Objective:This double-blind,placebo-controlled phase 3 study was designed to compare efficacy and safety of abiraterone acetate+prednisone(abiraterone)to prednisone alone in chemotherapy-naı¨ve,asymptomatic or mi...Objective:This double-blind,placebo-controlled phase 3 study was designed to compare efficacy and safety of abiraterone acetate+prednisone(abiraterone)to prednisone alone in chemotherapy-naı¨ve,asymptomatic or mildly symptomatic metastatic castrationresistant prostate cancer(mCRPC)patients from China,Malaysia,Thailand and Russia.Methods:Adult chemotherapy-naı¨ve patients with confirmed prostate adenocarcinoma,Eastern Cooperative Oncology Group(ECOG)performance status(PS)grade 0e1,ongoing androgen deprivation(serum testosterone<50 ng/dL)with prostate specific antigen(PSA)or radiographic progression were randomized to receive abiraterone acetate(1000 mg,QD)t prednisone(5 mg,BID)or placebo t prednisone(5 mg,BID),until disease progression,unacceptable toxicity or consent withdrawal.Primary endpoint was improvements in time to PSA progression(TTPP).Results:Totally,313 patients were randomized(abiraterone:n Z 157;prednisone:n Z 156);and baseline characteristics were balanced.At clinical cut-off(median follow-up time:3.9 months),80% patients received treatment(abiraterone:n Z 138,prednisone:n Z 112).Median time to PSA progression was not reached with abiraterone versus 3.8 months for prednisone,attaining 58%reduction in PSA progression risk(HR=0.418;p<0.0001).Abirateronetreated patients had higher confirmed PSA response rate(50%vs.21%;relative odds=2.4;p<0.0001)and were 5 times more likely to achieve radiographic response than prednisonetreated patients(22.9%vs.4.8%,p=0.0369).Median survival was not reached.Most common(≥10% abiraterone vs.prednisone-treated)adverse events:bone pain(7%vs.14%),pain in extremity(6%vs.12%),arthralgia(10%vs.8%),back pain(7%vs.11%),and hypertension(15%vs.14%).Conclusion:Interim analysis confirmed favorable benefit-to-risk ratio of abiraterone in chemotherapy-naı¨ve men with mCRPC,consistent with global study,thus supporting use of abiraterone in this patient population.展开更多
AIM: To study the efficacy and safety of abiraterone in patients with and without prior chemotherapy.METHODS: The databases including Pub Med and abstracts presented at the American Society of Clinical Oncology meetin...AIM: To study the efficacy and safety of abiraterone in patients with and without prior chemotherapy.METHODS: The databases including Pub Med and abstracts presented at the American Society of Clinical Oncology meetings up to April 2014 were systematically searched. Eligible studies included randomized controlled trials(RCTs) in which abiraterone plus prednisone was compared to placebo plus prednisone in metastatic castration-resistant prostate cancer(CRPC) patients. The summary incidence, relative risk, hazard ratio and 95%CI were calculated using random or fixed-effects models. Heterogeneity test was performed to test between-study differences in efficacy and toxicity.RESULTS: A total of two phase III RCTs were included in our analysis, with metastatic CPRC patients before(n = 1088) and after chemotherapy(n = 1195). Prior chemotherapy did not significantly alter the effect of abiraterone on overall survival(P = 0.92) and prostatespecific antigen(PSA) progression-free survival(P = 0.13), but reduced its effect on radiographic-prog-ression-free survival(P = 0.04), objective response rate(P < 0.001), and PSA response rate(P < 0.001). Prior chemotherapy significantly increased the specific risk of fluid retention and edema(P < 0.001) and hypokalemia(P < 0.001), but decreased the risk of all-grade hypertension(P < 0.001) attributable to abiraterone. There was no significant difference of cardiac disorders associated with abiraterone between the two settings(P = 0.58). CONCLUSION: Prior chemotherapy may reduce the effectiveness of abiraterone in patients with metastatic CRPC.展开更多
<strong>Background:</strong> According to the main prostate cancer guidelines, the response to treatment with abiraterone plus prednisone (AA+P) must be evaluated by assessing prostate-specific antigen (PS...<strong>Background:</strong> According to the main prostate cancer guidelines, the response to treatment with abiraterone plus prednisone (AA+P) must be evaluated by assessing prostate-specific antigen (PSA) levels at 12 weeks. Recent studies have shown that early PSA decline, at 4 weeks, maybe a surrogate marker for survival. The objective of this work was to analyze if a decline in PSA at 4 weeks correlates with a better outcome in terms of OS (overall survival) and PFS (progression-free survival). <strong>Methods:</strong> We evaluated 168 patients (with a median age of 71 years) with prostate cancer who had started AA+P treatment between February 2012 and July 2019. Patients were divided into three different groups according to the decline of PSA (≥30%, ≥50%, and ≥90%) at 4, 8, and 12 weeks. Statistical survival analysis was performed using the Kaplan-Meier method. <strong>Results:</strong> After a follow-up of 69 months, a PSA decline ≥ 30% at 4 weeks was associated with longer median OS times (28 vs. 18 months;<em>p</em> = 0.027). A decline in PSA by ≥50% was also associated with increased median OS times (36 vs. 21;<em>p</em> = 0.003). Cox univariable analysis indicated that a decrease in PSA (both by ≥30% and ≥50) were predictive of OS at 4 weeks (PSA ≥ 30%: HR = 1.568, 95%CI [1.041, 2.360], <em>p</em> = 0.031;PSA ≥ 50%: HR = 1.901, 95% CI [1.222, 2.956], <em>p</em> = 0.004);although multivariable analysis did not confirm these results. The prior administration of chemotherapy was an independent risk factor for death (HR = 2.511;p < 0.001) and progression (HR = 3.238;p < 0.001), probably because of different factors. <strong>Conclusion:</strong> A decrease in PSA by ≥30% or ≥50% at 4 weeks after starting treatment with AA+P correlated with longer PFS and OS, and provides clinically meaningful information guiding the physicians towards a personalized treatment.展开更多
This study investigated the clinical activity of abiraterone plus prednisone in docetaxel-naive and docetaxel-resistant Chinese patients with metastatic castratio n-resista nt prostate can cer(mCRPC).A total of 146 pa...This study investigated the clinical activity of abiraterone plus prednisone in docetaxel-naive and docetaxel-resistant Chinese patients with metastatic castratio n-resista nt prostate can cer(mCRPC).A total of 146 patie nts with docetaxel-naive group(103 cases)and docetaxel-resista nt group(43 cases)were en rolled from the Sha nghai Cancer Center(Sha nghai,Chin a)in this retrospective cohort study.The efficacy endpoints were prostate-specific antigen response rate,prostate-specific antigen progress!on-free survival,clinical/radiographic progression-free survival,and overall survival in response to abiraterone plus prednisone.Significantly higher prostate-specific antigen response rate was found in docetaxel-naive group(54.4%,56/103)compared to docetaxel-resistant group(34.9%,15/43)(P=0.047).In addition,significantly higher median prostate-specific antigen progress!on-free survival(14.0 vs 7.7 months,P=0.005),clinical or radiographic progression-free survival(17.0 vs 12.5 months,P=0.003),and overall survival(27.0 vs 18.0 mon ths,P=0.016)were found in docetaxel-naTve group compared to docetaxel-resistant group,respectively.The univariate and multivariate analyses indicated that lower albumin and visceral metastases were independent significant predictors for shorter overall survival.To sum up,our data suggested that abiraterone plus prednisone was efficient in both docetaxel-naTve and docetaxel-resistant Chinese patients.Moreover,higher PSA response rate and longer overall survival were observed in the docetaxel-naTve group,which suggested that abiraterone was more effective for docetaxel-naive patients than for docetaxel failures.展开更多
Individualized treatment of prostate cancer depends on an accurate stratification of patients who are sensitive to various treatments.Interleukin-23(IL-23)was reported to play a significant role in prostate cancer.Her...Individualized treatment of prostate cancer depends on an accurate stratification of patients who are sensitive to various treatments.Interleukin-23(IL-23)was reported to play a significant role in prostate cancer.Here,we aimed to explore the clinical value of IL-23-secreting(IL-23^(+))cells in prostate cancer patients.We evaluated interleukin-23A(IL-23A)expression in The Cancer Genome Atlas database and retrospectively enrolled 179 treatment-naive metastatic prostate cancer patients diagnosed in our institute between June 2012 and December 2014.IL-23^(+)cells were stained and evaluated via immunohistochemistry.Further,survival and multivariate Cox regression analyses were conducted to explore the prognostic value of IL-23^(+)cells.We found that IL-23A expression correlated with disease progression,while IL-23^(+)cells were clearly stained within prostate cancer tissue.Patients with higher Gleason scores and multiple metastatic lesions tended to have more IL-23^(+)cell infiltration.Further analyses showed that patients with higher levels of IL-23^(+)cells had significantly worse overall survival(hazard ratio[HR]=2.996,95%confidence interval[95%CI]:1.812–4.955;P=0.001)and a higher risk of developing castration resistance(HR=2.725,95%CI:1.865–3.981;P=0.001).Moreover,subgroup analyses showed that when patients progressed to a castration-resistant status,the prognostic value of IL-23^(+)cells was observed only in patients treated with abiraterone instead of docetaxel.Therefore,we showed that high IL-23^(+)cell infiltration is an independent prognosticator in patients with metastatic prostate cancer.IL-23^(+)cell infiltration may correlate with abiraterone effectiveness in castration-resistant prostate cancer patients.展开更多
Corticosteroid switching can reverse abiraterone resistance in some patients with metastatic castration-resistant prostate cancer(mCRPC).Here,we investigated the potential biomarkers for predicting the efficacy of cor...Corticosteroid switching can reverse abiraterone resistance in some patients with metastatic castration-resistant prostate cancer(mCRPC).Here,we investigated the potential biomarkers for predicting the efficacy of corticosteroid switching during treatment with abiraterone acetate(AA).We retrospectively analyzed 101 mCRPC patients receiving corticosteroid switching from West China Hospital and Sun Yat-Sen University Cancer Center between January 2016 and December 2018.All cases received AA plus prednisone as first-line therapy during mCRPC.Primary end points were biochemical progression-free survival(bPFS)and overall survival(OS).The risk groups were defined based on multivariate analysis.A total of 42(41.6%)and 25(24.8%)patients achieved 30%and 50%decline in prostate-specific antigen(PSA),respectively,after corticosteroid switching.The median bPFS and median OS on AA plus dexamethasone were 4.9(95%confidence interval[CI]:3.7–6.0)months and 18.8(95%CI:16.2–30.2)months,respectively.Aldo-keto reductase family 1 member C3(AKR1C3)expression(hazard ratio[HR]:2.15,95%Cl:1.22–3.80,P=0.008)and baseline serum alkaline phosphatase(ALP;HR:4.95,95%Cl:2.40–10.19,P<0.001)were independent predictors of efficacy before corticosteroid switching in the multivariate analysis of bPFS.Only baseline serum ALP>160 IU l−1(HR:3.41,95%Cl:1.57–7.38,P=0.002)together with PSA level at switch≥50 ng ml−1(HR:2.59,95%Cl:1.22–5.47,P=0.013)independently predicted poorer OS.Based on the predictive factors in multivariate analysis,we developed two risk stratification tools to select candidates for corticosteroid switching.Detection of serum ALP level,PSA level,and tissue AKR1C3 expression in mCRPC patients could help make clinical decisions for corticosteroid switching.展开更多
Dear Editor,Abiraterone has achieved great success in clinic by targeting cytochrome P45017A1(CYP17A)for prostate cancer therapy.1,2 However,drug resistance is inevitable and novel strategy is urgently required.Our pr...Dear Editor,Abiraterone has achieved great success in clinic by targeting cytochrome P45017A1(CYP17A)for prostate cancer therapy.1,2 However,drug resistance is inevitable and novel strategy is urgently required.Our previous work unveils a steroidal metabolic pathway for abiraterone in patients.3,4 Steroidogenic enzyme 3β-hydroxysteroid dehydrogenase 1(3βHSD1)catalyzes abiraterone toΔ4-abiraterone(D4A),which is further catalyzed to 5α-abiraterone(5α-Abi)by steroid-5α-reductase(SRD5A).The metabolite 5α-Abi binds to androgen receptor(AR)directly and activates AR signaling.展开更多
BACKGROUND A few reports have revealed induction of rhabdomyolysis by a red yeast rice(RYR)supplement or by RYR in combination with abiraterone(an androgen biosynthesis inhibitor).CASE SUMMARY A 76-year-old man presen...BACKGROUND A few reports have revealed induction of rhabdomyolysis by a red yeast rice(RYR)supplement or by RYR in combination with abiraterone(an androgen biosynthesis inhibitor).CASE SUMMARY A 76-year-old man presented with progressive limb weakness,muscle soreness,and acute kidney injury(AKI).He had been taking the anti-prostate cancer drug abiraterone for 14 mo and had added a RYR supplement 3 mo before symptom onset.After being diagnosed with rhabdomyolysis-induced AKI,the patient discontinued these drugs and responded well to hemodialysis and hemoperfusion.After 23 d of treatment,creatine kinase levels returned to normal and serum creatinine levels decreased.CONCLUSION We speculate that statins,the main lipid-lowering component of RYR,or a combination of statins and abiraterone,will increase the risk of rhabdomyolysis.展开更多
The therapies available for prostate cancer patients whom progress from hormonesensitive to castration resistant prostate cancer include both systemic drugs,including docetaxel and cabazitaxel,and drugs that inhibit a...The therapies available for prostate cancer patients whom progress from hormonesensitive to castration resistant prostate cancer include both systemic drugs,including docetaxel and cabazitaxel,and drugs that inhibit androgen signaling such as enzalutamide and abiraterone.Unfortunately,it is estimated that up to 30%of patients have primary resistance to these treatments and over time even those who initially respond to therapy will eventually develop resistance and their disease will continue to progress regardless of the presence of the drug.Determining the mechanisms involved in the development of resistance to these therapies has been the area of intense study and several adaptive pathways have been uncovered.Androgen receptor(AR)mutations,expression of AR-V7(or other constitutively active androgen receptor variants),intracrine androgen production and overexpression of androgen synthesis enzymes such as Aldo-Keto Reductase Family 1,Member C3(AKR1C3)are among the many mechanisms associated with resistance to anti-androgens.In regards to the taxanes,one of the key contributors to drug resistance is increased drug efflux through ATP Binding Cassette Subfamily B Member 1(ABCB1).Targeting these resistance mechanisms using different strategies has led to various levels of success in overcoming resistance to current therapies.For instance,targeting AR-V7 with niclosamide or AKR1C3 with indomethacin can improve enzalutamide and abiraterone treatment.ABCB1 transport activity can be inhibited by the dietary constituent apigenin and antiandrogens such as bicalutamide which in turn improves response to docetaxel.A more thorough understanding of how drug resistance develops will lead to improved treatment strategies.This review will cover the current knowledge of resistance mechanisms to castration resistant prostate cancer therapies and methods that have been identified which may improve treatment response.展开更多
Prostate cancer(PCa)growth and progression rely on the interaction between the androgen receptor(AR)and the testicular ligands,testosterone and dihydrotestosterone(DHT).Almost all men with advanced PCa receive androge...Prostate cancer(PCa)growth and progression rely on the interaction between the androgen receptor(AR)and the testicular ligands,testosterone and dihydrotestosterone(DHT).Almost all men with advanced PCa receive androgen deprivation therapy(ADT).ADT lowers circulating testosterone levels,which impairs AR activation and leads to PCa regression.However,ADT is palliative and PCa recurs as castration-recurrent/resistant PCa(CRPC).One mechanism for PCa recurrence relies on intratumoral synthesis of DHT,which can be synthesized using the frontdoor or primary or secondary backdoor pathway.Androgen metabolism inhibitors,such as those targeting 5a-reductase,aldo-keto-reductase family member 3(AKR1C3),or cytochrome P45017A1(CYP17A1)have either failed or produced only modest clinical outcomes.The goal of this review is to describe the therapeutic potential of combined inhibition of 5a-reductase and 3a-oxidoreductase enzymes that facilitate the terminal steps of the frontdoor and primary and secondary backdoor pathways for DHT synthesis.Inhibition of the terminal steps of the androgen metabolism pathways may be a way to overcome the shortcomings of existing androgen metabolism inhibitors and thereby delay PCa recurrence during ADT or enhance the response of CRPC to androgen axis manipulation.展开更多
The management of metastatic prostate cancer(mPCa)has changed over the past ten years.Several new drugs have been approved with significant overall survival benefits in metastatic castration resistant prostate cancer(...The management of metastatic prostate cancer(mPCa)has changed over the past ten years.Several new drugs have been approved with significant overall survival benefits in metastatic castration resistant prostate cancer(PCa)including chemotherapy(docetaxel,cabazitaxel),new hormonal therapies(abiraterone,enzalutamide),Radium-223 and immunotherapy.The addition of docetaxel to androgen deprivation therapy(ADT)versus ADT alone in the castration sensitive metastatic setting has gained significant overall survival benefit particularly for high volume disease.More recently two phase III trials have assessed the efficacy of abiraterone plus prednisone plus ADT over ADT alone in newly high risk castrate sensitive mPCa.Determination of the appropriate treatment sequence using these therapies is important for maximizing the clinical benefit in castration sensitive and castration resistant PCa patients.Emerging fields are the identification of new subtypes with molecular characterization and new therapeutic targets.展开更多
Three-weekly docetaxel plus prednisone is the standard first-line cytotoxic treatment for patients with metastatic castrate-resistant prostate cancer(m CRPC). Today, several new treatment options are available for pat...Three-weekly docetaxel plus prednisone is the standard first-line cytotoxic treatment for patients with metastatic castrate-resistant prostate cancer(m CRPC). Today, several new treatment options are available for patients with tumor progression after first-line docetaxel: Abiraterone, enzalutamide, cabazitaxel, sipuleucel-T immunotherapy, and the radionuclide radium-223. However, despite the evolving scenario in CRPC treatment, the optimal sequencing of the innovative therapies remains unclear. The reintroduction of docetaxel at the occurrence of disease progression after a drug holiday(docetaxel rechallenge) was often proposed, and this chemotherapeutic agent showed to maintain antitumor activity in m CRPC patients. Docetaxel rechallenge may still constitute a valid treatment option mainly for patients with favorable response to first-line docetaxel, at least > 3 mo progression-free interval, age less than 75 years, good performance status, and acceptable docetaxel toxicity. The risk of cumulative toxicity must be evaluated, since sensory neuropathy, nail disorders and fatigue might occur on docetaxel rechallenge.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
Several recent studies in mCRPC have identified the mechanisms of tumoral growth after the disease becomes unresponsive to standard hormonal therapy. These studies have highlighted the importance of residual intratumo...Several recent studies in mCRPC have identified the mechanisms of tumoral growth after the disease becomes unresponsive to standard hormonal therapy. These studies have highlighted the importance of residual intratumoral androgens in maintaining androgen receptor (AR) transcriptional activity in mCRPC [1]. Based on this findings, it has been possible to develop drugs, blocking the key enzyme in the biosynthesis of androgens through the inhibition of cytochrome p450 17 (CYP17) such as Abiraterone Acetate (AA) and drugs which directly target the AR including Enzalutamide (E) and Orteronel. Before this new knowledge, mCRPC treatment benefited from chemotherapy with taxanes. Recently a new taxane, Cabazitaxel (C), was approved in second line setting in association with prednisone. Retrospective analyses have tried to clarify the current role of chemotherapy in mCRPC patients and the right chemotherapy sequence of use of chemotherapy compared to new hormonal agents. Moreover, it would be important to address changes in the endpoints used in clinical trials, based on the stage of disease including the presence tumor-related symptoms, in order to identify the right therapeutic strategy.展开更多
Most of the early prostate cancer has no obvious symptoms, but its malignancy metastasis will cause largely deaths. The treatment options for patients with prostate cancer include traditional surgery, external beam th...Most of the early prostate cancer has no obvious symptoms, but its malignancy metastasis will cause largely deaths. The treatment options for patients with prostate cancer include traditional surgery, external beam therapy, hormone therapy, small molecular drug and cryosurgery. It was considered non-traditional treatments also can be used in alternative medicines for prostate cancer therapy. There are well-known molecular mechanisms and their pathogenesis, which provide potential targets for drug screening on the prostate cancer. Currently, natural plant extracts or human tissues active ingredients are widely used for the treatment of cancer. Then isolated effective substances in the extract, and further prepared large amounts of small molecule drugs by chemical synthesis. In this review, we summarized four small molecular drugs, abiraterone, docetaxel, isochaihulactone and butylidenephthalide, and their detailed anti-tumor mechanisms. These indicate that small molecular drug is a very efficient way and can be used for prostate cancer treatment.展开更多
If the treatment landscape for prostate cancer is to be transformed,clinicians and scientists must work together ever more closely.Prostate cancer defeats physicians when patients are not accurately stratified accordi...If the treatment landscape for prostate cancer is to be transformed,clinicians and scientists must work together ever more closely.Prostate cancer defeats physicians when patients are not accurately stratified according to patients’risk of dying of disease,when the effects of tumor heterogeneity are insufficiently understood,and when attempts at therapy by clinicians spur further disease evolution and the emergence of new resistance mechanisms.At the same time,clinicians’over-treat men who in reality do not need it,and some of those men needlessly suffer long term side effects as a result.This commentary is aimed at stimulating debate about how we as clinicians and scientists can assist one another and improve our knowledge to the benefit of patients dying from metastatic disease.展开更多
In recent years,many therapeutic advances have been made in the management of castration-resistant prostate cancer,with the development and approval of many new drugs.The androgen receptor(AR)is the main driver in pro...In recent years,many therapeutic advances have been made in the management of castration-resistant prostate cancer,with the development and approval of many new drugs.The androgen receptor(AR)is the main driver in prostate cancer growth and progression and the most effective therapeutic agents are still directed against this pathway.Among these,new generation hormonal agents(NHA)including enzalutamide,abiraterone acetate,apalutamide,and darolutamide have shown to improve overall survival and quality of life of prostate cancer patients.Unfortunately,despite the demonstrated benefit,not all patients respond to treatment and almost all are destined to develop a resistant phenotype.Although the resistance mechanisms are not fully understood,the most studied ones include the activation of both dependent and independent AR signalling pathways.Recent findings about multiple growth-promoting and survival pathways in advanced prostate cancer suggest the presence of alternative mechanisms involved in disease progression,and an interplay between these pathways and AR signalling.In this review we discuss the possible mechanisms of primary and acquired resistance to NHA with a focus on AR independent pathways.展开更多
Castration-resistant prostate cancer is the lethal form of prostate cancer and most commonly remains dependent on androgen receptor(AR)signaling.Current therapies use AR signaling inhibitors(ARSI)exemplified by abirat...Castration-resistant prostate cancer is the lethal form of prostate cancer and most commonly remains dependent on androgen receptor(AR)signaling.Current therapies use AR signaling inhibitors(ARSI)exemplified by abiraterone acetate,a P450c17 inhibitor,and enzalutamide,a potent AR antagonist.However,drug resistance to these agents occurs within 12-18 months and they only prolong overall survival by 3-4 months.Multiple mechanisms can contribute to ARSI drug resistance.These mechanisms can include but are not limited to germline mutations in the AR,post-transcriptional alterations in AR structure,and adaptive expression of genes involved in the intracrine biosynthesis and metabolism of androgens within the tumor.This review focuses on intracrine androgen biosynthesis,how this can contribute to ARSI drug resistance,and therapeutic strategies that can be used to surmount these resistance mechanisms.展开更多
文摘Objective:This double-blind,placebo-controlled phase 3 study was designed to compare efficacy and safety of abiraterone acetate+prednisone(abiraterone)to prednisone alone in chemotherapy-naı¨ve,asymptomatic or mildly symptomatic metastatic castrationresistant prostate cancer(mCRPC)patients from China,Malaysia,Thailand and Russia.Methods:Adult chemotherapy-naı¨ve patients with confirmed prostate adenocarcinoma,Eastern Cooperative Oncology Group(ECOG)performance status(PS)grade 0e1,ongoing androgen deprivation(serum testosterone<50 ng/dL)with prostate specific antigen(PSA)or radiographic progression were randomized to receive abiraterone acetate(1000 mg,QD)t prednisone(5 mg,BID)or placebo t prednisone(5 mg,BID),until disease progression,unacceptable toxicity or consent withdrawal.Primary endpoint was improvements in time to PSA progression(TTPP).Results:Totally,313 patients were randomized(abiraterone:n Z 157;prednisone:n Z 156);and baseline characteristics were balanced.At clinical cut-off(median follow-up time:3.9 months),80% patients received treatment(abiraterone:n Z 138,prednisone:n Z 112).Median time to PSA progression was not reached with abiraterone versus 3.8 months for prednisone,attaining 58%reduction in PSA progression risk(HR=0.418;p<0.0001).Abirateronetreated patients had higher confirmed PSA response rate(50%vs.21%;relative odds=2.4;p<0.0001)and were 5 times more likely to achieve radiographic response than prednisonetreated patients(22.9%vs.4.8%,p=0.0369).Median survival was not reached.Most common(≥10% abiraterone vs.prednisone-treated)adverse events:bone pain(7%vs.14%),pain in extremity(6%vs.12%),arthralgia(10%vs.8%),back pain(7%vs.11%),and hypertension(15%vs.14%).Conclusion:Interim analysis confirmed favorable benefit-to-risk ratio of abiraterone in chemotherapy-naı¨ve men with mCRPC,consistent with global study,thus supporting use of abiraterone in this patient population.
文摘AIM: To study the efficacy and safety of abiraterone in patients with and without prior chemotherapy.METHODS: The databases including Pub Med and abstracts presented at the American Society of Clinical Oncology meetings up to April 2014 were systematically searched. Eligible studies included randomized controlled trials(RCTs) in which abiraterone plus prednisone was compared to placebo plus prednisone in metastatic castration-resistant prostate cancer(CRPC) patients. The summary incidence, relative risk, hazard ratio and 95%CI were calculated using random or fixed-effects models. Heterogeneity test was performed to test between-study differences in efficacy and toxicity.RESULTS: A total of two phase III RCTs were included in our analysis, with metastatic CPRC patients before(n = 1088) and after chemotherapy(n = 1195). Prior chemotherapy did not significantly alter the effect of abiraterone on overall survival(P = 0.92) and prostatespecific antigen(PSA) progression-free survival(P = 0.13), but reduced its effect on radiographic-prog-ression-free survival(P = 0.04), objective response rate(P < 0.001), and PSA response rate(P < 0.001). Prior chemotherapy significantly increased the specific risk of fluid retention and edema(P < 0.001) and hypokalemia(P < 0.001), but decreased the risk of all-grade hypertension(P < 0.001) attributable to abiraterone. There was no significant difference of cardiac disorders associated with abiraterone between the two settings(P = 0.58). CONCLUSION: Prior chemotherapy may reduce the effectiveness of abiraterone in patients with metastatic CRPC.
文摘<strong>Background:</strong> According to the main prostate cancer guidelines, the response to treatment with abiraterone plus prednisone (AA+P) must be evaluated by assessing prostate-specific antigen (PSA) levels at 12 weeks. Recent studies have shown that early PSA decline, at 4 weeks, maybe a surrogate marker for survival. The objective of this work was to analyze if a decline in PSA at 4 weeks correlates with a better outcome in terms of OS (overall survival) and PFS (progression-free survival). <strong>Methods:</strong> We evaluated 168 patients (with a median age of 71 years) with prostate cancer who had started AA+P treatment between February 2012 and July 2019. Patients were divided into three different groups according to the decline of PSA (≥30%, ≥50%, and ≥90%) at 4, 8, and 12 weeks. Statistical survival analysis was performed using the Kaplan-Meier method. <strong>Results:</strong> After a follow-up of 69 months, a PSA decline ≥ 30% at 4 weeks was associated with longer median OS times (28 vs. 18 months;<em>p</em> = 0.027). A decline in PSA by ≥50% was also associated with increased median OS times (36 vs. 21;<em>p</em> = 0.003). Cox univariable analysis indicated that a decrease in PSA (both by ≥30% and ≥50) were predictive of OS at 4 weeks (PSA ≥ 30%: HR = 1.568, 95%CI [1.041, 2.360], <em>p</em> = 0.031;PSA ≥ 50%: HR = 1.901, 95% CI [1.222, 2.956], <em>p</em> = 0.004);although multivariable analysis did not confirm these results. The prior administration of chemotherapy was an independent risk factor for death (HR = 2.511;p < 0.001) and progression (HR = 3.238;p < 0.001), probably because of different factors. <strong>Conclusion:</strong> A decrease in PSA by ≥30% or ≥50% at 4 weeks after starting treatment with AA+P correlated with longer PFS and OS, and provides clinically meaningful information guiding the physicians towards a personalized treatment.
基金the National Natural Science Foundation(No.81702535,81572531)Natural Science Foundation of Shanghai Municipality(No.16ZR1406500)Outstanding Young Talent Training Plan of Shanghai Municipal Commission of Health and Family Planning(No.XYQ2013102).
文摘This study investigated the clinical activity of abiraterone plus prednisone in docetaxel-naive and docetaxel-resistant Chinese patients with metastatic castratio n-resista nt prostate can cer(mCRPC).A total of 146 patie nts with docetaxel-naive group(103 cases)and docetaxel-resista nt group(43 cases)were en rolled from the Sha nghai Cancer Center(Sha nghai,Chin a)in this retrospective cohort study.The efficacy endpoints were prostate-specific antigen response rate,prostate-specific antigen progress!on-free survival,clinical/radiographic progression-free survival,and overall survival in response to abiraterone plus prednisone.Significantly higher prostate-specific antigen response rate was found in docetaxel-naive group(54.4%,56/103)compared to docetaxel-resistant group(34.9%,15/43)(P=0.047).In addition,significantly higher median prostate-specific antigen progress!on-free survival(14.0 vs 7.7 months,P=0.005),clinical or radiographic progression-free survival(17.0 vs 12.5 months,P=0.003),and overall survival(27.0 vs 18.0 mon ths,P=0.016)were found in docetaxel-naTve group compared to docetaxel-resistant group,respectively.The univariate and multivariate analyses indicated that lower albumin and visceral metastases were independent significant predictors for shorter overall survival.To sum up,our data suggested that abiraterone plus prednisone was efficient in both docetaxel-naTve and docetaxel-resistant Chinese patients.Moreover,higher PSA response rate and longer overall survival were observed in the docetaxel-naTve group,which suggested that abiraterone was more effective for docetaxel-naive patients than for docetaxel failures.
基金This study was supported by grant from the National Key R&D Program of China(2017YFC0114303)grant from the Natural Science Foundation of Science and Technology Commission of Shanghai Municipality(20ZR1412300)+2 种基金grant from the Medical Innovation Research Project of the Science and Technology Commission of Shanghai Municipality(No.20Y11905000)grants from the AoXiang Project of the Shanghai Anti-Cancer Association(SACA-AX201908 and SACA-AX202005)All these study sponsors have no roles in the study design,collection,analysis,and interpretation of data.
文摘Individualized treatment of prostate cancer depends on an accurate stratification of patients who are sensitive to various treatments.Interleukin-23(IL-23)was reported to play a significant role in prostate cancer.Here,we aimed to explore the clinical value of IL-23-secreting(IL-23^(+))cells in prostate cancer patients.We evaluated interleukin-23A(IL-23A)expression in The Cancer Genome Atlas database and retrospectively enrolled 179 treatment-naive metastatic prostate cancer patients diagnosed in our institute between June 2012 and December 2014.IL-23^(+)cells were stained and evaluated via immunohistochemistry.Further,survival and multivariate Cox regression analyses were conducted to explore the prognostic value of IL-23^(+)cells.We found that IL-23A expression correlated with disease progression,while IL-23^(+)cells were clearly stained within prostate cancer tissue.Patients with higher Gleason scores and multiple metastatic lesions tended to have more IL-23^(+)cell infiltration.Further analyses showed that patients with higher levels of IL-23^(+)cells had significantly worse overall survival(hazard ratio[HR]=2.996,95%confidence interval[95%CI]:1.812–4.955;P=0.001)and a higher risk of developing castration resistance(HR=2.725,95%CI:1.865–3.981;P=0.001).Moreover,subgroup analyses showed that when patients progressed to a castration-resistant status,the prognostic value of IL-23^(+)cells was observed only in patients treated with abiraterone instead of docetaxel.Therefore,we showed that high IL-23^(+)cell infiltration is an independent prognosticator in patients with metastatic prostate cancer.IL-23^(+)cell infiltration may correlate with abiraterone effectiveness in castration-resistant prostate cancer patients.
基金This work was supported by the Natural Science Foundation of China(NSFC,No.81672547,81872107,81872108,81972502,81902577,and 81902577)1.3.5 project for disciplines of excellence,West China Hospital,Sichuan University(No.0040205301E21)+1 种基金the Research Foundation for the Postdoctoral Program of Sichuan University(2021SCU12014)Postdoctoral Research Project,West China Hospital,Sichuan University(20HXBH026).
文摘Corticosteroid switching can reverse abiraterone resistance in some patients with metastatic castration-resistant prostate cancer(mCRPC).Here,we investigated the potential biomarkers for predicting the efficacy of corticosteroid switching during treatment with abiraterone acetate(AA).We retrospectively analyzed 101 mCRPC patients receiving corticosteroid switching from West China Hospital and Sun Yat-Sen University Cancer Center between January 2016 and December 2018.All cases received AA plus prednisone as first-line therapy during mCRPC.Primary end points were biochemical progression-free survival(bPFS)and overall survival(OS).The risk groups were defined based on multivariate analysis.A total of 42(41.6%)and 25(24.8%)patients achieved 30%and 50%decline in prostate-specific antigen(PSA),respectively,after corticosteroid switching.The median bPFS and median OS on AA plus dexamethasone were 4.9(95%confidence interval[CI]:3.7–6.0)months and 18.8(95%CI:16.2–30.2)months,respectively.Aldo-keto reductase family 1 member C3(AKR1C3)expression(hazard ratio[HR]:2.15,95%Cl:1.22–3.80,P=0.008)and baseline serum alkaline phosphatase(ALP;HR:4.95,95%Cl:2.40–10.19,P<0.001)were independent predictors of efficacy before corticosteroid switching in the multivariate analysis of bPFS.Only baseline serum ALP>160 IU l−1(HR:3.41,95%Cl:1.57–7.38,P=0.002)together with PSA level at switch≥50 ng ml−1(HR:2.59,95%Cl:1.22–5.47,P=0.013)independently predicted poorer OS.Based on the predictive factors in multivariate analysis,we developed two risk stratification tools to select candidates for corticosteroid switching.Detection of serum ALP level,PSA level,and tissue AKR1C3 expression in mCRPC patients could help make clinical decisions for corticosteroid switching.
基金This research was partially funded by the National Key R&D program of China(2018YFA0508200 to ZFL)Clinical Innovations of Shanghai SHENKANG(SHDC12019112 to DLW)+2 种基金the Strategic Priority Research Program of Chinese Academy of Sciences(XDB19000000 and XDA12010318 to ZFL)the National Natural Science Foundation of China(81672526 to DLW and 81872075 to JJT)the Prostate Cancer Foundation Young Investigator Award(#15YOUN11 to ZFL).
文摘Dear Editor,Abiraterone has achieved great success in clinic by targeting cytochrome P45017A1(CYP17A)for prostate cancer therapy.1,2 However,drug resistance is inevitable and novel strategy is urgently required.Our previous work unveils a steroidal metabolic pathway for abiraterone in patients.3,4 Steroidogenic enzyme 3β-hydroxysteroid dehydrogenase 1(3βHSD1)catalyzes abiraterone toΔ4-abiraterone(D4A),which is further catalyzed to 5α-abiraterone(5α-Abi)by steroid-5α-reductase(SRD5A).The metabolite 5α-Abi binds to androgen receptor(AR)directly and activates AR signaling.
基金Supported by the Natural Science Foundation of Shandong Province,No.ZR2021QH110.
文摘BACKGROUND A few reports have revealed induction of rhabdomyolysis by a red yeast rice(RYR)supplement or by RYR in combination with abiraterone(an androgen biosynthesis inhibitor).CASE SUMMARY A 76-year-old man presented with progressive limb weakness,muscle soreness,and acute kidney injury(AKI).He had been taking the anti-prostate cancer drug abiraterone for 14 mo and had added a RYR supplement 3 mo before symptom onset.After being diagnosed with rhabdomyolysis-induced AKI,the patient discontinued these drugs and responded well to hemodialysis and hemoperfusion.After 23 d of treatment,creatine kinase levels returned to normal and serum creatinine levels decreased.CONCLUSION We speculate that statins,the main lipid-lowering component of RYR,or a combination of statins and abiraterone,will increase the risk of rhabdomyolysis.
基金This work is supported in part by grants NIH/NCI CA140468,CA168601,CA179970,DOD PC130062,Ralph de Vere White endowment,US Department of Veterans Affairs,Office of Research and Development VA Merits I01 BX002653by resources from the VA Northern California Health Care System,Sacramento,California.
文摘The therapies available for prostate cancer patients whom progress from hormonesensitive to castration resistant prostate cancer include both systemic drugs,including docetaxel and cabazitaxel,and drugs that inhibit androgen signaling such as enzalutamide and abiraterone.Unfortunately,it is estimated that up to 30%of patients have primary resistance to these treatments and over time even those who initially respond to therapy will eventually develop resistance and their disease will continue to progress regardless of the presence of the drug.Determining the mechanisms involved in the development of resistance to these therapies has been the area of intense study and several adaptive pathways have been uncovered.Androgen receptor(AR)mutations,expression of AR-V7(or other constitutively active androgen receptor variants),intracrine androgen production and overexpression of androgen synthesis enzymes such as Aldo-Keto Reductase Family 1,Member C3(AKR1C3)are among the many mechanisms associated with resistance to anti-androgens.In regards to the taxanes,one of the key contributors to drug resistance is increased drug efflux through ATP Binding Cassette Subfamily B Member 1(ABCB1).Targeting these resistance mechanisms using different strategies has led to various levels of success in overcoming resistance to current therapies.For instance,targeting AR-V7 with niclosamide or AKR1C3 with indomethacin can improve enzalutamide and abiraterone treatment.ABCB1 transport activity can be inhibited by the dietary constituent apigenin and antiandrogens such as bicalutamide which in turn improves response to docetaxel.A more thorough understanding of how drug resistance develops will lead to improved treatment strategies.This review will cover the current knowledge of resistance mechanisms to castration resistant prostate cancer therapies and methods that have been identified which may improve treatment response.
基金This study was supported by the DoD Prostate Cancer Research Program Award(No.W81XWH-16-1-0635)the National Cancer Institute(NO.P01CA77739 and NO.R21CA205108)to James L.Mohler+2 种基金Post-doctoral Training Award(No.W81XWH-15-1-0409)to Michael V.FiandaloDoD Synergistic Idea Development Award(No.W81XWH-14-1-0520)to Dan T.GewirthNCI Cancer Center Support Grant to Roswell Park Comprehensive Cancer Center for the Bioanalytics,Metabolomics and Pharmacokinetics,Pathology Network,and Genomics Shared Resources(No.P30CA016056).
文摘Prostate cancer(PCa)growth and progression rely on the interaction between the androgen receptor(AR)and the testicular ligands,testosterone and dihydrotestosterone(DHT).Almost all men with advanced PCa receive androgen deprivation therapy(ADT).ADT lowers circulating testosterone levels,which impairs AR activation and leads to PCa regression.However,ADT is palliative and PCa recurs as castration-recurrent/resistant PCa(CRPC).One mechanism for PCa recurrence relies on intratumoral synthesis of DHT,which can be synthesized using the frontdoor or primary or secondary backdoor pathway.Androgen metabolism inhibitors,such as those targeting 5a-reductase,aldo-keto-reductase family member 3(AKR1C3),or cytochrome P45017A1(CYP17A1)have either failed or produced only modest clinical outcomes.The goal of this review is to describe the therapeutic potential of combined inhibition of 5a-reductase and 3a-oxidoreductase enzymes that facilitate the terminal steps of the frontdoor and primary and secondary backdoor pathways for DHT synthesis.Inhibition of the terminal steps of the androgen metabolism pathways may be a way to overcome the shortcomings of existing androgen metabolism inhibitors and thereby delay PCa recurrence during ADT or enhance the response of CRPC to androgen axis manipulation.
文摘The management of metastatic prostate cancer(mPCa)has changed over the past ten years.Several new drugs have been approved with significant overall survival benefits in metastatic castration resistant prostate cancer(PCa)including chemotherapy(docetaxel,cabazitaxel),new hormonal therapies(abiraterone,enzalutamide),Radium-223 and immunotherapy.The addition of docetaxel to androgen deprivation therapy(ADT)versus ADT alone in the castration sensitive metastatic setting has gained significant overall survival benefit particularly for high volume disease.More recently two phase III trials have assessed the efficacy of abiraterone plus prednisone plus ADT over ADT alone in newly high risk castrate sensitive mPCa.Determination of the appropriate treatment sequence using these therapies is important for maximizing the clinical benefit in castration sensitive and castration resistant PCa patients.Emerging fields are the identification of new subtypes with molecular characterization and new therapeutic targets.
文摘Three-weekly docetaxel plus prednisone is the standard first-line cytotoxic treatment for patients with metastatic castrate-resistant prostate cancer(m CRPC). Today, several new treatment options are available for patients with tumor progression after first-line docetaxel: Abiraterone, enzalutamide, cabazitaxel, sipuleucel-T immunotherapy, and the radionuclide radium-223. However, despite the evolving scenario in CRPC treatment, the optimal sequencing of the innovative therapies remains unclear. The reintroduction of docetaxel at the occurrence of disease progression after a drug holiday(docetaxel rechallenge) was often proposed, and this chemotherapeutic agent showed to maintain antitumor activity in m CRPC patients. Docetaxel rechallenge may still constitute a valid treatment option mainly for patients with favorable response to first-line docetaxel, at least > 3 mo progression-free interval, age less than 75 years, good performance status, and acceptable docetaxel toxicity. The risk of cumulative toxicity must be evaluated, since sensory neuropathy, nail disorders and fatigue might occur on docetaxel rechallenge.
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.
文摘Several recent studies in mCRPC have identified the mechanisms of tumoral growth after the disease becomes unresponsive to standard hormonal therapy. These studies have highlighted the importance of residual intratumoral androgens in maintaining androgen receptor (AR) transcriptional activity in mCRPC [1]. Based on this findings, it has been possible to develop drugs, blocking the key enzyme in the biosynthesis of androgens through the inhibition of cytochrome p450 17 (CYP17) such as Abiraterone Acetate (AA) and drugs which directly target the AR including Enzalutamide (E) and Orteronel. Before this new knowledge, mCRPC treatment benefited from chemotherapy with taxanes. Recently a new taxane, Cabazitaxel (C), was approved in second line setting in association with prednisone. Retrospective analyses have tried to clarify the current role of chemotherapy in mCRPC patients and the right chemotherapy sequence of use of chemotherapy compared to new hormonal agents. Moreover, it would be important to address changes in the endpoints used in clinical trials, based on the stage of disease including the presence tumor-related symptoms, in order to identify the right therapeutic strategy.
文摘Most of the early prostate cancer has no obvious symptoms, but its malignancy metastasis will cause largely deaths. The treatment options for patients with prostate cancer include traditional surgery, external beam therapy, hormone therapy, small molecular drug and cryosurgery. It was considered non-traditional treatments also can be used in alternative medicines for prostate cancer therapy. There are well-known molecular mechanisms and their pathogenesis, which provide potential targets for drug screening on the prostate cancer. Currently, natural plant extracts or human tissues active ingredients are widely used for the treatment of cancer. Then isolated effective substances in the extract, and further prepared large amounts of small molecule drugs by chemical synthesis. In this review, we summarized four small molecular drugs, abiraterone, docetaxel, isochaihulactone and butylidenephthalide, and their detailed anti-tumor mechanisms. These indicate that small molecular drug is a very efficient way and can be used for prostate cancer treatment.
文摘If the treatment landscape for prostate cancer is to be transformed,clinicians and scientists must work together ever more closely.Prostate cancer defeats physicians when patients are not accurately stratified according to patients’risk of dying of disease,when the effects of tumor heterogeneity are insufficiently understood,and when attempts at therapy by clinicians spur further disease evolution and the emergence of new resistance mechanisms.At the same time,clinicians’over-treat men who in reality do not need it,and some of those men needlessly suffer long term side effects as a result.This commentary is aimed at stimulating debate about how we as clinicians and scientists can assist one another and improve our knowledge to the benefit of patients dying from metastatic disease.
文摘In recent years,many therapeutic advances have been made in the management of castration-resistant prostate cancer,with the development and approval of many new drugs.The androgen receptor(AR)is the main driver in prostate cancer growth and progression and the most effective therapeutic agents are still directed against this pathway.Among these,new generation hormonal agents(NHA)including enzalutamide,abiraterone acetate,apalutamide,and darolutamide have shown to improve overall survival and quality of life of prostate cancer patients.Unfortunately,despite the demonstrated benefit,not all patients respond to treatment and almost all are destined to develop a resistant phenotype.Although the resistance mechanisms are not fully understood,the most studied ones include the activation of both dependent and independent AR signalling pathways.Recent findings about multiple growth-promoting and survival pathways in advanced prostate cancer suggest the presence of alternative mechanisms involved in disease progression,and an interplay between these pathways and AR signalling.In this review we discuss the possible mechanisms of primary and acquired resistance to NHA with a focus on AR independent pathways.
基金This work was supported by the National Institute of Environmental Health Science(P30ES013508)(to Penning TM)by DoD Idea Development grant from the National Cancer Institute(W81XWH-17-1-0404 and R01CA249210)(Asangani IA)and by Department of Defense Prostate Cancer Research Program(W81XWH-17-1-0484,W81XWH-17-2-0323,W81XWH-20-1-0146),Lopker Foundation,Institute for Prostate Cancer Research,and Veterans Affairs Research Program(to Sprenger C and Plymate S).
文摘Castration-resistant prostate cancer is the lethal form of prostate cancer and most commonly remains dependent on androgen receptor(AR)signaling.Current therapies use AR signaling inhibitors(ARSI)exemplified by abiraterone acetate,a P450c17 inhibitor,and enzalutamide,a potent AR antagonist.However,drug resistance to these agents occurs within 12-18 months and they only prolong overall survival by 3-4 months.Multiple mechanisms can contribute to ARSI drug resistance.These mechanisms can include but are not limited to germline mutations in the AR,post-transcriptional alterations in AR structure,and adaptive expression of genes involved in the intracrine biosynthesis and metabolism of androgens within the tumor.This review focuses on intracrine androgen biosynthesis,how this can contribute to ARSI drug resistance,and therapeutic strategies that can be used to surmount these resistance mechanisms.
