A Review of Abiraterone Acetate for the Treatment of Metastatic Castration-Resistant Prostate Cancer

Prostate cancer is a common malignant tumor of the urinary system in men,and the incidence and detection rate of prostate cancer have been rising significantly in recent years.Androgens play an important role in the occurrence and development of prostate cancer,so hormone deprivation therapy has become an essential means of prostate cancer treatment.Abiraterone acetate is a therapeutic agent for prostate cancer by inhibiting the enzyme activity of CYP17,thereby blocking androgen biosynthesis.In this paper,we present a review of the current mechanism of action of abiraterone acetate for prostate cancer treatment,research progress,and its side effects and limitations.It is expected to provide help for further research on the treatment of prostate cancer.

Clinical Exploration of Immunosuppressants Combined with Abiraterone in the Treatment of Metastatic Castration-Resistant Prostate Cancer

Prostate cancer is a malignant tumor with a high incidence in elderly men.In recent years,with the improvement of people’s living standards and the advancement of detection technology,the incidence of prostate cancer has been increasing year by year.Castration-resistant prostate cancer(CRPC)is a highly challenging type of advanced prostate cancer treatment,which clinically shows resistance to hormonal deprivation therapy.The overall treatment efficacy of CRPC is currently poor and further relevant therapeutic studies are needed to improve patient survival and quality of life.Immunosuppressants can play a role in combating the immune system of tumors,and abiraterone has also achieved remarkable results in prostate cancer treatment.This study will investigate the possible clinical effects and safety of immunosuppressants combined with abiraterone in the treatment of metastatic CRPC.The population-based study will provide clinicians with more effective treatment options,as well as enhance the understanding of novel combination therapy strategies to be implemented in the future for such patients.

A phase 3,double-blind,randomized placebo-controlled efficacy and safety study of abiraterone acetate in chemotherapynaı¨ve patients with mCRPC in China,Malaysia,Thailand and Russia

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.

抗前列腺癌药Abiraterone acetate

雄激素剥夺疗法作为晚期前列腺癌的标准疗法迄今已有50余年。去势手术对多数患者起初有效,但最终会发展为去势抵抗性前列腺癌（CRPC）,主要原因是前列腺癌的发生和发展与雄激素受体（AR）受到雄激素的持续刺激有关，

Comparative analysis of the effectiveness of abiraterone before and after docetaxel in patients with metastatic castration-resistant prostate cancer

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.

Abiraterone用于未化疗的转移性激素抵抗性前列腺癌(mCRPC)

背景:醋酸阿比特龙,被美国FDA批准作为化疗后的二线治疗药物用于转移性激素抵抗性前列腺癌(mCRPC),提高了总生存率。在此评估其用于未接受过化疗患者的效果。方法:在这项双盲研究中,随机分配1088例患者接受醋酸阿比特龙(1000mg)加泼尼松(5mg,每日2次)或安慰剂加泼尼松。共同主要终点为影像学无进展生存期和总生存期。结果:预期死亡人数达到43%后。

Early Evaluation of PSA Response in Metastatic Prostate Cancer Treated with Abiraterone

Background: 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). Methods: 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. Results: 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;p = 0.027). A decline in PSA by ≥50% was also associated with increased median OS times (36 vs. 21;p = 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], p = 0.031;PSA ≥ 50%: HR = 1.901, 95% CI [1.222, 2.956], p = 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. Conclusion: 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.

Indirect comparison between abiraterone acetate and enzalutamide for the treatment of metastatic castration-resistant prostate cancer： a systematic review

This study was designed to evaluate the efficacy, tolerability, and sequential administration of abiraterone acetate （AA） and enzalutamide （Enz） for metastatic castration-resistant prostate cancer （mCRPC）. A literature search was performed with PubMed, Embase, and Web of Science databases to identify relevant studies. Reviewed literature included published phase III trials of AA or Enz in mCRPC and studies regarding their sequential administration. Given the difference in control arms in AA （active comparator） and Enz （true placebo） randomized phase III studies, indirect comparisons between AA and Enz in mCRPC showed no statistically significant difference in overall survival in prechemotherapy and postchemotherapy settings （HR. 0.90, 95% CI, 0.73-1.11; HR： 0.85, 95% CI, 0.68-1.07）. Compared with AA, Enz may better outperform control arms in treating mCRPC both before and after chemotherapy regarding secondary endpoints based on indirect comparisons： time to prostate-specific antigen （PSA） progression （HR. 0.34, 95% CI, 0.28-0.42; HR： 0.40, 95% CI, 0.30-0.53）, radiographic progression-free survival （HR： 0.37, 95% CI, 0.28-0.48; HR： 0.61, 95% CI, 0.50-0.74）, and PSA response rate （OR： 18.29, 95% CI, 11.20-29.88; OR： 10.69, 95% CI, 3.92-29.20）. With regard to the effectiveness of Enz following AA or AA following Enz, recent retrospective case series reported overall survival and secondary endpoints for patients with mCRPC progression after chemotherapy. However, confirmatory head-to-head trials are necessary to determine the optimal sequencing of these agents.

Prior switching to a second-line nonsteroidal antiandrogen does not impact the therapeutic efficacy of abiraterone acetate in patients with metastatic castration-resistant prostate cancer： a real-world retrospective study

Even in the era of novel targeted agents, switching to a second-line nonsteroidal antiandrogen （NSAA） is still widely used in treating metastatic castration-resistant prostate cancer （mCRPC）, especially in undeveloped countries. However, whether prior treatment with a second-line NSAA would impact the efficacy of abiraterone acetate （Abi） remains uncertain, in the current study, 87 mCRPC patients treated with Abi were analyzed. Among them, 21 were treated with a second-line NSAA （from bicalutamide to flutamide） before receiving abiraterone, while the remaining 66 received Abi directly. Therapeutic efficacy of Abi was compared between those with and without prior second-line NSAA using Kaplan-Meier curves, log-rank test, and Cox regression models. The therapeutic efficacy of Abi was similar between those with or without the prior switching treatment of flutamide, in terms of either prostate-specific antigen progression-free survival （PSA-PFS, 5.5 vs 5.6 months, P = 0.967）, radiographic progression-free survival （rPFS, 12.8 vs 13.4 months, P = 0.508）, overall survival （OS, not reached vs 30.6 months, P = 0.606）, or PSA-response rate （71.4% [15121] vs 60.6% [40166], P = 0.370）. This is the first time that the impact of prior switching of treatment to a second-line NSAA on the efficacy of Abi in mCRPC patients has been addressed. Our data support that, use of prior sequential bicalutamide and flutamide does not seem to preclude response to abiraterone, although larger cohort studies and, ideally, a randomized controlled trial are needed. These findings will facilitate doctors＇ decision-making in the treatment of mCRPC patients, especially for those with previous experience of switching NSAA second-line treatments in the clinic.

Clinical activity of abiraterone plus prednisone in docetaxel-naive and docetaxel-resistant Chinese patients with metastatic castration-resistant prostate cancer

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.

External validation and newly development of a nomogram to predict overall survival of abiraterone-treated, castration-resistant patients with metastatic prostate cancer

Abiraterone acetate is approved for the treatment of castration-resistant prostate cancer （CRPC）; however, its effects vary. An accurate prediction model to identify patient groups that will benefit from abiraterone treatment is therefore urgently required. The Chi model exhibits a good profile for risk classification, although its utility for the chemotherapy-naive group is unclear. This study aimed to externally validate the Chi model and develop a new nomogram to predict overall survival （OS）. We retrospectively analyzed a cohort of 110 patients. Patients were distributed among good-, intermediate-, and poor-risk groups, according to the Chi model. The good-, intermediate-, and poor-risk groups had a sample size of 59 （53.6%）, 34 （30.9%）, and 17 （15.5%） in our dataset, and a median OS of 48.4, 29.1, and 10.5 months, respectively. The C-index of external validation of Chi model was 0.726. Univariate and multivariate analyses identified low hemoglobin concentrations （〈110 g l^-1）, liver metastasis, and a short time interval from androgen deprivation therapy to abiraterone initiation （〈36 months） as predictors of OS. Accordingly, a new nomogram was developed with a C-index equal to 0.757 （95% CI, 0.678-0.836）. In conclusion, the Chi model predicted the prognosis of abiraterone-treated, chemotherapy-naive patients with mCRPC, and we developed a new nomogram to predict the overall survival of this group of patients with less parameters.

Predictors of efficacy of corticosteroid switching from abiraterone plus prednisone to dexamethasone in patients with metastatic castration-resistant prostate cancer

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.

High IL-23^(+)cells infiltration correlates with worse clinical outcomes and abiraterone effectiveness in patients with prostate cancer

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.

Response of prostate cancer to addition of dutasteride after progression on abiraterone

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.

Rhabdomyolysis-induced acute kidney injury after administration of a red yeast rice supplement:A case report

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.

Current paradigms and evolving concepts in metastatic castration-resistant prostate cancer

Until recently, docetaxel-based therapy represented the only therapy shown to prolong survival in patients with metastatic castration-resistant prostate cancer （mCRPC）. The past year and a half has been marked by unprecedented progress in treatments for this disease. Three positive phase III clinical trials have emerged, each evaluating agents （sipuleuceI-T, cabazitaxel and abiraterone） with distinct mechanisms of action. Herein, the three pivotal trials are described alongside both past and current large phase III studies conducted in this mCRPC. The overall survival for patients with mCRPC treated in current clinical trials is considerably longer than noted in the past. We note that more recent trials with older agents have also shown improved survival and discuss potential non-therapeutic biases that influence this critical measure of outcome. The necessity for utilizing randomized trials when evaluating new therapeutics is emphasized given the changing prognosis in this mCRPC.

Adaptive pathways and emerging strategies overcoming treatment resistance in castration resistant prostate cancer

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.

Potential impact of combined inhibition of 3a-oxidoreductases and 5a-reductases on prostate cancer

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.

Systemic treatment for metastatic 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.

Treatment sequencing in metastatic castrate-resistant prostate cancer

Six different treatments have demonstrated improved survival in phase III trials targeted to patients with metastatic castration-resistant prostate cancer （mCRPC）. Front-line therapeutic options for mCRPC include docetaxel, sipuleuceI-T, abiraterone and radium-223. Post-docetaxel options include cabazitaxel, abiraterone, enzalutamide and radium-223. Despite much progress in recent years, much is yet unknown and debates occur over optimal treatment choices and sequences. None of the new agents have been compared to one another, thus physicians in practice today must make choices based on non-randomized comparisons, toxicity considerations and various assumptions. Abiraterone is now moving into the front line mCRPC space given recent regulatory approvals and enzalutamide will follow soon. Both of the hormonal agents have less toxicity when compared to chemotherapeutic options and both of these hormonal agents are expected to be used in a considerable number of mCRPC patients in the years ahead. Little data are available for the post-abiraterone or post-enzalutamide setting. In this review the currently available sequencing data are summarized and interpreted. It is now clear that cross resistance is a potential issue between various treatments, especially those agents that target the androgen axis. This review highlights the need for additional studies to optimize the current treatments for these patients.