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*Only for medical professionals to read the reference research overview▎Research background: Endocrine therapy is the basic treatment for patients with advanced prostate cancer, but after endocrine therapy with a median time of 18-24 months, almost all patients have progressed to castration resistance Prostate cancer (CRPC).
The pathogenic mechanism of CRPC is unknown, the related molecular network is complex, and multiple signal pathways cooperate to cause disease, and change with the development of the disease; common molecular mechanisms include the synthesis of adrenal androgen and androgen in tumors, and AR gene mutations (gene amplification and Overexpression, point mutations, splice variants), etc.
Therefore, targeted therapy for a single molecule is difficult to completely remove the disease [1].
Both apatamide and abiraterone acetate have been approved for the treatment of prostate cancer, which have potent AR inhibition and total blockade of testosterone synthesis, respectively [2,3].
The ACIS study aimed to compare the imaging-free survival of new dual endocrine suppression (apatamide + abiraterone + prednisone) and standard endocrine therapy (abiraterone + prednisone) in mCRPC patients without chemotherapy Time (rPFS) [4].
▎Research method: ACIS is a randomized, double-blind, placebo-controlled Phase III study.
The enrolled patients were patients with metastatic castration-resistant prostate cancer (mCRPC) who met the PCWG2 diagnostic criteria and did not receive other life-prolonging treatments.
They were randomly assigned to apatamide (240 mg po QD) + apatamide at a ratio of 1:1 Bitelong (1000 mg QD) + prednisone (5 mg BID) group or abiraterone (1000 mg QD) + prednisone (5 mg BID) group, according to whether there is visceral metastasis, ECOG status 0 or 1, And geographical area for preset layering.
The primary endpoint of the study is rPFS.
Secondary/other endpoints include overall survival (OS), time to start cytotoxic treatment, time to pain progression, time to start opioid use, time to clinical progression, etc.
▎Research results: From December 2014 to August 2016, a total of 982 mCRPC patients were enrolled, and the median follow-up time was 54.
8 months.
The final analysis of the primary endpoint rPFS showed that compared with the abiraterone + prednisone group, the median rPFS of the apataamide + abiraterone + prednisone group was extended by 7.
4 months [24.
0 months vs.
16.
6 Month, HR 0.
70 (95% CI 0.
60-0.
83)], consistent with the results of the first interim analysis in 2018 [22.
6 months vs.
16.
6 months, HR 0.
69 (95% CI 0.
58-0.
83); p<0.
0001].
In the secondary end point analysis, compared with the abiraterone + prednisone group, the median OS of the apartamide + abiraterone + prednisone group had a prolonged trend, but it was not statistically significant [36.
2 months vs.
.
33.
7 months, HR 0.
95 (95% CI 0.
81-1.
11); p=0.
498].
The time to start cytotoxic treatment, the time to pain progression, the time to start opioids, the median time to clinical progression, and the median time to prostate-specific antigen (PSA) progression were also not statistically different between the two groups.
It is worth noting that the 50% PSA response rate and the rate of patients with PSA<0.
2 ng/ml in the apatamide+abiraterone+prednisone group have significant benefits.
The hierarchical analysis of the preset subgroups suggests that patients aged ≥75 years, visceral metastases, glandular cavity type by PAM50 test, and AR activity at an average level or above can be treated from apatamide + abiraterone + There are further clinical benefits in prednisone combination therapy.
Among them, the subgroups of age ≥75 years old had sufficient sample size (n=353).
There were significant differences in rPFS and OS in the apatamide + abiraterone + prednisone combination treatment group. However, the three subgroups of visceral metastasis, PAM50 test for glandular cavity type, and AR activity at an average level or above were too small after stratification.
The apatamide + abiraterone + prednisone combination treatment group showed gains.
However, there is no statistical difference, which needs to be verified by further research later.
In terms of adverse reactions, the safety of the two treatment groups is consistent with the previous experience of medication, and there are no new safety issues.
The incidence of grade 3/4 adverse events in the apatamide+abiraterone+prednisone combination treatment group was 63.
3% (310/490), and that in the abiraterone+prednisone group was 56.
2% (275/489).
Common types of adverse reactions in the two groups were fatigue, hypertension, skin rash, cardiovascular disease, and fractures.
The final analysis of the ACIS study announced at this conference confirmed that compared with abiraterone acetate and prednisone treatment, apatamide combined with abiraterone acetate and prednisone treatment can reduce the risk of imaging progression in mCRPC patients by 30%.
It will not cause new security issues.
Experts comment that abiraterone combined with prednisone is now the standard treatment for mCRPC and has been recommended by authoritative guidelines at home and abroad.
The results of the 302 study showed that for mCRPC patients without chemotherapy, the median rPFS treatment with abiraterone was 16.
5 months, and the median OS could reach 34.
7 months [5].
In recent years, with the advent of new AR inhibitors represented by apatamide, it has brought more options for the optimization of mCRPC treatment.
Can the all-source blocker of testosterone synthesis and powerful AR inhibitors work together to achieve a 1+1>2 therapeutic effect? This is a frontier issue that has plagued colleagues in the industry for many years.
The announcement of the ACIS research results at this ASCO-GU conference can provide a true and reliable reference for this issue.
ACIS is derived from an ordinary young shepherd living in Sicily in ancient Greek mythology.
He fell in love with Galatea, the goddess of the sea, and finally turned into Assis in order to fight against the cyclops.
River, and become an eternal remembrance. The research in the name of ACIS also indicates that the combination of apatamide and abiraterone will bring new hope for the intensive treatment of advanced prostate cancer.
Although different studies are not suitable for direct horizontal comparison, we can still find that the median rPFS of the abiraterone group in the 302 study and the ACIS study were 16.
5 months and 16.
6 months, respectively.
The highly consistent rPFS data suggest that these two random Controlled trials (RCTs) have extremely high objective authenticity.
The treatment of apatamide combined with abiraterone can further extend the median rPFS by 7.
4 months, reaching a total of 24 months, which is a quite remarkable achievement in the treatment of mCRPC.
And in terms of the PSA response rate and the ratio of patients with PSA<0.
2 ng/ml, which are the clinical indicators that doctors and patients pay close attention to in the early stage, apatamide combined with abiraterone treatment can also bring more significant benefits, which allows clinicians to discuss There will be stronger confidence in the treatment of the combined treatment plan.
It is worth noting that although the median OS of the combination group of apatamide and abiraterone in the ACIS study is as long as 36.
2 months, it is the longest OS option among the large-scale mCRPC-related RCTs so far, but compared with abiraterone There was no statistical difference in the benefit trend of the treatment group.
This reminds us that abiraterone, the first choice for mCRPC patients, is also excellent enough to bring patients a good survival expectation.
And because OS is not the primary end point of the ACIS study, the key factors such as the entry and discharge criteria and sample size in the study design are all considered based on the primary end point rPFS.
The non-statistical difference in some secondary end points is also a common phenomenon in many large RCTs.
.
Further subgroup analysis showed that the four types of patients with ≥75 years of age, visceral metastases, glandular cavity type by PAM50 test, and AR activity at an average level or above were treated with apatamide and abiraterone combined treatment, and their clinical results The benefit will be further expanded.
This is also the patient characteristic that can be prioritized when planning to adopt combination therapy in our clinical practice.
Before this study, there have been many attempts to combine new treatment strategies in the first-line treatment of mCRPC, but the results were not satisfactory.
The ALLIANCE A031201 study was announced at the 2019 ASCO conference.
This study compared the therapeutic effects of enzalutamide combined with abiraterone and enzalutamide alone.
The primary endpoint of the study was OS.
The results confirmed that there was no statistical difference between the two groups (p=0.
19), and the adverse reactions in the combined treatment group increased significantly [6].
The combined study of radium 223 and abiraterone (ERA 223) was also terminated early due to fractures and high mortality [7].
The publication of the ACIS study confirms that treatment with apatamide combined with abiraterone can significantly prolong rPFS compared to standard abiraterone treatment without causing new safety issues, bringing new authoritative evidence for the first-line intensive treatment of mCRPC It also brings longer survival expectations to patients.
Expert profile Professor Cui Diansheng, Director of Urology, Hubei Cancer Hospital, Vice Chairman of the Youth Committee of the Chinese Anti-Cancer Association Urinary and Male Reproductive Oncology Committee, and member of the Minimally Invasive Group.
Young member of the Society of Surgery, member of the Hubei Anti-Cancer Association, member of the Urology and Oncology Society, member of the Hubei Province Endoscopic Urology Clinical Medicine Center, member of the Hubei Provincial Society of Integrated Traditional Chinese and Western Medicine, and member of the Urology Society of Hubei Province.
Endoscopic in situ bladder surgery for bladder cancer, laparoscopic radical prostatectomy, comprehensive treatment of difficult and complicated urinary tract tumors. References: 1.
2019 Chinese prostate cancer diagnosis and treatment guidelines 2.
Apatamide tablets instructions 3.
Abiraterone acetate instructions 4.
Rathkopf, DE.
et al.
Results From ACIS, a Randomized, Placebo-Controlled Double-Blind Phase 3 Study of Apalutamide and Abiraterone Acetate Plus Prednisone Versus Abiraterone in Patients With Chemo-Naive Metastatic Castration-Resistant Prostate Cancer.
ASCO-GU 2021.
Oral Presentation #9.
5.
Ryan CJ et al.
Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men with metastatic castration-resistant prostate cancer (COU-AA-302): fi nal overall survival analysis of a randomised, double-blind, placebo-controlled phase 3 study.
Lancet Oncol 2015;16:152-606.
Morris MJ, et al.
Alliance A031201: A phase III trial of enzalutamide(ENZ) versus enzalutamide, abiraterone, and prednisone(ENZ/AAP) for metastatic castration resistant prostate cancer(mCRPC).
Annals of Oncology.
2019;371(Supplement 15):5008-20087.
Smith M, et al.
Addition of radium-223 to abiraterone acetate and prednisone or prednisolone in patients with castration-resistant prostate cancer and bone metastases (ERA 223): a randomised, double-blind , placebo-controlled, phase 3 trial.
Lancet.
2019;20(3):408-419.
The pathogenic mechanism of CRPC is unknown, the related molecular network is complex, and multiple signal pathways cooperate to cause disease, and change with the development of the disease; common molecular mechanisms include the synthesis of adrenal androgen and androgen in tumors, and AR gene mutations (gene amplification and Overexpression, point mutations, splice variants), etc.
Therefore, targeted therapy for a single molecule is difficult to completely remove the disease [1].
Both apatamide and abiraterone acetate have been approved for the treatment of prostate cancer, which have potent AR inhibition and total blockade of testosterone synthesis, respectively [2,3].
The ACIS study aimed to compare the imaging-free survival of new dual endocrine suppression (apatamide + abiraterone + prednisone) and standard endocrine therapy (abiraterone + prednisone) in mCRPC patients without chemotherapy Time (rPFS) [4].
▎Research method: ACIS is a randomized, double-blind, placebo-controlled Phase III study.
The enrolled patients were patients with metastatic castration-resistant prostate cancer (mCRPC) who met the PCWG2 diagnostic criteria and did not receive other life-prolonging treatments.
They were randomly assigned to apatamide (240 mg po QD) + apatamide at a ratio of 1:1 Bitelong (1000 mg QD) + prednisone (5 mg BID) group or abiraterone (1000 mg QD) + prednisone (5 mg BID) group, according to whether there is visceral metastasis, ECOG status 0 or 1, And geographical area for preset layering.
The primary endpoint of the study is rPFS.
Secondary/other endpoints include overall survival (OS), time to start cytotoxic treatment, time to pain progression, time to start opioid use, time to clinical progression, etc.
▎Research results: From December 2014 to August 2016, a total of 982 mCRPC patients were enrolled, and the median follow-up time was 54.
8 months.
The final analysis of the primary endpoint rPFS showed that compared with the abiraterone + prednisone group, the median rPFS of the apataamide + abiraterone + prednisone group was extended by 7.
4 months [24.
0 months vs.
16.
6 Month, HR 0.
70 (95% CI 0.
60-0.
83)], consistent with the results of the first interim analysis in 2018 [22.
6 months vs.
16.
6 months, HR 0.
69 (95% CI 0.
58-0.
83); p<0.
0001].
In the secondary end point analysis, compared with the abiraterone + prednisone group, the median OS of the apartamide + abiraterone + prednisone group had a prolonged trend, but it was not statistically significant [36.
2 months vs.
.
33.
7 months, HR 0.
95 (95% CI 0.
81-1.
11); p=0.
498].
The time to start cytotoxic treatment, the time to pain progression, the time to start opioids, the median time to clinical progression, and the median time to prostate-specific antigen (PSA) progression were also not statistically different between the two groups.
It is worth noting that the 50% PSA response rate and the rate of patients with PSA<0.
2 ng/ml in the apatamide+abiraterone+prednisone group have significant benefits.
The hierarchical analysis of the preset subgroups suggests that patients aged ≥75 years, visceral metastases, glandular cavity type by PAM50 test, and AR activity at an average level or above can be treated from apatamide + abiraterone + There are further clinical benefits in prednisone combination therapy.
Among them, the subgroups of age ≥75 years old had sufficient sample size (n=353).
There were significant differences in rPFS and OS in the apatamide + abiraterone + prednisone combination treatment group. However, the three subgroups of visceral metastasis, PAM50 test for glandular cavity type, and AR activity at an average level or above were too small after stratification.
The apatamide + abiraterone + prednisone combination treatment group showed gains.
However, there is no statistical difference, which needs to be verified by further research later.
In terms of adverse reactions, the safety of the two treatment groups is consistent with the previous experience of medication, and there are no new safety issues.
The incidence of grade 3/4 adverse events in the apatamide+abiraterone+prednisone combination treatment group was 63.
3% (310/490), and that in the abiraterone+prednisone group was 56.
2% (275/489).
Common types of adverse reactions in the two groups were fatigue, hypertension, skin rash, cardiovascular disease, and fractures.
The final analysis of the ACIS study announced at this conference confirmed that compared with abiraterone acetate and prednisone treatment, apatamide combined with abiraterone acetate and prednisone treatment can reduce the risk of imaging progression in mCRPC patients by 30%.
It will not cause new security issues.
Experts comment that abiraterone combined with prednisone is now the standard treatment for mCRPC and has been recommended by authoritative guidelines at home and abroad.
The results of the 302 study showed that for mCRPC patients without chemotherapy, the median rPFS treatment with abiraterone was 16.
5 months, and the median OS could reach 34.
7 months [5].
In recent years, with the advent of new AR inhibitors represented by apatamide, it has brought more options for the optimization of mCRPC treatment.
Can the all-source blocker of testosterone synthesis and powerful AR inhibitors work together to achieve a 1+1>2 therapeutic effect? This is a frontier issue that has plagued colleagues in the industry for many years.
The announcement of the ACIS research results at this ASCO-GU conference can provide a true and reliable reference for this issue.
ACIS is derived from an ordinary young shepherd living in Sicily in ancient Greek mythology.
He fell in love with Galatea, the goddess of the sea, and finally turned into Assis in order to fight against the cyclops.
River, and become an eternal remembrance. The research in the name of ACIS also indicates that the combination of apatamide and abiraterone will bring new hope for the intensive treatment of advanced prostate cancer.
Although different studies are not suitable for direct horizontal comparison, we can still find that the median rPFS of the abiraterone group in the 302 study and the ACIS study were 16.
5 months and 16.
6 months, respectively.
The highly consistent rPFS data suggest that these two random Controlled trials (RCTs) have extremely high objective authenticity.
The treatment of apatamide combined with abiraterone can further extend the median rPFS by 7.
4 months, reaching a total of 24 months, which is a quite remarkable achievement in the treatment of mCRPC.
And in terms of the PSA response rate and the ratio of patients with PSA<0.
2 ng/ml, which are the clinical indicators that doctors and patients pay close attention to in the early stage, apatamide combined with abiraterone treatment can also bring more significant benefits, which allows clinicians to discuss There will be stronger confidence in the treatment of the combined treatment plan.
It is worth noting that although the median OS of the combination group of apatamide and abiraterone in the ACIS study is as long as 36.
2 months, it is the longest OS option among the large-scale mCRPC-related RCTs so far, but compared with abiraterone There was no statistical difference in the benefit trend of the treatment group.
This reminds us that abiraterone, the first choice for mCRPC patients, is also excellent enough to bring patients a good survival expectation.
And because OS is not the primary end point of the ACIS study, the key factors such as the entry and discharge criteria and sample size in the study design are all considered based on the primary end point rPFS.
The non-statistical difference in some secondary end points is also a common phenomenon in many large RCTs.
.
Further subgroup analysis showed that the four types of patients with ≥75 years of age, visceral metastases, glandular cavity type by PAM50 test, and AR activity at an average level or above were treated with apatamide and abiraterone combined treatment, and their clinical results The benefit will be further expanded.
This is also the patient characteristic that can be prioritized when planning to adopt combination therapy in our clinical practice.
Before this study, there have been many attempts to combine new treatment strategies in the first-line treatment of mCRPC, but the results were not satisfactory.
The ALLIANCE A031201 study was announced at the 2019 ASCO conference.
This study compared the therapeutic effects of enzalutamide combined with abiraterone and enzalutamide alone.
The primary endpoint of the study was OS.
The results confirmed that there was no statistical difference between the two groups (p=0.
19), and the adverse reactions in the combined treatment group increased significantly [6].
The combined study of radium 223 and abiraterone (ERA 223) was also terminated early due to fractures and high mortality [7].
The publication of the ACIS study confirms that treatment with apatamide combined with abiraterone can significantly prolong rPFS compared to standard abiraterone treatment without causing new safety issues, bringing new authoritative evidence for the first-line intensive treatment of mCRPC It also brings longer survival expectations to patients.
Expert profile Professor Cui Diansheng, Director of Urology, Hubei Cancer Hospital, Vice Chairman of the Youth Committee of the Chinese Anti-Cancer Association Urinary and Male Reproductive Oncology Committee, and member of the Minimally Invasive Group.
Young member of the Society of Surgery, member of the Hubei Anti-Cancer Association, member of the Urology and Oncology Society, member of the Hubei Province Endoscopic Urology Clinical Medicine Center, member of the Hubei Provincial Society of Integrated Traditional Chinese and Western Medicine, and member of the Urology Society of Hubei Province.
Endoscopic in situ bladder surgery for bladder cancer, laparoscopic radical prostatectomy, comprehensive treatment of difficult and complicated urinary tract tumors. References: 1.
2019 Chinese prostate cancer diagnosis and treatment guidelines 2.
Apatamide tablets instructions 3.
Abiraterone acetate instructions 4.
Rathkopf, DE.
et al.
Results From ACIS, a Randomized, Placebo-Controlled Double-Blind Phase 3 Study of Apalutamide and Abiraterone Acetate Plus Prednisone Versus Abiraterone in Patients With Chemo-Naive Metastatic Castration-Resistant Prostate Cancer.
ASCO-GU 2021.
Oral Presentation #9.
5.
Ryan CJ et al.
Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men with metastatic castration-resistant prostate cancer (COU-AA-302): fi nal overall survival analysis of a randomised, double-blind, placebo-controlled phase 3 study.
Lancet Oncol 2015;16:152-606.
Morris MJ, et al.
Alliance A031201: A phase III trial of enzalutamide(ENZ) versus enzalutamide, abiraterone, and prednisone(ENZ/AAP) for metastatic castration resistant prostate cancer(mCRPC).
Annals of Oncology.
2019;371(Supplement 15):5008-20087.
Smith M, et al.
Addition of radium-223 to abiraterone acetate and prednisone or prednisolone in patients with castration-resistant prostate cancer and bone metastases (ERA 223): a randomised, double-blind , placebo-controlled, phase 3 trial.
Lancet.
2019;20(3):408-419.
