The main purpose of this study is a better comprehension of the non-bonded interaction between an anticancer drug apalutamide and deoxyribonucleic acid(DNA).In the prese nt work,the in teraction between an ticancer dr...The main purpose of this study is a better comprehension of the non-bonded interaction between an anticancer drug apalutamide and deoxyribonucleic acid(DNA).In the prese nt work,the in teraction between an ticancer drug apalutamide and one of the DNA bases called 2,-deoxythymidine 5,-monophosphate(thymine)by Density Functional Theory(DFT)calculations in the solvent water has been investigated for the first time.The non-bonded interaction effects of the molecule apalutamide with thymine on the electronic properties,chemical shift tensors and natural charges have been also detected.The natural bond orbital(NBO)analysis was performed for determining the role of electron donor and acceptor of the molecules apalutamide and thymine at the complex thymine/apalutamide.Both Electron location function(ELF),localized orbital locator(LOL)and quantum theory of atoms in molecules(QTAIM)analysis were carried out in order to determine the chemical bond nature in the investigated compounds.The values of ELF and LOL parameters for the selected bonds are small,which confirms the non-covalent character of these bonds in nature.The electronic spectra of the apalutamide drug,thymine and complex thymine/apalutamide in solvent water were calculated by Time Dependent Density Functional Theory(TD-DFT)for the investigation of interaction effect;Non-bonded interaction between the compound apalutamide and thymine has changed the value of λmax.展开更多
The final analysis of the phase 3 Targeted Investigational Treatment Analysis of Novel Anti-androgen(TITAN)trial showed improvement in overall survival(OS)and other efficacy endpoints with apalutamide plus androgen de...The final analysis of the phase 3 Targeted Investigational Treatment Analysis of Novel Anti-androgen(TITAN)trial showed improvement in overall survival(OS)and other efficacy endpoints with apalutamide plus androgen deprivation therapy(ADT)versus ADT alone in patients with metastatic castration-sensitive prostate cancer(mCSPC).As ethnicity and regional differences may affect treatment outcomes in advanced prostate cancer,a post hoc final analysis was conducted to assess the efficacy and safety of apalutamide in the Asian subpopulation.Event-driven endpoints were OS,and time from randomization to initiation of castration resistance,prostate-specific antigen(PSA)progression,and second progression-free survival(PFS2)on first subsequent therapy or death.Efficacy endpoints were assessed using the Kaplan–Meier method and Cox proportional-hazards models without formal statistical testing and adjustment for multiplicity.Participating Asian patients received once-daily apalutamide 240 mg(n=111)or placebo(n=110)plus ADT.After a median follow-up of 42.5 months and despite crossover of 47 placebo recipients to open-label apalutamide,apalutamide reduced the risk of death by 32%(hazard ratio[HR]:0.68;95%confidence interval[CI]:0.42–1.13),risk of castration resistance by 69%(HR:0.31;95%CI:0.21–0.46),PSA progression by 79%(HR:0.21;95%CI:0.13–0.35)and PFS2 by 24%(HR:0.76;95%CI:0.44–1.29)relative to placebo.The outcomes were comparable between subgroups with low-and high-volume disease at baseline.No new safety issues were identified.Apalutamide provides valuable clinical benefits to Asian patients with mCSPC,with an efficacy and safety profile consistent with that in the overall patient population.展开更多
Ethnicity might be associated with treatment outcomes in advanced prostate cancer.This study aimed to evaluate the efficacy and safety of androgen deprivation therapy(ADT)combined with apalutamide in East Asians with ...Ethnicity might be associated with treatment outcomes in advanced prostate cancer.This study aimed to evaluate the efficacy and safety of androgen deprivation therapy(ADT)combined with apalutamide in East Asians with metastatic castration-sensitive prostate cancer(mCSPC).The original phase 3 Targeted Investigational Treatment Analysis of Novel Anti-androgen(TITAN)trial was conducted at 260 sites in 23 countries.This subgroup analysis included patients enrolled in 62 participating centers in China,Japan,and Korea.Radiographic progression-free survival(PFS),time to prostate-specific antigen(PSA)progression,and PSA changes from baseline were compared between groups in the East Asian population.The intent-to-treat East Asian population included 111 and 110 participants in the apalutamide and placebo groups,respectively.The 24-month radiographic PFS rates were 76.1%and 52.3%in the apalutamide and placebo groups,respectively(apalutamide vs placebo:hazard ratio[HR]=0.506;95%confidence interval[CI],0.302–0.849;P=0.009).Median time to PSA progression was more favorable with apalutamide than placebo(HR=0.210;95%CI,0.124–0.357;P<0.001).Median maximum percentages of PSA decline from baseline were 99.0%and 73.9%in the apalutamide and placebo groups,respectively.The most common adverse event(AE)was rash in the apalutamide group,with a higher rate than that in the placebo group(37.3%vs 9.1%).The most common grade 3 or 4 AEs were rash(12[10.9%])and hypertension(12[10.9%])for apalutamide.The efficacy and safety of apalutamide in the East Asian subgroup of the TITAN trial are consistent with the global results.展开更多
BACKGROUND The 2020 European Association of Urology prostate cancer guidelines recommend androgen deprivation therapy(ADT)in combination with apalutamide and enzalutamide,a new generation of androgen receptor antagoni...BACKGROUND The 2020 European Association of Urology prostate cancer guidelines recommend androgen deprivation therapy(ADT)in combination with apalutamide and enzalutamide,a new generation of androgen receptor antagonists,as first-line therapy.A decrease in prostate-specific antigen(PSA)levels may occur in the early stages of novel hormonal therapy;however,radionuclide bone imaging may suggest disease progression.During follow-up,PSA,radionuclide bone imaging,and prostate-specific membrane antigen(PSMA)positron emission tomography–computed tomography(PET-CT)are needed for systematic evaluation.CASE SUMMARY We admitted a 56-year-old male patient with metastatic hormone-sensitive prostate cancer.Initial radionuclide bone imaging,magnetic resonance imaging(MRI),and PSMA PET-CT showed prostate cancer with multiple bone metastases.Ultrasound-guided needle biopsy of the prostate revealed a poorly differentiated adenocarcinoma of the prostate with a Gleason score:5+4=9.The final diagnosis was a prostate adenocarcinoma(T4N1M1).ADT with novel hormonal therapy(goseraline sustained-release implant 3.6 mg monthly and apalutamide 240 mg daily)was commenced.Three months later,radionuclide bone imaging and MRI revealed advanced bone metastasis.However,PSMA PET-CT examination showed a significant reduction in PSMA aggregation on the bone,indicating improved bone metastases.Considering that progressive decrease in the presenting lumbar pain,treatment strategies were considered to be effective.CONCLUSION ADT using novel hormonal therapy is effective for treating patients with prostate adenocarcinoma.Careful evaluation must precede treatment plan changes.展开更多
Nonmetastatic castration-resistant prostate cancer(nmCRPC)-defined as prostate-specific antigen(PSA)>2 ng/mL,testosterone castration levels<1.7 nm/L,and the absence of metastatic lesions on conventional imaging(...Nonmetastatic castration-resistant prostate cancer(nmCRPC)-defined as prostate-specific antigen(PSA)>2 ng/mL,testosterone castration levels<1.7 nm/L,and the absence of metastatic lesions on conventional imaging(computed tomography or bone scan)-has been defined as a lethal disease by the Prostate Cancer Work Group.One-third of patients with prostate cancer who receive androgen deprivation therapy for biochemical recurrence after local treatment will develop CRPC,with death occurring an average of 2.5 years after diagnosis of castration resistance.Most patients diagnosed with nmCRPC are asymptomatic or minimally symptomatic at diagnosis due to local treatment.In patients with short PSA doubling times(<10 mo)and high baseline PSA levels,there is a high risk of bone metastases followed by prostate cancer-related mortality.These patients also present significant morbidity that negatively impacts quality of life(QoL).Recently,the results of three randomized trials(PROSPER,SPARTAN,and ARAMIS)were published.Those trials evaluated the efficacy of three different androgen receptor inhibitors-enzalutamide,apalutamide,and darolutamide-in patients with nmCRPC.In all three trials,the study drugs improved both metastasis-free survival and overall survival compared to placebo,plus on-going androgen deprivation therapy without a negative impact on QoL.In patients with nmCRPC,the most important clinical objective is early detection and treatment to maintain a low tumor burden and to prolong the symptom-free interval.For patients with nmCRPC,these novel drugs offer new hope for better QoL and survival outcomes.展开更多
The number of treatment options for metastatic hormone-sensitive prostate cancer has increased substantially in recent years.The classic treatment approach for these patients—androgen-deprivation therapy alone—is no...The number of treatment options for metastatic hormone-sensitive prostate cancer has increased substantially in recent years.The classic treatment approach for these patients—androgen-deprivation therapy alone—is now considered suboptimal.Several randomized phase III clinical trials have demonstrated significant clinical benefits—including significantly better overall survival and quality of life—for treatments that combine androgen-deprivation therapy with docetaxel,abiraterone acetate,enzalutamide,apalutamide,and/or radiotherapy to the primary tumour.As a result,these approaches are now included in treatment guidelines and considered standard of care.However,the different treatment strategies have not been directly compared,and thus treatment selection remains at the discretion of the individual physician or,ideally,a multidisciplinary team.Given the range of available treatment approaches with varying toxicity profiles,treatment selection should be individualized based on the patient’s clinical characteristics and preferences,which implies active patient participation in the decision-making process.In the present document,we discuss the changing landscape of the management of patients with metastatic hormonesensitive prostate cancer in the context of several recently-published landmark randomized trials.In addition,we discuss several unresolved issues,including the optimal sequencing of systemic treatments and the incorporation of local treatment of the primary tumour and metastases.展开更多
基金supported by the National Academy of Sciences of Belarus
文摘The main purpose of this study is a better comprehension of the non-bonded interaction between an anticancer drug apalutamide and deoxyribonucleic acid(DNA).In the prese nt work,the in teraction between an ticancer drug apalutamide and one of the DNA bases called 2,-deoxythymidine 5,-monophosphate(thymine)by Density Functional Theory(DFT)calculations in the solvent water has been investigated for the first time.The non-bonded interaction effects of the molecule apalutamide with thymine on the electronic properties,chemical shift tensors and natural charges have been also detected.The natural bond orbital(NBO)analysis was performed for determining the role of electron donor and acceptor of the molecules apalutamide and thymine at the complex thymine/apalutamide.Both Electron location function(ELF),localized orbital locator(LOL)and quantum theory of atoms in molecules(QTAIM)analysis were carried out in order to determine the chemical bond nature in the investigated compounds.The values of ELF and LOL parameters for the selected bonds are small,which confirms the non-covalent character of these bonds in nature.The electronic spectra of the apalutamide drug,thymine and complex thymine/apalutamide in solvent water were calculated by Time Dependent Density Functional Theory(TD-DFT)for the investigation of interaction effect;Non-bonded interaction between the compound apalutamide and thymine has changed the value of λmax.
基金The study was funded by Janssen Pharmaceutical Ltd.Writing assistance was provided by Katherine A Lyseng-Williamson and Kerry Dechant,ISMPP CMPP^(TM),on behalf of Content Ed Net,and was funded by Janssen Pharmaceutical Ltd.Janssen Pharmaceutical Ltd.is not involved in the process of experimental design,results,or discussion,and has no competing interests with this study.
文摘The final analysis of the phase 3 Targeted Investigational Treatment Analysis of Novel Anti-androgen(TITAN)trial showed improvement in overall survival(OS)and other efficacy endpoints with apalutamide plus androgen deprivation therapy(ADT)versus ADT alone in patients with metastatic castration-sensitive prostate cancer(mCSPC).As ethnicity and regional differences may affect treatment outcomes in advanced prostate cancer,a post hoc final analysis was conducted to assess the efficacy and safety of apalutamide in the Asian subpopulation.Event-driven endpoints were OS,and time from randomization to initiation of castration resistance,prostate-specific antigen(PSA)progression,and second progression-free survival(PFS2)on first subsequent therapy or death.Efficacy endpoints were assessed using the Kaplan–Meier method and Cox proportional-hazards models without formal statistical testing and adjustment for multiplicity.Participating Asian patients received once-daily apalutamide 240 mg(n=111)or placebo(n=110)plus ADT.After a median follow-up of 42.5 months and despite crossover of 47 placebo recipients to open-label apalutamide,apalutamide reduced the risk of death by 32%(hazard ratio[HR]:0.68;95%confidence interval[CI]:0.42–1.13),risk of castration resistance by 69%(HR:0.31;95%CI:0.21–0.46),PSA progression by 79%(HR:0.21;95%CI:0.13–0.35)and PFS2 by 24%(HR:0.76;95%CI:0.44–1.29)relative to placebo.The outcomes were comparable between subgroups with low-and high-volume disease at baseline.No new safety issues were identified.Apalutamide provides valuable clinical benefits to Asian patients with mCSPC,with an efficacy and safety profile consistent with that in the overall patient population.
基金This study was funded by Janssen Pharmaceutical Ltd.,which designed the study.
文摘Ethnicity might be associated with treatment outcomes in advanced prostate cancer.This study aimed to evaluate the efficacy and safety of androgen deprivation therapy(ADT)combined with apalutamide in East Asians with metastatic castration-sensitive prostate cancer(mCSPC).The original phase 3 Targeted Investigational Treatment Analysis of Novel Anti-androgen(TITAN)trial was conducted at 260 sites in 23 countries.This subgroup analysis included patients enrolled in 62 participating centers in China,Japan,and Korea.Radiographic progression-free survival(PFS),time to prostate-specific antigen(PSA)progression,and PSA changes from baseline were compared between groups in the East Asian population.The intent-to-treat East Asian population included 111 and 110 participants in the apalutamide and placebo groups,respectively.The 24-month radiographic PFS rates were 76.1%and 52.3%in the apalutamide and placebo groups,respectively(apalutamide vs placebo:hazard ratio[HR]=0.506;95%confidence interval[CI],0.302–0.849;P=0.009).Median time to PSA progression was more favorable with apalutamide than placebo(HR=0.210;95%CI,0.124–0.357;P<0.001).Median maximum percentages of PSA decline from baseline were 99.0%and 73.9%in the apalutamide and placebo groups,respectively.The most common adverse event(AE)was rash in the apalutamide group,with a higher rate than that in the placebo group(37.3%vs 9.1%).The most common grade 3 or 4 AEs were rash(12[10.9%])and hypertension(12[10.9%])for apalutamide.The efficacy and safety of apalutamide in the East Asian subgroup of the TITAN trial are consistent with the global results.
文摘BACKGROUND The 2020 European Association of Urology prostate cancer guidelines recommend androgen deprivation therapy(ADT)in combination with apalutamide and enzalutamide,a new generation of androgen receptor antagonists,as first-line therapy.A decrease in prostate-specific antigen(PSA)levels may occur in the early stages of novel hormonal therapy;however,radionuclide bone imaging may suggest disease progression.During follow-up,PSA,radionuclide bone imaging,and prostate-specific membrane antigen(PSMA)positron emission tomography–computed tomography(PET-CT)are needed for systematic evaluation.CASE SUMMARY We admitted a 56-year-old male patient with metastatic hormone-sensitive prostate cancer.Initial radionuclide bone imaging,magnetic resonance imaging(MRI),and PSMA PET-CT showed prostate cancer with multiple bone metastases.Ultrasound-guided needle biopsy of the prostate revealed a poorly differentiated adenocarcinoma of the prostate with a Gleason score:5+4=9.The final diagnosis was a prostate adenocarcinoma(T4N1M1).ADT with novel hormonal therapy(goseraline sustained-release implant 3.6 mg monthly and apalutamide 240 mg daily)was commenced.Three months later,radionuclide bone imaging and MRI revealed advanced bone metastasis.However,PSMA PET-CT examination showed a significant reduction in PSMA aggregation on the bone,indicating improved bone metastases.Considering that progressive decrease in the presenting lumbar pain,treatment strategies were considered to be effective.CONCLUSION ADT using novel hormonal therapy is effective for treating patients with prostate adenocarcinoma.Careful evaluation must precede treatment plan changes.
文摘Nonmetastatic castration-resistant prostate cancer(nmCRPC)-defined as prostate-specific antigen(PSA)>2 ng/mL,testosterone castration levels<1.7 nm/L,and the absence of metastatic lesions on conventional imaging(computed tomography or bone scan)-has been defined as a lethal disease by the Prostate Cancer Work Group.One-third of patients with prostate cancer who receive androgen deprivation therapy for biochemical recurrence after local treatment will develop CRPC,with death occurring an average of 2.5 years after diagnosis of castration resistance.Most patients diagnosed with nmCRPC are asymptomatic or minimally symptomatic at diagnosis due to local treatment.In patients with short PSA doubling times(<10 mo)and high baseline PSA levels,there is a high risk of bone metastases followed by prostate cancer-related mortality.These patients also present significant morbidity that negatively impacts quality of life(QoL).Recently,the results of three randomized trials(PROSPER,SPARTAN,and ARAMIS)were published.Those trials evaluated the efficacy of three different androgen receptor inhibitors-enzalutamide,apalutamide,and darolutamide-in patients with nmCRPC.In all three trials,the study drugs improved both metastasis-free survival and overall survival compared to placebo,plus on-going androgen deprivation therapy without a negative impact on QoL.In patients with nmCRPC,the most important clinical objective is early detection and treatment to maintain a low tumor burden and to prolong the symptom-free interval.For patients with nmCRPC,these novel drugs offer new hope for better QoL and survival outcomes.
文摘The number of treatment options for metastatic hormone-sensitive prostate cancer has increased substantially in recent years.The classic treatment approach for these patients—androgen-deprivation therapy alone—is now considered suboptimal.Several randomized phase III clinical trials have demonstrated significant clinical benefits—including significantly better overall survival and quality of life—for treatments that combine androgen-deprivation therapy with docetaxel,abiraterone acetate,enzalutamide,apalutamide,and/or radiotherapy to the primary tumour.As a result,these approaches are now included in treatment guidelines and considered standard of care.However,the different treatment strategies have not been directly compared,and thus treatment selection remains at the discretion of the individual physician or,ideally,a multidisciplinary team.Given the range of available treatment approaches with varying toxicity profiles,treatment selection should be individualized based on the patient’s clinical characteristics and preferences,which implies active patient participation in the decision-making process.In the present document,we discuss the changing landscape of the management of patients with metastatic hormonesensitive prostate cancer in the context of several recently-published landmark randomized trials.In addition,we discuss several unresolved issues,including the optimal sequencing of systemic treatments and the incorporation of local treatment of the primary tumour and metastases.
