiraterone? We specially invite Professor Guo Hongqian and Professor Zhang Shun from the Department of Urology of Nanjing Drum Tower Hospital to give a wonderful interpretation
.
01Olaparib is a PARP inhibitor suitable for combination therapy.
One of the important safety issues to be addressed in the combination therapy of the two drugs is whether there is any interaction between the drugs and whether it will affect the exposure of the two drugs.
concentration affects
.
Secondly, because all current PARP inhibitors can inhibit PARP1 and PARP2, especially PARP2 is related to bone marrow hematopoietic function, which is easy to cause anemia
.
Therefore, a PARP inhibitor suitable for combined NHA treatment should have at least two characteristics of no significant drug-related effect with NHA and relatively mild inhibition of bone marrow hematopoiesis
.
In the phase I study of olaparib and abiraterone combined treatment, the exposure of the two drugs did not appear to be higher or lower than the exposure of either monotherapy after the combination, and there was no obvious drug-related effect.
A full-dose combination regimen of the two drugs is supported from a pharmacokinetic point of view
.
The plasma concentration of olaparib at steady state after administration of olaparib combined with abiraterone and olaparib alone at steady state The study of different PARP inhibitors on the plasma concentration of ilaparone shows that olaparib is a PARP inhibitor with little distribution in the bone marrow and no accumulation, so the effect of olaparib combination therapy on the hematopoietic function of the bone marrow will be relatively small
.
Bone Marrow Distribution and Accumulation Concentrations of Different PARP Inhibitors Safety Profile of Combination Therapy in the 02PROpel Study Overall and grade 3 or higher adverse event rates were similar between combination therapy versus monotherapy
.
The discontinuation rate of olaparib/placebo was slightly higher in combination therapy than monotherapy, and most patients were able to adhere to treatment until disease progression
.
The safety profile of the combination therapy observed in the PROpel study was consistent with the known profile of the two drugs as single agents, in terms of common adverse events in the study
.
In the two adverse events of special clinical concern, heart failure and vascular embolism, the incidence rates of the combination therapy group and the single-agent group were basically the same
.
At the same time, the analysis of the cases of combined embolism found that most of the embolic events were incidental pulmonary embolism detected by CT follow-up examination, and did not lead to discontinuation of olaparib or abiraterone
.
Conclusion The combination therapy of olaparib combined with abiraterone did not significantly increase the incidence of adverse events compared with monotherapy, and the types of common adverse events were consistent with the characteristics of the two monotherapy in previous studies
.
Therefore, the overall safety of olaparib combined with abiraterone can be predicted and managed
.
Compared with the safety characteristics of olaparib's back-line clinical studies, we can even find that the incidence of adverse events in the first-line mCRPC combination therapy seems to be lower, which may also indicate that patients with earlier lines are generally better , from the perspective of safety, it is more suitable for olaparib treatment
.
Initiated by Professor Guo Hongqian of Nanjing Drum Tower Hospital, "a study on the efficacy of olaparib combined with abiraterone acetate + prednisone in subjects with metastatic hormone-sensitive prostate cancer (mHSPC) carrying homologous recombination repair (HRR) gene mutations.
" The single-center, single-arm, prospective study of efficacy and safety (PROact)” (NCT05167175) is about to officially start enrollment.
This is the first domestic study to explore the efficacy and safety of olaparib combined with abiraterone in the mHSPC stage.
Clinical research, on the basis of PROpel, further explores the performance of combined therapy after forward shift, which is expected to fill the gap in this field at home and abroad
.
Expert Profile Professor Guo Hongqian, Chief Physician, Chief Physician, Professor and Doctoral Supervisor of Urology Department of Nanjing Drum Tower Hospital Director of the Institute of Urology of Nanjing University, enjoys special allowances from the State Council Experts are the first to open a single-disease ward for urologic tumors and interventional therapy for urologic tumors in China Ward Chairman of the Urinary System Disease Committee of Jiangsu Quality Control Association Chairman of the Medical Robot Professional Committee of the Jiangsu Medical Doctor Association Member of the National Health Commission Surgical Robot Clinical Application Management Expert Committee Member of the Urology Branch of the Chinese Medical Association Member of the Oncology Group of the Urology Branch of the Chinese Medical Association Cancer, urothelial cancer, kidney cancer and other drug treatment Good at urological tumor chemotherapy, immune, targeted therapy and whole-process standardized management Responsible for more than 40 clinical trials in urology department Familiar with the latest progress of various international cutting-edge new drugs Nanjing Drum Tower Hospital Urology Clinic Location of research center: Urology Clinical Research Office, 18/F, Building 1, Nanjing Drum Tower Hospital Contact: Zhang Shun Contact: explorershun@126.
com
Foreword An interim analysis of the PROpel study published by ASCO GU2022 shows that olaparib combined with abiraterone is the first and only first-line population-based comparison of abiraterone in metastatic castration-resistant prostate cancer (mCRPC).
Long monotherapy has significant benefits in radiographic progression-free survival (rPFS), time to sequential therapy (TSFT) and other efficacy indicators, and although the data are immature, combination therapy has significant benefits in overall survival (OS) and secondary therapy.
Time to progression (PFS2) has also shown a trend of benefit
.
So in addition to the excellent efficacy, what is the safety of olaparib combined with abiraterone? We specially invite Professor Guo Hongqian and Professor Zhang Shun from the Department of Urology of Nanjing Drum Tower Hospital to give a wonderful interpretation
.
01Olaparib is a PARP inhibitor suitable for combination therapy.
One of the important safety issues to be addressed in the combination therapy of the two drugs is whether there is any interaction between the drugs and whether it will affect the exposure of the two drugs.
concentration affects
.
Secondly, because all current PARP inhibitors can inhibit PARP1 and PARP2, especially PARP2 is related to bone marrow hematopoietic function, which is easy to cause anemia
.
Therefore, a PARP inhibitor suitable for combined NHA treatment should have at least two characteristics of no significant drug-related effect with NHA and relatively mild inhibition of bone marrow hematopoiesis
.
In the phase I study of olaparib and abiraterone combined treatment, the exposure of the two drugs did not appear to be higher or lower than the exposure of either monotherapy after the combination, and there was no obvious drug-related effect.
A full-dose combination regimen of the two drugs is supported from a pharmacokinetic point of view
.
The plasma concentration of olaparib at steady state after administration of olaparib combined with abiraterone and olaparib alone at steady state The study of different PARP inhibitors on the plasma concentration of ilaparone shows that olaparib is a PARP inhibitor with little distribution in the bone marrow and no accumulation, so the effect of olaparib combination therapy on the hematopoietic function of the bone marrow will be relatively small
.
Bone Marrow Distribution and Accumulation Concentrations of Different PARP Inhibitors Safety Profile of Combination Therapy in the 02PROpel Study Overall and grade 3 or higher adverse event rates were similar between combination therapy versus monotherapy
.
The discontinuation rate of olaparib/placebo was slightly higher in combination therapy than monotherapy, and most patients were able to adhere to treatment until disease progression
.
The safety profile of the combination therapy observed in the PROpel study was consistent with the known profile of the two drugs as single agents, in terms of common adverse events in the study
.
In the two adverse events of special clinical concern, heart failure and vascular embolism, the incidence rates of the combination therapy group and the single-agent group were basically the same
.
At the same time, the analysis of the cases of combined embolism found that most of the embolic events were incidental pulmonary embolism detected by CT follow-up examination, and did not lead to discontinuation of olaparib or abiraterone
.
Conclusion The combination therapy of olaparib combined with abiraterone did not significantly increase the incidence of adverse events compared with monotherapy, and the types of common adverse events were consistent with the characteristics of the two monotherapy in previous studies
.
Therefore, the overall safety of olaparib combined with abiraterone can be predicted and managed
.
Compared with the safety characteristics of olaparib's back-line clinical studies, we can even find that the incidence of adverse events in the first-line mCRPC combination therapy seems to be lower, which may also indicate that patients with earlier lines are generally better , from the perspective of safety, it is more suitable for olaparib treatment
.
Initiated by Professor Guo Hongqian of Nanjing Drum Tower Hospital, "a study on the efficacy of olaparib combined with abiraterone acetate + prednisone in subjects with metastatic hormone-sensitive prostate cancer (mHSPC) carrying homologous recombination repair (HRR) gene mutations.
" The single-center, single-arm, prospective study of efficacy and safety (PROact)” (NCT05167175) is about to officially start enrollment.
This is the first domestic study to explore the efficacy and safety of olaparib combined with abiraterone in the mHSPC stage.
Clinical research, on the basis of PROpel, further explores the performance of combined therapy after forward shift, which is expected to fill the gap in this field at home and abroad
.
Expert Profile Professor Guo Hongqian, Chief Physician, Chief Physician, Professor and Doctoral Supervisor of Urology Department of Nanjing Drum Tower Hospital Director of the Institute of Urology of Nanjing University, enjoys special allowances from the State Council Experts are the first to open a single-disease ward for urologic tumors and interventional therapy for urologic tumors in China Ward Chairman of the Urinary System Disease Committee of Jiangsu Quality Control Association Chairman of the Medical Robot Professional Committee of the Jiangsu Medical Doctor Association Member of the National Health Commission Surgical Robot Clinical Application Management Expert Committee Member of the Urology Branch of the Chinese Medical Association Member of the Oncology Group of the Urology Branch of the Chinese Medical Association Cancer, urothelial cancer, kidney cancer and other drug treatment Good at urological tumor chemotherapy, immune, targeted therapy and whole-process standardized management Responsible for more than 40 clinical trials in urology department Familiar with the latest progress of various international cutting-edge new drugs Nanjing Drum Tower Hospital Urology Clinic Location of research center: Urology Clinical Research Office, 18/F, Building 1, Nanjing Drum Tower Hospital Contact: Zhang Shun Contact: explorershun@126.
com
