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*For medical professionals' reference only, the 2021 American Society of Clinical Oncology Symposium on Urogenital Oncology (ASCO-GU) will be held on February 11-13, US Central Time.
This conference is co-organized by the American Society of Clinical Oncology (ASCO), American Society of Radiation Oncology (ASTRO) and American Society of Urological Oncology (SUO).
Related professionals in the treatment of urinary tumors provide a platform for academic discussion and cutting-edge knowledge exchange.
The conference announced the results of a number of major researches in the field of urinary tumors.
This article will share the heavy oral report data in the field of prostate cancer: the final analysis result of the TITAN study, and invite Professor Tan Wanlong from the Southern Hospital of Southern Medical University to conduct an in-depth interpretation.
[Abs 11] Final analysis of the TITAN study: a phase III study of apatamide combined with ADT in the treatment of mHSPC[1] TITAN study evaluated apatamide combined with androgen deprivation therapy (ADT) versus placebo combined with ADT for metastatic hormone sensitivity Phase III clinical study of prostate cancer (mHSPC), the study included a variety of patient types, high tumor burden, low tumor burden, localized disease stage received treatment (local treatment or systemic treatment), M1 stage received ≤6 Cycles of docetaxel chemotherapy or ADT treatment less than 6 months can be included in the group.
The study included 1052 mHSPC patients who were randomized 1:1 to receive ADT combined with apatamide (240 mg qd) or placebo.
The main study endpoints are overall survival (OS) and imaging progression-free survival (rPFS).
At the 2019 ASCO conference, the results of the first interim analysis were announced.
The results showed that at a median follow-up time of 22.
7 months, compared with placebo, apatamide significantly improved the two main study endpoints: OS (HR=0.
67) and rPFS (HR=0.
48).Since then, because apatamide can significantly benefit patients, the study was unblinded, allowing patients who are still receiving placebo treatment and have not progressed to be crossed into the group to receive apatamide treatment.
After the study was unblinded, a total of 208 (39.
5%) patients in the placebo group were crossed into the group to receive apatamide treatment (cross-treatment group).
At this year's ASCO-GU conference, Professor Kim Chi from Canada announced the final analysis of the efficacy and safety of the TITAN study in the form of an oral report.
The results showed that when the median follow-up time was 44 months, the overall median treatment time of the apatamide group and the placebo group were 39.
3 months and 20.
2 months, respectively.
The bit time is 15.
4 months.
Compared with placebo, apatamide can significantly reduce the risk of death by 35%, and the 4-year survival rate is 65% and 52% respectively; after the inverse probability censoring weighting (IPCW) method is used to exclude the influence of cross-entry factors, Apataamide can reduce the death risk of mHSPC patients by 48% (Table 1).
The median value of mHSPC patients receiving ADT treatment progressed to metastatic castration-resistant prostate cancer (mCRPC) at a median of 11.
4 months, while the median value of the apatamide group has not been reached, and apatamide can significantly reduce patients by 76% to The risk of castration resistance and the risk of 34% to the second disease progression (Table 1).
The results of subgroup analysis showed that different types of subgroups can benefit from OS from the treatment of apatamide (Figure 1).
The prostate cancer quality of life assessment scale (FACT-P) data showed that during the study follow-up, the quality of life of patients treated with apatamide can be maintained at a good baseline level, which is not significantly different from placebo (Figure 2) .
In addition, the safety data is also consistent with previous reports, no new types of adverse events have been reported, and the incidence of treatment-related adverse events does not increase significantly with the extension of follow-up time.
Table 1 Summary of the efficacy endpoint data of the final analysis of the TITAN study Figure 1 TITAN study: subgroup analysis of OS data Figure 2 TITAN study: The quality of life score of prostate cancer patients treated with ADT combined with apatamide or placebo compared to baseline Change expert comment (Professor Tan Wanlong, Nanfang Hospital, Southern Medical University) mHSPC refers to metastatic prostate cancer that responds curatively to ADT [2].
ADT treatment has always been the standard treatment for mHSPC, but almost all patients will eventually develop into the castration resistance stage, resulting in a poor prognosis.
Therefore, delaying the progression of mHSPC patients to the castration resistance stage is an important treatment strategy [3].
Since 2015, more and more combination treatments based on ADT have emerged in the mHSPC stage, which can significantly delay the progression of patients and prolong OS.
These include docetaxel chemotherapy, abiraterone, and apata New endocrine therapy represented by amines [4, 5, 6].
Because the treatment of docetaxel and abiraterone is limited to some patient types, they are mHSPC patients with high tumor burden and newly diagnosed high-risk mHSPC patients [5, 7]; for a wider range of mHSPC patients, there is still a lack of more active Treatment options.
The phase III TITAN study of apatamide included a wide range of mHSPC patient types, including high tumor burden, low tumor burden, high-risk, low-risk, progression after treatment at the newly diagnosed or localized disease stage, and even mHSPC stage.
≤6 cycles of docetaxel chemotherapy can be included in the group, which is in line with the complex source and type of patients in the real world [6].
Therefore, when the data of the TITAN study was first announced at the 2019 ASCO conference, it received extensive attention from clinicians [8].
In the first interim analysis, compared with ADT alone, apatamide combined with ADT treatment can significantly reduce the overall risk of death of mHSPC patients by 33%, and the risk of imaging progression or death by 52%.
Prostate-specific antigen ( PSA) The risk of progression is reduced by 74% [6]. Although the median follow-up time is only 22.
3 months [6], the long-term benefits of apatamide have been very clear.
Therefore, the indications for mHSPC were approved in the United States and China in 2019 and 2020, respectively.
But for clinicians, we still look forward to the efficacy and safety data of apatamide after a longer follow-up to better guide clinical practice.
This year's ASCO-GU finally revealed the mystery.
After nearly 4 years of follow-up, compared with ADT alone, apatamide combined with ADT can significantly reduce the risk of death by 35%, and the 4-year survival rate is 65% and 65% respectively.
52%[1, 6].
However, because apatamide showed excellent efficacy in the first interim analysis, about 40% of patients in the placebo group were crossed into the group to receive apatamide treatment [1], therefore, this data It has a large bias; if the factors of cross-entry are excluded, the median survival time of mHSPC patients receiving ADT treatment is only 39.
8 months, suggesting that this type of patients should be actively intervened as soon as possible regardless of the tumor burden; The combined treatment plan of apatamide can significantly reduce the risk of death by up to 48% [1], which is very shocking data and far superior to the results of phase III clinical studies of other new drugs.
As we mentioned earlier, delaying progression to mCRPC is also an important treatment goal for mHSPC patients.
So how long will it take for mHSPC patients under traditional endocrine therapy to progress to mCRPC? In the phase III clinical LATITUDE study of abiraterone, high-risk mHSPC patients received ADT treatment for about 7.
4 months to develop PSA progression.
In the TITAN study, overall mHSPC patients received ADT treatment and the time to progress to mCRPC was only 11.
4 months.
After up to 4 years of follow-up in the apatamide group, the median time to CRPC has not yet been reached.
These evidences suggest that, regardless of tumor burden or risk, mHSPC patients should choose new endocrine treatment options as early as possible to delay the progression of the disease and obtain better long-term benefits [1, 5].
In addition, due to the emergence of new treatment options, the course of mHSPC has been greatly extended, and the safety of long-term drug application has also become a very important consideration in clinical decision-making.
Docetaxel chemotherapy may have serious adverse reactions such as neutropenia and febrile neutropenia in clinical application, which can increase the hospitalization rate of patients and increase the difficulty of clinical management [4, 9, 10].
Common adverse reactions of abiraterone are mostly hypertension, hypokalemia, etc.
[5], which are easier to manage; but long-term combination with glucocorticoids may increase the management difficulty of patients with cardiovascular and metabolic complications.
As a new generation of androgen receptor inhibitor, apatamide neither has serious hematological adverse reactions like chemotherapy, nor does it require a combination of hormones, so it is more suitable for long-term use by patients in terms of mechanism.
A high-quality meta-analysis published in 2020 included a variety of treatment options for the mHSPC stage.
The study found that compared with ADT alone, docetaxel significantly increased the risk of serious adverse events, and abiraterone slightly increased serious adverse events The risk of events, and apatamide does not increase the risk of serious adverse events [11].
Further data from the TITAN study also showed that when the follow-up time was extended from 2 years to 4 years, the incidence of common adverse reactions of apatamide did not increase significantly, and the patient’s quality of life was still maintained at a good level, indicating that apa The long-term application of tamine still has good safety [1].
The results published in the early stage of the TITAN study have confirmed that mHSPC patients can quickly and persistently reduce PSA, prolong rPFS, and do not increase the frequency of AR mutations after receiving apatamide combined with ADT.
After progression, both sequential new endocrine therapy and chemotherapy can be used.
There are significant benefits.
This final analysis further confirmed that for mHSPC patients, the combination of apatamide and ADT can significantly prolong OS, and provide clear long-term clinical benefits and definite safety features.
94 Chinese cases were also included in the study.
Patients, once again brought confidence to our clinicians in applying apatamide [1, 12]. As Chinese urologists become more and more skilled in the use of apatamide as a powerful weapon, I am looking forward to the publication of evidence on the localization of apatamide in the real world in China in the future! Expert Profile Professor Tan Wanlong Director, Professor, Chief Physician, and Doctoral Supervisor, Department of Urology, Nanfang Hospital, Southern Medical University, Deputy Director, Urology Branch, Guangdong Medical Association, Director, Urology and Laparoscopy Branch, Guangdong Urogenital Association, Guangdong Medical Doctors Association, Urology Vice Chairman of the Science Branch Vice Chairman of the Urology Branch of Guangdong Association of Integrative Medicine and Vice Chairman of the Urogenital Oncology Committee of Guangdong Anticancer Association Vice Chairman of the Minimally Invasive Surgery Branch of the Guangdong Association of Integrative Medicine Guangdong Medical Education Association Deputy Chairman of the Urology Branch of the Minimally Invasive Group of the Urology Branch of Guangdong Medical Association References: 1.
Chi KM, et al.
Final analysis results from TITAN: a phase 3 study of apalutamide vs placebo in patients with metastatic castration-sensitive prostate cancer receiving androgen deprivation therapy.
J Clin Oncol 39, 2021 (suppl 6; abstr 11).
2.
2018 Chinese Expert Consensus on the Diagnosis and Treatment of Metastatic Prostate Cancer[J].
Zhu Yao.
Chinese Journal of Surgery.
2018; 56(9 ): 646-652.
3.
Guidelines for Diagnosis and Treatment of Urological Diseases in China[M].
Science Press, Editor-in-Chief Huang Jian, 2019.
4.
Sweeney CJ et al.
Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer.
N Engl J Med.
2015; 373 :737-46.
5.
Fizazi K, et al.
Lancet Oncol.
This conference is co-organized by the American Society of Clinical Oncology (ASCO), American Society of Radiation Oncology (ASTRO) and American Society of Urological Oncology (SUO).
Related professionals in the treatment of urinary tumors provide a platform for academic discussion and cutting-edge knowledge exchange.
The conference announced the results of a number of major researches in the field of urinary tumors.
This article will share the heavy oral report data in the field of prostate cancer: the final analysis result of the TITAN study, and invite Professor Tan Wanlong from the Southern Hospital of Southern Medical University to conduct an in-depth interpretation.
[Abs 11] Final analysis of the TITAN study: a phase III study of apatamide combined with ADT in the treatment of mHSPC[1] TITAN study evaluated apatamide combined with androgen deprivation therapy (ADT) versus placebo combined with ADT for metastatic hormone sensitivity Phase III clinical study of prostate cancer (mHSPC), the study included a variety of patient types, high tumor burden, low tumor burden, localized disease stage received treatment (local treatment or systemic treatment), M1 stage received ≤6 Cycles of docetaxel chemotherapy or ADT treatment less than 6 months can be included in the group.
The study included 1052 mHSPC patients who were randomized 1:1 to receive ADT combined with apatamide (240 mg qd) or placebo.
The main study endpoints are overall survival (OS) and imaging progression-free survival (rPFS).
At the 2019 ASCO conference, the results of the first interim analysis were announced.
The results showed that at a median follow-up time of 22.
7 months, compared with placebo, apatamide significantly improved the two main study endpoints: OS (HR=0.
67) and rPFS (HR=0.
48).Since then, because apatamide can significantly benefit patients, the study was unblinded, allowing patients who are still receiving placebo treatment and have not progressed to be crossed into the group to receive apatamide treatment.
After the study was unblinded, a total of 208 (39.
5%) patients in the placebo group were crossed into the group to receive apatamide treatment (cross-treatment group).
At this year's ASCO-GU conference, Professor Kim Chi from Canada announced the final analysis of the efficacy and safety of the TITAN study in the form of an oral report.
The results showed that when the median follow-up time was 44 months, the overall median treatment time of the apatamide group and the placebo group were 39.
3 months and 20.
2 months, respectively.
The bit time is 15.
4 months.
Compared with placebo, apatamide can significantly reduce the risk of death by 35%, and the 4-year survival rate is 65% and 52% respectively; after the inverse probability censoring weighting (IPCW) method is used to exclude the influence of cross-entry factors, Apataamide can reduce the death risk of mHSPC patients by 48% (Table 1).
The median value of mHSPC patients receiving ADT treatment progressed to metastatic castration-resistant prostate cancer (mCRPC) at a median of 11.
4 months, while the median value of the apatamide group has not been reached, and apatamide can significantly reduce patients by 76% to The risk of castration resistance and the risk of 34% to the second disease progression (Table 1).
The results of subgroup analysis showed that different types of subgroups can benefit from OS from the treatment of apatamide (Figure 1).
The prostate cancer quality of life assessment scale (FACT-P) data showed that during the study follow-up, the quality of life of patients treated with apatamide can be maintained at a good baseline level, which is not significantly different from placebo (Figure 2) .
In addition, the safety data is also consistent with previous reports, no new types of adverse events have been reported, and the incidence of treatment-related adverse events does not increase significantly with the extension of follow-up time.
Table 1 Summary of the efficacy endpoint data of the final analysis of the TITAN study Figure 1 TITAN study: subgroup analysis of OS data Figure 2 TITAN study: The quality of life score of prostate cancer patients treated with ADT combined with apatamide or placebo compared to baseline Change expert comment (Professor Tan Wanlong, Nanfang Hospital, Southern Medical University) mHSPC refers to metastatic prostate cancer that responds curatively to ADT [2].
ADT treatment has always been the standard treatment for mHSPC, but almost all patients will eventually develop into the castration resistance stage, resulting in a poor prognosis.
Therefore, delaying the progression of mHSPC patients to the castration resistance stage is an important treatment strategy [3].
Since 2015, more and more combination treatments based on ADT have emerged in the mHSPC stage, which can significantly delay the progression of patients and prolong OS.
These include docetaxel chemotherapy, abiraterone, and apata New endocrine therapy represented by amines [4, 5, 6].
Because the treatment of docetaxel and abiraterone is limited to some patient types, they are mHSPC patients with high tumor burden and newly diagnosed high-risk mHSPC patients [5, 7]; for a wider range of mHSPC patients, there is still a lack of more active Treatment options.
The phase III TITAN study of apatamide included a wide range of mHSPC patient types, including high tumor burden, low tumor burden, high-risk, low-risk, progression after treatment at the newly diagnosed or localized disease stage, and even mHSPC stage.
≤6 cycles of docetaxel chemotherapy can be included in the group, which is in line with the complex source and type of patients in the real world [6].
Therefore, when the data of the TITAN study was first announced at the 2019 ASCO conference, it received extensive attention from clinicians [8].
In the first interim analysis, compared with ADT alone, apatamide combined with ADT treatment can significantly reduce the overall risk of death of mHSPC patients by 33%, and the risk of imaging progression or death by 52%.
Prostate-specific antigen ( PSA) The risk of progression is reduced by 74% [6]. Although the median follow-up time is only 22.
3 months [6], the long-term benefits of apatamide have been very clear.
Therefore, the indications for mHSPC were approved in the United States and China in 2019 and 2020, respectively.
But for clinicians, we still look forward to the efficacy and safety data of apatamide after a longer follow-up to better guide clinical practice.
This year's ASCO-GU finally revealed the mystery.
After nearly 4 years of follow-up, compared with ADT alone, apatamide combined with ADT can significantly reduce the risk of death by 35%, and the 4-year survival rate is 65% and 65% respectively.
52%[1, 6].
However, because apatamide showed excellent efficacy in the first interim analysis, about 40% of patients in the placebo group were crossed into the group to receive apatamide treatment [1], therefore, this data It has a large bias; if the factors of cross-entry are excluded, the median survival time of mHSPC patients receiving ADT treatment is only 39.
8 months, suggesting that this type of patients should be actively intervened as soon as possible regardless of the tumor burden; The combined treatment plan of apatamide can significantly reduce the risk of death by up to 48% [1], which is very shocking data and far superior to the results of phase III clinical studies of other new drugs.
As we mentioned earlier, delaying progression to mCRPC is also an important treatment goal for mHSPC patients.
So how long will it take for mHSPC patients under traditional endocrine therapy to progress to mCRPC? In the phase III clinical LATITUDE study of abiraterone, high-risk mHSPC patients received ADT treatment for about 7.
4 months to develop PSA progression.
In the TITAN study, overall mHSPC patients received ADT treatment and the time to progress to mCRPC was only 11.
4 months.
After up to 4 years of follow-up in the apatamide group, the median time to CRPC has not yet been reached.
These evidences suggest that, regardless of tumor burden or risk, mHSPC patients should choose new endocrine treatment options as early as possible to delay the progression of the disease and obtain better long-term benefits [1, 5].
In addition, due to the emergence of new treatment options, the course of mHSPC has been greatly extended, and the safety of long-term drug application has also become a very important consideration in clinical decision-making.
Docetaxel chemotherapy may have serious adverse reactions such as neutropenia and febrile neutropenia in clinical application, which can increase the hospitalization rate of patients and increase the difficulty of clinical management [4, 9, 10].
Common adverse reactions of abiraterone are mostly hypertension, hypokalemia, etc.
[5], which are easier to manage; but long-term combination with glucocorticoids may increase the management difficulty of patients with cardiovascular and metabolic complications.
As a new generation of androgen receptor inhibitor, apatamide neither has serious hematological adverse reactions like chemotherapy, nor does it require a combination of hormones, so it is more suitable for long-term use by patients in terms of mechanism.
A high-quality meta-analysis published in 2020 included a variety of treatment options for the mHSPC stage.
The study found that compared with ADT alone, docetaxel significantly increased the risk of serious adverse events, and abiraterone slightly increased serious adverse events The risk of events, and apatamide does not increase the risk of serious adverse events [11].
Further data from the TITAN study also showed that when the follow-up time was extended from 2 years to 4 years, the incidence of common adverse reactions of apatamide did not increase significantly, and the patient’s quality of life was still maintained at a good level, indicating that apa The long-term application of tamine still has good safety [1].
The results published in the early stage of the TITAN study have confirmed that mHSPC patients can quickly and persistently reduce PSA, prolong rPFS, and do not increase the frequency of AR mutations after receiving apatamide combined with ADT.
After progression, both sequential new endocrine therapy and chemotherapy can be used.
There are significant benefits.
This final analysis further confirmed that for mHSPC patients, the combination of apatamide and ADT can significantly prolong OS, and provide clear long-term clinical benefits and definite safety features.
94 Chinese cases were also included in the study.
Patients, once again brought confidence to our clinicians in applying apatamide [1, 12]. As Chinese urologists become more and more skilled in the use of apatamide as a powerful weapon, I am looking forward to the publication of evidence on the localization of apatamide in the real world in China in the future! Expert Profile Professor Tan Wanlong Director, Professor, Chief Physician, and Doctoral Supervisor, Department of Urology, Nanfang Hospital, Southern Medical University, Deputy Director, Urology Branch, Guangdong Medical Association, Director, Urology and Laparoscopy Branch, Guangdong Urogenital Association, Guangdong Medical Doctors Association, Urology Vice Chairman of the Science Branch Vice Chairman of the Urology Branch of Guangdong Association of Integrative Medicine and Vice Chairman of the Urogenital Oncology Committee of Guangdong Anticancer Association Vice Chairman of the Minimally Invasive Surgery Branch of the Guangdong Association of Integrative Medicine Guangdong Medical Education Association Deputy Chairman of the Urology Branch of the Minimally Invasive Group of the Urology Branch of Guangdong Medical Association References: 1.
Chi KM, et al.
Final analysis results from TITAN: a phase 3 study of apalutamide vs placebo in patients with metastatic castration-sensitive prostate cancer receiving androgen deprivation therapy.
J Clin Oncol 39, 2021 (suppl 6; abstr 11).
2.
2018 Chinese Expert Consensus on the Diagnosis and Treatment of Metastatic Prostate Cancer[J].
Zhu Yao.
Chinese Journal of Surgery.
2018; 56(9 ): 646-652.
3.
Guidelines for Diagnosis and Treatment of Urological Diseases in China[M].
Science Press, Editor-in-Chief Huang Jian, 2019.
4.
Sweeney CJ et al.
Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer.
N Engl J Med.
2015; 373 :737-46.
5.
Fizazi K, et al.
Lancet Oncol.
