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*For medical professionals to read for reference only Foreword Prostate cancer is the second most common malignant tumor in males in the world [1], and it is an important threat to the health of middle-aged and elderly men
.
With the publication of the results of two phase III clinical studies, PROfound and PROpel, olaparib has become an important drug in the treatment of advanced prostate cancer, and is expected to bring more hope to patients
.
This paper specially invites Dean Huang Jian and Professor Liu Hao of Sun Yat-sen Memorial Hospital Affiliated to Sun Yat-sen University to introduce the treatment strategy of olaparib, a new drug, in advanced prostate cancer
.
Olaparib's Anticancer Mechanism "Synthetic lethality" is the most well-known anticancer mechanism of olaparib: Olaparib can inhibit PARP activity in both "direct inhibition" and "PARP trapping", leading to DNA replication forks The pause and collapse of the tumor cells eventually induce the death of tumor cells carrying mutations in the homologous recombination repair (HRR) gene due to the inability to complete DNA repair
.
The phase III clinical study PROfound of olaparib clearly confirmed that olaparib monotherapy can bring more significant survival gains to HRR/BRCA mutation patients who have progressed on NHA (abiraterone or enzalutamide, etc.
) benefit [2]
.
In addition to monotherapy, olaparib can enhance the activity of abiraterone by regulating AR receptor-dependent transcriptional activity, thereby achieving a synergistic anti-tumor effect of 1+1>2 in combination
.
Abiraterone induces an HRR-deficient phenotype and increases olaparib sensitivity
.
The latest published results of the PROpel study also confirmed that olaparib combined with abiraterone compared with abiraterone monotherapy can help first-line patients with metastatic castration-resistant prostate cancer (mCRPC) achieve better survival benefits [3]
.
"So on the premise that olaparib has obtained two pivotal phase III clinical studies, how to help patients choose the most appropriate treatment plan? The answer is that the target population needs to be more accurately selected according to the treatment that the patient has received in the past
.
NHA-treated mCRPC patients For mCRPC patients who have not been treated with NHA, the conventional treatment is to use NHA
.
The results of COU-AA-302 and PREVAIL studies [4], abiraterone or enzalutamide in first-line mCRPC patients The median survival time was 34.
7 and 35.
3 months, respectively, and both were less than 3 years
.
However, real-world studies showed that since about 50% of patients did not receive other effective treatments after the progression of mCRPC first-line therapy, the actual median survival time of mCRPC patients Even less than two years [5]
.
Therefore, strengthening the first-line treatment of mCRPC patients is an important treatment strategy to prolong the survival of mCRPC patients
.
The PROpel study included 796 first-line mCRPC patients who had not been treated with abiraterone.
Laparib combined with abiraterone therapy or abiraterone monotherapy group
.
The primary endpoint of the study showed a significant efficacy advantage in the combination therapy group compared with the monotherapy group: median rPFS 24.
8 vs 16.
6 months, HR 0.
66, 95% CI 0.
54-0.
81, P<0.
0001; subgroup analysis showed that both HRR-mutated and non-mutated patients could benefit from combination therapy; PROpel's OS data is not yet mature, but the KM curve has been separated, which means that OS has already occurred The trend of benefit (HR 0.
86)
.
Therefore, the results of the PROpel study suggest that patients with mCRPC who have not been treated with NHA are suitable for the combination therapy of olaparib and abiraterone
.
Patients with mCRPC who have progressed after NHA treatment For mCRPC patients who have received NHA treatment and have progressed, due to the possible cross-resistance between different NHAs, the guidelines do not recommend the use of NHA sequential therapy in the mCRPC stage [6,7]
.
With the advent of more and more precision medicines, patients at this stage may benefit from genetic sequencing and precision therapy
.
Olaparib is the only PARP inhibitor approved for prostate cancer indications in China and can be used for mCRPC patients who have progressed on NHA treatment and carry BRCA mutations
.
In the PROfound study of olaparib, olaparib reduced the risk of radiographic progression or death by 66% in patients with BRCA and ATM mutations compared with the control group (7.
4 months vs 3.
6 months, HR=0.
34; 95%CI 0.
25-0.
47; p<0.
0001) and a 31% risk of all-cause mortality (19.
1 vs 14.
7 months HR=0.
69; 95%CI 0.
50-0.
97; p=0.
0175)
.
In all HRR-mutated patients, olaparib also reduced the risk of radiographic progression or death by 51% (5.
8 months vs 3.
5 months HR=0.
49; 95% CI 0.
38-0.
63; p<0.
0001) and 21 % risk of death from any cause (HR=0.
79; 95% CI 0.
61-1.
03)
.
Therefore, for mCRPC patients who have progressed after NHA treatment, due to the timely identification of mutation characteristics through genetic testing, HRR/BRCA mutation patients can benefit from olaparib treatment
.
Conclusion Olaparib, as a new class of antitumor drugs, has changed the treatment landscape of advanced prostate cancer through two pivotal Phase III clinical studies
.
However, it should be noted that the target population of olaparib monotherapy/combination regimens is different
.
For combination regimens, it is suitable for patients with first-line mCRPC who have not been treated with NHA
.
Monotherapy is more suitable for patients with HRR/BRCA mutations who have progressed after NHA therapy
.
In specific clinical practice, it is necessary to identify the population, accumulate experience, and better benefit patients
.
Expert Profile Professor Huang Jian Director, Chief Physician, Doctoral Supervisor, Department of Urology, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Chairman of the Urology Branch of the Chinese Medical Association, Vice President of the Medical Robotic Physician Branch of the Chinese Medical Doctor Association, Chairman of the China Bladder Cancer Alliance, President of the Chinese Journal of Urology Editor and Expert Profile Professor Liu Hao, Deputy Chief Physician of the Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Master's Tutor, Prostate Cancer Single Disease Specialist, Secretary of the Guidelines Office of the Urology Branch of the Chinese Medical Association References: [1] GLOBOCAN 2020 Statistics.
http://gco .
iarc.
fr.
[2] Hussain M, et al.
N Engl J Med 2020;383:2345-57.
[3] 2022 ASCO GU abstract 11.
PROpel: Phase III trial of olaparib (ola) and abiraterone (abi) placebo (pbo) and abi as first-line (1L) therapy versus patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).
[4] Ryan CJ, et al.
Lancet Oncol 2015;16:152–60.
[5] George DJ, et al.
Clin Genitourin Cancer.
2020;18:284-294.
[6] Van Soest RJ, et al.
Eur J Cancer.
2013 Dec;49(18):3821-30.
[7] EAU Guidelines on Prostate Cancer 2021.
*This article is for the purpose of providing scientific information to medical professionals only and does not represent the views of this platform
.
With the publication of the results of two phase III clinical studies, PROfound and PROpel, olaparib has become an important drug in the treatment of advanced prostate cancer, and is expected to bring more hope to patients
.
This paper specially invites Dean Huang Jian and Professor Liu Hao of Sun Yat-sen Memorial Hospital Affiliated to Sun Yat-sen University to introduce the treatment strategy of olaparib, a new drug, in advanced prostate cancer
.
Olaparib's Anticancer Mechanism "Synthetic lethality" is the most well-known anticancer mechanism of olaparib: Olaparib can inhibit PARP activity in both "direct inhibition" and "PARP trapping", leading to DNA replication forks The pause and collapse of the tumor cells eventually induce the death of tumor cells carrying mutations in the homologous recombination repair (HRR) gene due to the inability to complete DNA repair
.
The phase III clinical study PROfound of olaparib clearly confirmed that olaparib monotherapy can bring more significant survival gains to HRR/BRCA mutation patients who have progressed on NHA (abiraterone or enzalutamide, etc.
) benefit [2]
.
In addition to monotherapy, olaparib can enhance the activity of abiraterone by regulating AR receptor-dependent transcriptional activity, thereby achieving a synergistic anti-tumor effect of 1+1>2 in combination
.
Abiraterone induces an HRR-deficient phenotype and increases olaparib sensitivity
.
The latest published results of the PROpel study also confirmed that olaparib combined with abiraterone compared with abiraterone monotherapy can help first-line patients with metastatic castration-resistant prostate cancer (mCRPC) achieve better survival benefits [3]
.
"So on the premise that olaparib has obtained two pivotal phase III clinical studies, how to help patients choose the most appropriate treatment plan? The answer is that the target population needs to be more accurately selected according to the treatment that the patient has received in the past
.
NHA-treated mCRPC patients For mCRPC patients who have not been treated with NHA, the conventional treatment is to use NHA
.
The results of COU-AA-302 and PREVAIL studies [4], abiraterone or enzalutamide in first-line mCRPC patients The median survival time was 34.
7 and 35.
3 months, respectively, and both were less than 3 years
.
However, real-world studies showed that since about 50% of patients did not receive other effective treatments after the progression of mCRPC first-line therapy, the actual median survival time of mCRPC patients Even less than two years [5]
.
Therefore, strengthening the first-line treatment of mCRPC patients is an important treatment strategy to prolong the survival of mCRPC patients
.
The PROpel study included 796 first-line mCRPC patients who had not been treated with abiraterone.
Laparib combined with abiraterone therapy or abiraterone monotherapy group
.
The primary endpoint of the study showed a significant efficacy advantage in the combination therapy group compared with the monotherapy group: median rPFS 24.
8 vs 16.
6 months, HR 0.
66, 95% CI 0.
54-0.
81, P<0.
0001; subgroup analysis showed that both HRR-mutated and non-mutated patients could benefit from combination therapy; PROpel's OS data is not yet mature, but the KM curve has been separated, which means that OS has already occurred The trend of benefit (HR 0.
86)
.
Therefore, the results of the PROpel study suggest that patients with mCRPC who have not been treated with NHA are suitable for the combination therapy of olaparib and abiraterone
.
Patients with mCRPC who have progressed after NHA treatment For mCRPC patients who have received NHA treatment and have progressed, due to the possible cross-resistance between different NHAs, the guidelines do not recommend the use of NHA sequential therapy in the mCRPC stage [6,7]
.
With the advent of more and more precision medicines, patients at this stage may benefit from genetic sequencing and precision therapy
.
Olaparib is the only PARP inhibitor approved for prostate cancer indications in China and can be used for mCRPC patients who have progressed on NHA treatment and carry BRCA mutations
.
In the PROfound study of olaparib, olaparib reduced the risk of radiographic progression or death by 66% in patients with BRCA and ATM mutations compared with the control group (7.
4 months vs 3.
6 months, HR=0.
34; 95%CI 0.
25-0.
47; p<0.
0001) and a 31% risk of all-cause mortality (19.
1 vs 14.
7 months HR=0.
69; 95%CI 0.
50-0.
97; p=0.
0175)
.
In all HRR-mutated patients, olaparib also reduced the risk of radiographic progression or death by 51% (5.
8 months vs 3.
5 months HR=0.
49; 95% CI 0.
38-0.
63; p<0.
0001) and 21 % risk of death from any cause (HR=0.
79; 95% CI 0.
61-1.
03)
.
Therefore, for mCRPC patients who have progressed after NHA treatment, due to the timely identification of mutation characteristics through genetic testing, HRR/BRCA mutation patients can benefit from olaparib treatment
.
Conclusion Olaparib, as a new class of antitumor drugs, has changed the treatment landscape of advanced prostate cancer through two pivotal Phase III clinical studies
.
However, it should be noted that the target population of olaparib monotherapy/combination regimens is different
.
For combination regimens, it is suitable for patients with first-line mCRPC who have not been treated with NHA
.
Monotherapy is more suitable for patients with HRR/BRCA mutations who have progressed after NHA therapy
.
In specific clinical practice, it is necessary to identify the population, accumulate experience, and better benefit patients
.
Expert Profile Professor Huang Jian Director, Chief Physician, Doctoral Supervisor, Department of Urology, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Chairman of the Urology Branch of the Chinese Medical Association, Vice President of the Medical Robotic Physician Branch of the Chinese Medical Doctor Association, Chairman of the China Bladder Cancer Alliance, President of the Chinese Journal of Urology Editor and Expert Profile Professor Liu Hao, Deputy Chief Physician of the Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Master's Tutor, Prostate Cancer Single Disease Specialist, Secretary of the Guidelines Office of the Urology Branch of the Chinese Medical Association References: [1] GLOBOCAN 2020 Statistics.
http://gco .
iarc.
fr.
[2] Hussain M, et al.
N Engl J Med 2020;383:2345-57.
[3] 2022 ASCO GU abstract 11.
PROpel: Phase III trial of olaparib (ola) and abiraterone (abi) placebo (pbo) and abi as first-line (1L) therapy versus patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).
[4] Ryan CJ, et al.
Lancet Oncol 2015;16:152–60.
[5] George DJ, et al.
Clin Genitourin Cancer.
2020;18:284-294.
[6] Van Soest RJ, et al.
Eur J Cancer.
2013 Dec;49(18):3821-30.
[7] EAU Guidelines on Prostate Cancer 2021.
*This article is for the purpose of providing scientific information to medical professionals only and does not represent the views of this platform
