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REVIEWS The changing therapeutic landscape of castration-resistant prostate cancer Timothy A. Yap, Andrea Zivi, Aurelius Omlin and Johann S. de Bono Abstract | Castration-resistant prostate cancer (CRPC) has a poor prognosis and remains a significant therapeutic challenge. Before 2010, only docetaxel-based chemotherapy improved survival in patients with CRPC compared with mitoxantrone. Our improved understanding of the underlying biology of CRPC has heralded a new era in molecular anticancer drug development, with a myriad of novel anticancer drugs for CRPC entering the clinic. These include the novel taxane cabazitaxel, the vaccine sipuleucel‑T, the CYP17 inhibitor abiraterone, the novel androgen-receptor antagonist MDV‑3100 and the radioisotope alpharadin. With these developments, the management of patients with CRPC is changing. In this Review, we discuss these promising therapies along with other novel agents that are demonstrating early signs of activity in CRPC. We propose a treatment pathway for patients with CRPC and consider strategies to optimize the use of these agents, including the incorporation of predictive and intermediate end point biomarkers, such as circulating tumor cells. Yap, T. A. et al. Nat. Rev. Clin. Oncol. 8, 597–610 (2011); published online 9 August 2011; doi:10.1038/nrclinonc.2011.117 Introduction Prostate cancer is the most common malignancy, and the second leading cause of cancer mortality among men.1,2 Approximately 10–20% of patients with prostate cancer present with advanced-stage disease, while others develop disease progression to castration-resistant prostate cancer (CRPC), which has a poor prognosis and is a therapeutic challenge.3,4 Strategies developed to counteract androgendeprivation therapy (ADT) resistance have had only modest clinical benefit.5–8 Indeed, before 2010, only docetaxelbased chemot herapy improved overall survival in patients with CRPC compared with mitoxantrone.9,10 Improved understanding of the biology underlying CRPC has heralded a new era in molecular-targeted anticancer drug development.11 Many novel anticancer drugs are currently in clinical studies, and several promising agents are nearing completion or have recently completed late-phase clinical trials. It is likely that the treatment landscape for patients with CRPC will change inextri cably in the near future. In this Review, we focus on these promising therapies, propose a treatment pathway for patients with CRPC and suggest strategies to optimize the application of these agents. Finally, we detail promising novel targets, against which future agents in CRPC Competing interests T. A. Yap, A. Zivi, A. Omlin and J. S. de Bono declare an association with the following organization: The Institute of Cancer Research. J. S. de Bono also declares associations with the following companies: Amgen, Astellas, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Cougar Biotechnology, Dendreon, Enzon, Exelixis, Genentech, GlaxoSmithKline, Medivation, Merck, Novartis, Pfizer, Roche, Sanofi-Aventis, Supergen, Takeda. See the article online for full details of the relationships. may potentially be developed, and consider paradigms for modern clinical therapy for CRPC. Targeting the AR The development of CRPC is characterized by a rise in prostate-specific antigen (PSA) and subsequent prog ression of disease despite castrate blood levels of testo sterone (<50 ng/dl or 1.7 nmol/l).12 There is a growing body of evidence of the continued dependence of CRPC on androgen-receptor (AR) signaling and related underlying mechanisms.13 Androgens from the adrenal glands account for 10–30% of serum androgens and are an important source of continued AR activation.14 Importantly, dehydroepiandrosterone (DHEA) and other precursor steroids secreted by the adrenal glands can be converted into potent androgens.15 Recurrent prostate cancer might be able to synthesize testicular androgens through intracrine production from adrenal androgens and cholesterol.16 Maintained AR signaling that leads to CRPC can be explained by a number of mechanisms (Box 1). Current AR antagonists in CRPC Translocation of the AR into the nucleus and subsequent receptor activation is mediated by androgen binding.17 Available AR antagonists have agonistic properties in advanced-stage CRPC, either by increased sensiti vity and activity caused by AR mutation, or through AR overexpression.18,19 Antiandrogens can be divided into steroidal and nonsteroidal agents and compete with endogenous androgens for the AR binding site.12 The steroidal compounds (mifepristone, spironolactone and cyproterone acetate) NATURE REVIEWS | CLINICAL ONCOLOGY Drug Development Unit, The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, Downs Road, Sutton, Surrey SM2 5PT, UK (T. A. Yap, A. Zivi, A. Omlin, J. S. de Bono). Correspondence to: J. S. de Bono johann.de-bono@ icr.ac.uk VOLUME 8 | OCTOBER 2011 | 597 © 2011 Macmillan Publishers Limited. All rights reserved REVIEWS Key points ■■ Castration-resistant prostate cancer (CRPC) is associated with a poor prognosis and remains a significant therapeutic challenge ■■ Before 2010, there was an urgent unmet clinical need for more-effective and well-tolerated therapies for CRPC ■■ Improved understanding of the underlying biology of CRPC heralded a new era in molecular anticancer drug development ■■ New treatments for CRPC imparting an overall survival benefit include cabazitaxel, sipuleucel‑T, abiraterone and alpharadin ■■ The management of patients with CRPC is changing; therefore, we propose a novel treatment pathway including the incorporation of predictive and intermediate end point biomarkers Box 1 | Mechanisms of maintained androgen-receptor signaling leading to CRPC ■■ Increased androgen-receptor (AR) copy number is found in 25–30% of patients with CRPC.19,164,165 AR amplification is significantly higher in CRPC tumors compared with androgen-dependent disease (20% versus 2%; P = 0.0085).166 ■■ AR point mutations decrease the binding specificity of AR, allowing activation through related molecules, such as endogenous steroids and antiandrogens, in up to 20% of locally advanced tumors and 50% of patients with distant metastasis.167–174 AR mutations are the most likely explanation for the antiandrogen withdrawal syndrome observed in patients with CRPC on maximum androgen blockade (gonadotropin-releasing hormone agonist and AR antagonist), where prostate-specific antigen declines following discontinuation of the AR antagonist.8,175,176 ■■ Activation of the AR can occurr through alternative signaling pathways such as the Ras/Raf/MEK/ERK pathway, or tyrosine kinases Src and Ack1.177–182 ■■ HER2 activates AR through the PI3K/AKT pathway; inhibition of the PI3K pathway in PTEN-negative prostate cancer results in feedback signaling to HER2/HER3, resulting in AR activation. Conversely, AR blockade leads to activation of AKT through decreased levels of FKBP5 impairing the stability of the phosphatase PHLPP.183–185 Insulin-like growth factor‑1 is associated with androgen-independent AR activation;182,186,187 and the AR represses the expression of c‑Met in a ligand-dependent manner.188 ■■ Altered levels of co-factors, especially proteins that co-activate AR, include nuclear receptor co-activator 1, 2 and 4, steroid receptor co-activator 3, melanoma-associated antigen 11 and nuclear factor κB p100 subunit.177,189–192 ■■ Intratumoral enzymes involved in androgen biosynthesis, such as cytochrome P450 (CYP)17 (steroid 17α-hydroxylase/C17,20 lyase) and CYP19A1, are frequently unregulated in CRPC.165 ■■ Constitutively active AR splice variants, which lack the ligand-binding domain, can be expressed alone or as a heterodimer with full-length AR.193 have variable levels of androgenic activity; therefore, they are not frequently used for CRPC treatment.15,18 The nonsteroidal antiandrogens flutamide, nilutamide and bicalutamide are used either alone or in combination with gonadotropin-releasing hormone (GnRH) agonists as neoadjuvant therapy, with radiation therapy, and in intermittent androgen suppression; the clinical benefits of these agents are modest at best.20 Corticosteroids including prednisone, hydrocortisone and dexamethasone suppress adrenal androgens and have PSA response rates of 20–25%.21 However, in most cases, these therapies are associated with a short median timeto-disease progression (<5 months with prednisone and 5–7 months with dexamethasone).7,22–28 In vitro studies have shown agonistic effects of endogenous steroids and dexamethasone on the Thr877Ala-mutant AR; the clinical significance of this finding has not been demonstrated.29 598 | OCTOBER 2011 | VOLUME 8 Synthesized 20-aminosteroids inhibited both wild-type and Thr877Ala-mutant AR‑mediated transactivation, indicating AR antagonistic function; these agents are the first steroids that are complete AR antagonists and may represent promising novel antitumor compounds.30 AR antagonists in development In preclinical studies, the second generation AR antagonist MDV3100 (Medivation, CA, USA) had fivefold to eightfold increased affinity for the AR compared with bicalutamide, reduced the efficiency of AR nuclear translocation and prevented co-activator recruitment of the ligand–receptor complex.31 In a multicenter phase I–II trial, 140 patients with metastatic CRPC received daily oral MDV3100 (30–600 mg).32 This trial established a maximum-tolerated dose of 240 mg daily after seizures were observed in patients receiving higher doses. The most common grade 3 or 4 toxic effect was dose-dependent fatigue. Antitumor activity was observed at all doses, and included PSA responses of ≥50% in 56% of patients.32 MDV3100 is being assessed in multinational phase III, randomized double-blind placebo-controlled studies in chemotherapy-naive patients with CRPC (PREVAIL) and patients with CRPC who have been previously treated with docetaxel-based chemotherapy (AFFIRM). A concern for all the ongoing clinical trials in this disease setting is that there is likely to be crossover of patients to other—potentially highly efficacious—experimental or novel therapies after disease progression on the original trial. This could confound the results for the efficacy of the trial drug. Other novel AR inhibitors currently in earlyphase clinical trials include the small molecules ARN‑509 (Aragon Pharmaceuticals, CA, USA) and BMS‑641988 (Bristol-Myers Squibb, NY, USA).33 CYP17 inhibitors Abiraterone Abiraterone acetate is a small-molecule inhibitor of cytochrome P450 (CYP)17.34–37 CYP17 is a key enzyme with dual functions of 17α-hydroxylase and C17,20-lyase acti vity, which are necessary for both adrenal and intratumoral de novo biosynthesis of androgen hormones.38 Abiraterone is highly potent and selective and is 10–30 fold more potent against CYP17 than ketoconazole.4 Ketoconazole—a weak, reversible and nonspecific inhibitor of CYP17—is associated with toxicities that result in early treatment discontinuation in up to 20% of patients.4 Despite this, ketoconazole has antitumor activity in prostate cancer, with PSA response rates of 20–62% and a median duration of response of 3–7 months; however, it has never been demonstrated to improve overall survival.38 Although initial clinical studies of abiraterone in patients with non-castrate prostate cancer showed suppression of testosterone to castrate levels, this was followed by a gonadotropin surge, which restored serum testosterone levels.39 Therefore, a phase I study was conducted to assess a continuous dosing schedule of abiraterone in patients with CRPC, administered with a GnRH analog to overcome the feedback gonadotropin surge; abiraterone was well tolerated with www.nature.com/nrclinonc © 2011 Macmillan Publishers Limited. All rights reserved REVIEWS promising antitumor activity.40 Phase II clinical trials in patients with CRPC in both chemotherapy-naive and post‑docetaxel settings reported a PSA response of ≥50% in 67% and 51% of patients and a median timeto-PSA progression of 225 days and 169 days, respectively.41,42 A separate trial of abiraterone in patients with docetaxel-naive CRPC showed PSA responses of ≥50% in nine of 19 ketoconazole‑pretreated and nine of 14 ketoconazole-naive patients.43 A further phase II trial of abiraterone in combination with prednisone in patients with docetaxel-treated CRPC demonstrated PSA responses of ≥50% in both ketoconazole-pretreated (seven of 27) and ketoconazole-naive (14 of 31) patients.44 The early-phase studies confirmed the safety and tolerability of abiraterone, with the main (expected) toxic effects of mild-to-moderate hypertension, hypokalemia and fluid retention, which are class effects and effectively managed with treatment with the mineralocorticoid antagonist eplerenone and/or a low dose of steroids to blunt the secondary adrenocorticotropic hormone feedback loop.41,42 A phase III multinational, multicenter, randomized, double-blind, placebo-controlled study of 1,000 mg of abiraterone plus 5 mg twice daily of prednisone versus placebo plus prednisone was conducted in 1,195 patients with docetaxel-treated CRPC.45 Abiraterone improved median overall survival compared with the placebo arm (14.8 months versus 10.9 months; P <0.001). Importantly, the survival benefit was similar between patients who had received one or two previous lines of chemotherapy and across all patient subgroups studied, including age, performance status and the presence of visceral disease. All secondary end points achieved significance in favor of abiraterone, including time-to-PSA progression (P <0.001), radiological-progression-free survival (P <0.001) and confirmed PSA response rate (P <0.001). Adverse events were similar in both arms of treatment. Of note, grade 3 or 4 mineralocorticoid toxic effects were only seen in less than 4% of patients. Based on this trial, abiraterone was approved by the FDA for the treatment of CRPC in the post-docetaxel setting.46 A separate phase III trial of abiraterone plus prednisone in patients with chemotherapy-naive and ketoconazole-naive CRPC has completed patient accrual (NCT00887198);33 this trial will address the efficacy in treatment-naive patients. Future trials will be required to determine the optimum use of steroids in combination with abiraterone and the efficacy of abiraterone in the first-line treatment of patients with prostate cancer. Abiraterone has the highest chance of having an impact by increasing cure rates in high-risk disease. However, the potential adverse effects associated with long-term administration of prednisone and the castrating effects of abiraterone, especially with regards to potential increased cardiovascular effects and bone health effects of protracted ADT, will need to be considered. Orteronel In a phase I–II trial, 26 patients with CRPC received the selective 17,20-lyase inhibitor orteronel (100–600 mg twice daily) as monotherapy and six patients received orteronel (400 mg twice daily) in combination with prednisone (5 mg twice daily).47 Drug-related toxic effects included fatigue (including three patients with grade ≥3 fatigue at 600 mg) and gastrointestinal symptoms. Pharmacokinetics were dose proportional. Following 4 weeks of orteronel treatment, median testosterone and DHEA levels decreased from 5.5 ng/dl to 0.6 ng/dl and 50.0 μg/dl to below quantifiable levels, respectively. All patients treated at doses ≥300 mg had a reduction in PSA levels; in 12 patients the reduction was ≥50% and in four it was ≥90%. The phase II expansion of the study and a randomized, double-blind, phase III study evaluating orteronel plus prednisone versus placebo plus prednisone in both chemotherapy-naive patients and post-docetaxel patients with CRPC are ongoing.33 TOK‑001 TOK‑001 (Tokai Pharmaceuticals, MA, USA) is an oral small-molecule inhibitor of AR and CYP17.48,49 It is being assessed in a phase I–II study (ARMOR) and results are expected soon. Although inhibition of the AR by TOK‑001 may enhance its CYP17-mediated antitumor activity, the binding of the inhibitor to the AR might result in an agonistic effect on AR signaling if genetic aberrations of the AR result in ligand promiscuity.4 Chemotherapy in prostate cancer Mitoxantrone In a phase III study, the combination of type II topoiso merase inhibitor mitoxantrone with predisone was significantly more efficacious than prednisone alone for palliative symptom management.22 When these palliative benefits were confirmed in the CALGB 9182 study,23 regulatory approval for mitoxantrone was obtained from the FDA. No significant differences in median overall survival were found between the treatment arms, probably because of small patient numbers (242 patients). Prostate cancer was considered to be predominately insensitive to chemotherapy until results from two key phase III clinical trials assessing docetaxel chemo therapy (TAX327 and SWOG9916) were published in 2004 (Table 1).9,10 Docetaxel and docetaxel combinations The TAX327 phase III clinical trial enrolled 1,006 men with chemotherapy-naive metastatic CRPC to receive prednisone (5 mg twice daily) and were randomly assigned to weekly docetaxel for 5 out of 6 weeks or mitoxantrone or docetaxel every 3 weeks (Table 1).9 Compared with the men in the mitoxantrone group (overall survival 16.5 months), patients in the 3‑weekly docetaxel group had an increased overall survival of 18.9 months with a hazard ratio (HR) for death of 0.76 (95% CI 0.62–0.94; P = 0.009). A total of 45% of patients had a ≥50% decline in their serum PSA levels (P <0.001); 35% had predefined reductions in pain (P = 0.01), and 22% had improvements in their quality of life (P = 0.009).9 The updated extended follow-up survival data from this study showed an absolute median overall NATURE REVIEWS | CLINICAL ONCOLOGY VOLUME 8 | OCTOBER 2011 | 599 © 2011 Macmillan Publishers Limited. All rights reserved REVIEWS Table 1 | Completed clinical trials in patients with CRPC* Agent Phase n (setting) PSA RR >50% Median OS (months) Median PFS (months) Conclusions Prednisone + 3-weekly docetaxel vs prednisone + 1-weekly docetaxel vs prednisone + mitoxantrone9 III 1,006 (CT-naive) 45% vs 48% vs 32% 18.9 vs 17.4 vs 16.5 NA Docetaxel approved as first-line therapy for CRPC Docetaxel + estramustine vs mitoxantrone + prednisone10 III 770 (CT-naive) 50% vs 27% 17.5 vs 15.6 6.3 vs 3.2 Estramustine increased side effects without enhancing efficacy Prednisone + satraplatin vs prednisone + placebo106 III 950 (post-CT) 25.4% vs 12.2% (overall PSA RR) 15.3 vs 15.4 2.8 vs 2.4 No statistical improvement of OS (P = 0.8) Sipuleucel‑T vs placebo78 III 512 (CT-naive) 2.6% vs 1.3% 25.8 vs 21.7 3.7 vs 3.6 (TTrP) Sipuleucel‑T approved for CT‑naive patients with asymptomatic or mildly symptomatic CRPC Prednisone + abiraterone vs prednisone + placebo45 III 1,195 (post-CT) 29.1% vs 5.5% 14.8 vs 10.9 5.6 vs 3.6 Abiraterone approved for post-docetaxel setting Docetaxel + prednisone vs docetaxel + prednisone + bevacizumab53 III 1,050 (CT-naive) 69.5% vs 57.9% 22.6 vs 21.5 9.9 vs 7.5 No significant improvement of OS (P = 0.181) Prednisone + cabazitaxel vs prednisone + mitoxantrone61 III 755 (post-CT) 39.2% vs 17.8% (overall PSA RR) 15.1 vs 12.7 2.8 vs 1.4 Cabazitaxel new standard second-line chemotherapy MDV310032 I–II 140 (CT-naive [46%] and post-CT [54%]) 56% NA 10.8 (TTrP) Phase III trials ongoing Docetaxel + prednisone vs docetaxel + prednisone + oblimersen107 II 115 (CT-naive) 37% vs 46% NA 4.4 vs 6.2 (TTP) Primary end point of PSA response not met Sunitinib108 II 36 (post-CT) 12.1% NA 4.9 Phase III trial halted for lack of efficacy Cetuximab + docetaxel109 II 38 (post-docetaxel) 17% NA NA Combination was well tolerated Atrasentan vs placebo84 III 809 (CT-naive) NA 20.5 vs 20.3 NA Primary end point (TTP, radiological and biochemical) not met *The alpharadin phase III trial data were not fully available at the time of publication; however, in June 2011 a press release reported that this trial had met its primary end point of improved OS, improving OS by 2.7 months. Abbreviations: CRPC, castration-resistant prostate cancer; CT, chemotherapy, NA, not available; OS, overall survival; PFS, progression-free survival; PSA, prostate-specific antigen; RR, response rate; TTP, time to progression; TTrP, time to radiological progression. survival of 19.2 months (95% CI 17.5–21.3 months) in the 3‑weekly docetaxel arm versus 16.3 months (95% CI 14.3–17.9 months) in the mitoxantrone arm.50 Since the absolute advantage in overall survival in patients receiving docetaxel was only approximately 3 months, several docetaxel-based trials were designed with the goal of improving these results (Table 1). Particularly interesting are studies evaluating the combination of novel molecular therapies with the docetaxel and prednisone regimen in the first-line chemo therapy setting. These include two large randomized phase II trials of high-dose calcitriol (ASCENT‑1 and ASCENT‑2).51 Docetaxel and prednisone were also combined with a vaccine (GVAX) and a monoclonal antibody against VEGF (bevacizumab).52,53 Unfortunately, all of these trials failed to meet their respective primary end points. Other trials are currently ongoing (Supplementary Table 1 online) and we are cautiously optimistic that with the large range of agents undergoing trials, we will ultimately be able to improve the survival benefit for patients using docetaxel-based treatments. A recent small study suggested that docetaxel clearance is raised approximately twofold in patients with CRPC when compared with patients with non-CRPC, due to increased hepatic drug uptake and thus decreased systemic exposure. Therefore, patients with CRPC might have altered docetaxel dose requirements. 54 These 600 | OCTOBER 2011 | VOLUME 8 findings might explain the low incidence of neutropenia in patients with CRPC following docetaxel treatment. A key challenge in CRPC is the management of patients with disease progression during or following docetaxel-based chemotherapy. Since docetaxel is the gold-standard treatment for CRPC, mitoxantrone is often used as a second-line treatment. However, there have been no data that show an improvement in overall survival with this treatment. A number of new treatments are in late-phase trials, with the intent of improving the outcomes of patients with CRPC who have developed disease progression on docetaxel-based chemotherapy (Table 1 and Supplementary Table 2 online). Several small retrospective studies have shown that patients with advanced-stage CRPC who responded to first-line docetaxel-based chemotherapy continue to be sensitive to retreatment, with favorable toxicity profiles.55,56 It should, however, be noted that the extent and duration of response to docetaxel decreases with each consecutive line of retreatment, and docetaxel retreatment has not been demonstrated to result in any survival benefits.57 Satraplatin The SPARC phase III trial was conducted in patients with metastatic CRPC who had received at least one line of chemotherapy,58 to evaluate satraplatin, the first orally www.nature.com/nrclinonc © 2011 Macmillan Publishers Limited. All rights reserved REVIEWS available platinum compound.59 A total of 950 patients with CRPC were randomly assigned to receive prednisone (5 mg twice daily) with or without satraplatin (80 mg/m2) for 5 days every 4 weeks.58 Despite significantly higher PSA declines (P <0.001), pain responses (P <0.005), time-to-pain progression (P <0.001) and median progression-free survival (PFS; P <0.001) in the satraplatin arm, the primary end point of significantly improved overall survival was not achieved (HR = 0.98) and the drug was not approved. Despite this result, satraplatin might have a role in patients with BRCA1 and/or BRCA2 mutated CRPC—or in those who display a ‘BRCAness’ phenotype—since BRCA-mutated tumors are exquisitely sensitive to platinum-based chemotherapies.60 Cabazitaxel Cabazitaxel has also been investigated in the postdocetaxel setting in patients with CRPC.61 Cabazitaxel is a taxane that is as potent as docetaxel in tumor cell lines,62 and exhibits antitumor activity in preclinical models resistant to paclitaxel and docetaxel.63,64 A phase I clinical study established neutropenia as the dose-limiting toxicity and 20 mg/m2 as the recommended dose.65 A higher dose (25 mg/m2) was examined in the phase II trial of cabazitaxel in patients with taxane-resistant metastatic breast cancer in patients who did not experience significant toxicity during the first cycle.66 Cabazitaxel was progressed from phase I directly to a randomized open-label phase III trial (EFC6193; TROPIC); 755 patients with docetaxel-treated metastatic CRPC were treated with prednisone (5 mg twice daily) and either mitoxantrone (12 mg/m2; n = 377) or cabazitaxel (25 mg/m2; n = 378).61 The median overall survival was 15.1 months (95% CI 14.1–16.3) in the cabazitaxel group and 12.7 months (95% CI 11.6–13.7) in the mito xantrone group. The HR for death of men treated with cabazitaxel compared with those taking mitoxantrone was 0.70 (95% CI 0.59–0.83; P <0.0001). The most common grade 3 or worse toxic effects included neutropenia and diarrhea.61 In addition, 8% of patients in the cabazitaxel group and 1% in the mito xantrone group had febrile neutropenia, suggesting that cabazitaxel treatment will require close surveillance; prophylactic granulocyte-colony-stimulating factors (G-CSF) and a low threshold for dose modifi cations should be considered in high-risk patients. These high-risk patients might be identified based on pharmacog enomic factors such as mutations in CYP3A4 and CYP3A5, which are associated with slow cabazitaxel clearance.62 Cabazitaxel is the first drug to improve overall survival in patients with metastatic CRPC who had developed disease progression during and after docetaxel-based therapy. 61 As a result of these data, cabazitaxel was recently approved by the FDA as the new standard of care for the second-line treatment of CRPC following failure of docetaxel chemotherapy.67 Although the cabazitaxel phase III trial was a ‘success’, several criticisms have been made against this study. For example, one has to question if it is reasonable to bypass conducting a phase II trial with a potentially toxic agent. In addition, despite exclusion of patients who had extensive prior radiotherapy or concurrent serious illness, the treatment-related death rate was 5%, with no data demonstrating improved quality of life. Further studies evaluating drug safety in this patient population and assessing the quality-of-life benefits imparted by cabazitaxel are warranted. Finally, would the results of this phase III trial have been significant if the comparator arm was docetaxel retreatment, especially given the lack of a standardized definition of docetaxel progression or resistance? The superiority of cabazitaxel versus docetaxel is being addressed by a randomized, open-label, multicenter phase III study comparing cabazitaxel (25 mg/m2 and 20 mg/m² 3‑weekly) with docetaxel, both in combination with prednisone; however, this study is being conducted in patients with chemotherapy-naive CRPC.33 Other novel chemotherapies Apart from cabazitaxel, other microtubule stabilizers, including third-generation taxanes (TPI‑287 [Tapestry Pharmaceuticals, CO, USA]) and the epothilones (ixabepilone and patupilone) are currently in phase II clinical trials in patients with CRPC and are showing promising antitumor activity.33,68,69 It is likely that they will need to be compared head-to-head with cabazitaxel in a phase III post-docetaxel trial setting. Immunotherapy The concept of immune modulation—aimed at generating a clinically meaningful antitumor immune response —has been extensively evaluated in melanoma and renal cancers.70 This principle has since been extended to prostate cancer because it can be a slow-growing, indolent disease, allowing sufficient time for the generation of an effective antitumor immune response. 71 Moreover, recent data have demonstrated that prostate cancer is more immunogenic than previously appreciated, with evidence of prostate cancer-specific autoantibodies in blood samples of patients.72 The challenges in the successful development of immunotherapy for prostate cancer are multifold. First, prostate cancer is not a homogenous disease, implying that there are several antigenic targets that could have a role in the development of an immune response. Second, defining clinical responses and demonstrating a clear relationship between the induction of antigen-specific immune responses and clinical outcomes is challenging. Third, there is a mismatch between the need to have a rapid and realistic drug development timeline and the selection of patients with a low likelihood of immunosuppressive mechanisms—that is, enrolling patients with minimal disease burden, but in whom time to clinically meaningful events such as disease progression or death can be prohibitively long. The most promising immuno therapies are sipuleucel‑T and ipilimumab (Table 2) and antibodies to the immune checkpoint programmed death‑1 (PD‑1) protein, of which only sipuleucel‑T has received FDA approval for CRPC.73–75 NATURE REVIEWS | CLINICAL ONCOLOGY VOLUME 8 | OCTOBER 2011 | 601 © 2011 Macmillan Publishers Limited. All rights reserved REVIEWS Table 2 | Immunotherapy clinical trials in patients with CRPC Agent Immunotherapy mechanism of action Phase n (setting) Conclusions Docetaxel (q3w) + GVAX or prednisone33 2 prostate cancer cell lines (engineered to secrete G‑CSF) to increase DC antigen presentation III 1,006 (CT-naive) Trial halted early because of negative futility analysis (NCT00133224) Docetaxel + prednisone vs GVAX33 2 prostate cancer cell lines (engineered to secrete G‑CSF) to increase DC antigen presentation III 770 (CT-naive) Trial halted early because of increased rate of death in the experimental arm (NCT00089856) Ipilimumab (3 mg/kg q4w × 4) ± docetaxel (75 mg/m2 × 1)110 Anti-CTLA‑4 monoclonal antibody II 43 (CT-naive) 3 patients in each arm had PSA decrease >50%; most frequent adverse events were fatigue (44%), pruritus (26%), nausea (19%), rash (12%), constipation (12%) and weight loss (12%); 6% experienced an immune breakthrough event—phenomenon correlated in other studies with efficacy; no enhancement of activity by co-administration of docetaxel Ipilimumab vs placebo111 Anti-CTLA‑4 monoclonal antibody III Estimated 600 (CT-naive, asymptomatic/minimally symptomatic Primary end point overall survival (NCT01057810) Ipilimumab vs placebo112 Anti-CTLA‑4 monoclonal antibody III Estimated 800 (post-CT) Primary end point overall survival (NCT00861614) Leuprolide + bicalutamide ± ipilimumab113 Anti-CTLA‑4 monoclonal antibody II Estimated 108 (advanced-stage or post-surgery for recurrent cancer) Primary end point PFS; patients treated with ipilimumab + hormonotherapy were more likely to have an undetectable PSA by 3 months (55% vs 38%); some patients treated with ipilimumab experienced a significant clinical response and disease downstaging; the most common severe (grade 3 or 4) immune-related (ipilimumab arm) adverse events were colitis (4.5%) and diarrhea (4.5%); 15 patients (27.7%) treated with ipilimumab experienced cutaneous changes (NCT00170157) Ipilimumab + leuprolide114 Anti-CTLA‑4 monoclonal antibody II Estimated 20 (neoadjuvant) In 12 patients treated, the combination seems to facilitate a profound local tumor response; trial ongoing and recruiting (NCT01194271) Ipilimumab + sargramostim + PROSTVAC115,116 Anti-CTLA‑4 monoclonal antibody + pox-virus based vaccine expressing PSA and 3 co-stimulatory molecules I 30 (CT-naive, metastatic CRPC) No dose-limiting toxicity found; 20 grade ≥2 immune-related adverse events and no grade >2 adverse events attributed to PROSTVAC; this combination has clinical activity in this patient population Ipilimumab + sargramostim117 Anti-CTLA‑4 monoclonal antibody I Estimated 36 (CT-naive) 3 of 24 patients experienced a >50% decline in PSA; 1 patient had PR by RECIST criteria on liver metastasis at week 12 confirmed by a follow-up scan 12 weeks later, 1 patient had grade 3 pan-hypopituitarism, 1 patient had grade 3 temporal arteritis, 1 patient had grade 3 stroke (unlikely related), 1 patient had grade 3 diarrhea and 1 patient had grade 3 rash; trial ongoing (NCT00064129) PROSTVAC + G-CSF vs placebo118 Pox-virus based vaccine expressing PSA and 3 co-stimulatory molecules II 125 (post-docetaxel) Overall survival: 25.1 vs 16.6 months (HR = 0.56 [95% CI, 0.37–0.85]); PFS: 3.8 vs 3.7 months (HR = 0.88 [95% CI, 0.57–1.38]); primary end point PFS ONY‑P1 vs placebo33 3 irradiated cancer cell lines II Estimated 54 (CT-naive, M0) Trial ongoing (NCT00514072); primary end point time-to-progression Abbreviations: CRPC, castration-resistant prostate cancer; CT, chemotherapy; DC, dendritic cell; G‑CSF, granulocyte-colony-stimulating factor; HR, hazard ratio; PFS, progression-free survival; PR, partial response; PSA, prostate-specific antigen; q3w, every 3 weeks; q4w, every 4 weeks. Sipuleucel‑T is an immunotherapeutic comprising the reinfusion of autologous peripheral blood mononuclear cells, including antigen-presenting cells (APCs) activated ex vivo with the recombinant fusion protein PA2024.74 PA2024 is formed by prostatic acid phosphatase fused to granulocyte macrophage colony-stimulating factor (GM-CSF). The vaccine is created by harvesting white blood cells from patients, then dendritic cell precursors are enriched and incubated with PA2024 before being infused back into the patient. Following two randomized, placebo-controlled phase III clinical trials involving sipuleucel‑T in patients 602 | OCTOBER 2011 | VOLUME 8 with CRPC that did not show significant effects on the time-to-disease progression,76,77 a double-blind, placebocontrolled, multicenter trial (IMPACT) involving patients with metastatic CRPC was conducted (Table 1). A total of 512 asymptom atic or minimally sympto matic men were randomized to receive sipuleucel‑T or placebo. There was a relative reduction of 22% in the risk of death in the sipuleucel‑T group (HR = 0.78; 95% CI 0.61–0.98; P = 0.03) representing an absolute 4.1 month improvement in median overall survival (25.8 months versus 21.7 months). Toxic effects observed more frequently in the sipuleucel‑T arm included chills, fever, www.nature.com/nrclinonc © 2011 Macmillan Publishers Limited. All rights reserved REVIEWS and headaches.78 Based on these results, sipuleucel‑T was approved by the FDA for the treatment of asymptomatic or minimally symptomatic metastatic CRPC, representing the first therapeutic cancer vaccine in prostate cancer to receive FDA approval.79 Alpharadin Alpharadin (Bayer Schering Pharma, Berlin, Germany) is a radioisotope containing an α‑particle emitting nuclide, which was recently assessed in a randomized, placebocontrolled phase III trial (ALSYMPCA) in 922 patients with symptomatic CRPC with bone metastases. 33,80 Alpharadin targets bone metastases with high-energy α radiation of extremely short range that spares bone marrow and, therefore, limits toxic effects. Based on a recommendation from an Independent Data Monitoring Committee following a pre-planned interim analysis, the phase III study was stopped and patients on the placebo arm were offered treatment with alpharadin.81 The primary end point of the study, overall survival, was significantly increased in the alpharadin arm (two-sided P value = 0.0022, HR = 0.699); the median overall survival was 14.0 months for patients in the alpharadin arm and 11.2 months for those receiving placebo.80 Key issues for drug development There is now an impressive range of targeted therapies being assessed at different phases of clinical trial development (Tables 1–3 and Supplementary Tables 1 and 2 online). These include novel agents against a wide array of rational targets involving multiple key biological mechanistic drivers of CRPC, ranging from antiangiogenic agents to MET inhibitors (Figure 1 and Table 3). Multiple compounds have proceeded to phase I–II trials following promising preclinical data, although not all have been assessed in CRPC-specific studies. It is important to note, however, that despite this myriad of agents making the transition to phase II trials, many of these studies are failing to correctly predict phase III trial outcomes.38 Examples of these include zibotentan and atrasentan.82–84 These expensive and late-stage failures cause a major impact and strain on patient care, the pharmaceutical and health-care industry and academic institutions. Therefore, to optimize the development of molecular therapies for CRPC, several key issues need to be considered, such as combinatorial studies and biomarkers, including predictive and intermediate end point assays. Combination studies Given the selective nature of targeted molecular therapeutics, it is likely that combinatorial regimens will be key to the future of drug development in CRPC. The increased number of novel compounds being tested and new high-throughput technologies available for the generation of molecular data have facilitated the study of the most promising combinations.85 In theory, ‘vertical combinations’—drugs that act along the same pathway —or ‘horizontal combinations’—drugs that target parallel pathways—seem rational approaches (Figure 1). However, the likely reality is one that involves complex interplay and crosstalk between signaling networks, and feedback loops within individual pathways, rather than simple linear pathways. Nonetheless, a combinatorial strategy will be key to the future development of effective regimens in CRPC management. Patient stratification A cancer biomarker is a molecule that can be objectively measured and evaluated as an indicator of normal biol ogical, pathogenic, or pharmacologic responses to a therapeutic intervention. 86 Predictive and intermediate end point biomarkers should be scientifically sound and analytically validated to ensure robust and reproducible results. Predictive biomarkers Predictive biomarkers to define the appropriate patient population for molecular therapies are likely to be essential for the development of novel agents for CRPC. Such an approach will not be applicable to all therapeutics (for example, chemotherapies such as docetaxel and cabazitaxel); however, in a heterogeneous disease such as CRPC, a strategy using predictive biomarkers will help define antitumor responses to selective targeted agents.87 A recent example is that of the TMPRSS2–ETS gene fusion, which can be detected by fluorescence in situ hybridization in tumor cells and circulating tumor cells (CTCs) of patients with CRPC and might predict antitumor responses to abiraterone.88 The ERG gene (a member of the ETS family of oncogenes) was identified as the most commonly overexpressed proto-oncogene in prostate cancer—present in about 72% of cases89—and TMPRSS2 (which codes for a serine protease secreted in response to androgen exposure) was observed to be fused to ERG.90 This TMPRSS2–ETS fusion leads to overexpression of ERG, initially under the control of androgen and the AR but androgen dependence may be lost in advanced-stage disease; activation of this pathway might be central to prostate oncogenesis.91,92 Clinical trials assessing abiraterone have indicated that the presence of an ERG rearrangement was associated with the magnitude of PSA decline following abiraterone treatment (P = 0.007).88 This association is being prospectively evaluated in the phase III trial of abiraterone and prednisone versus placebo and prednisone and results are expected soon. Intermediate end point biomarkers One of the main hurdles for studies assessing the efficacy of agents in the post-docetaxel setting remains the lack of a standardized definition for docetaxel progression or resistance. This issue does not just belie docetaxel treatment, but is a wider challenge in patients with metastatic CRPC. Current strategies to evaluate disease response and progression employ a combination of parameters, including rising serum PSA levels using the prostate working group criteria, 93 RECIST radiological cri teria94 and worsening clinical symptoms. 95 However, NATURE REVIEWS | CLINICAL ONCOLOGY VOLUME 8 | OCTOBER 2011 | 603 © 2011 Macmillan Publishers Limited. All rights reserved REVIEWS Table 3 | Novel targets in prostate cancer Target Clinical data HSP90 Phase II trial of 17-AAG in CRPC: closed prematurely owing to lack of response119,120 Clusterin Phase II with OGX‑011 trial in chemotherapy-naive PC: improved PFS and OS121 BCL2 Phase I of oblimersen and mitoxantrone: good tolerance122 Phase I of oblimersen plus docetaxel in CRPC: PSA response in 7 of 12 taxane-naive patients, no response in taxane-treated patients123 Randomized phase II trial of oblimersen and docetaxel vs docetaxel in CRPC: similar response rates but increased toxicity in the combination arm107 Phase I–II trial of AT‑101 in CRPC: PSA declines124 Survivin Phase I and II trials of YM155 in CRPC: PSA responses125 Combination of YM155, docetaxel and predisone: well tolerated with antitumor activity observed126 PARP‑1 Phase I trial of olaparib in BRCA1 or BRCA2 mutated CRPC: activity reported127 DNA methyltransferase Phase II trial with azacitidine in CRPC: promising results128,129 HDACs Phase II trial of vorinostat in CRPC: limited activity and considerable toxicity130 Phase I trial of vorinostat and docetaxel in solid tumors: poorly tolerated, no objective responses131 Phase II trial of romidepsin in CRPC: minimal activity and high toxicity132 VEGF or VEGFR Phase II trial of docetaxel, estramustine and bevacizumab in CRPC: ≥50% PSA response in 75% of patients with median OS of 24 months133 Phase III trial of docetaxel and prednisolone with or without bevacizumab: no improvement in OS53 Phase II trial of bevacizumab, thalidomide, docetaxel and prednisolone: PSA decline of ≥50% in 90% of patients and a median OS of 28.2 months134 Phase II trial of sorafenib in CRPC: no objective responses and no PSA responses, regression of bone disease was seen135 Two phase II trials of sorafenib in chemotherapy-naive CRPC: limited activity136,137 Sunitinib in CRPC after docetaxel failure: 12% of patients had >50% PSA decline, 11% of patients with measurable disease had a partial response and, median PFS of 19.4 weeks138 Phase I–II trial of aflibercept in solid tumors: well tolerated with early signals of activity139 Phase II trials of cediranib in post-docetaxel CRPC: promising activity140 Vandetanib in CRPC: no activity compared with placebo141 PDGFR Trial of imatinib and zoledronic acid: no response and the trial was closed prematurely142 Trial of imatinib plus docetaxel vs docetaxel: closed prematurely owing to gastrointestinal toxicity in the combination arm143 Src Phase I trial of saracatinib in solid tumors: well tolerated144 Phase II trial of dasatinib in chemotherapy-naive patients with CRPC: lack of disease progression achieved in 21 (44%) patients at week 12 and in 8 (17%) patients at week 24145 Endothelin Two placebo-controlled phase III trials of atrasentan in CRPC: no reduction in risk of disease progression83,84 Phase III trial of atrasentan plus docetaxel: ongoing following results of phase I–II trial146 Randomized phase II trial of zibotentan vs placebo in CRPC: promising survival results82,147 EGFR Phase Ib–IIa trial of doxorubicin and cetuximab in CRPC: minimal activity148 Several trials of gefitinib in CRPC: minimal activity as single agent,149–151 and no added efficacy in combination with docetaxel152 HER2 Trastuzumab in CRPC: very limited activity153 Small study of docetaxel, estramustine and trastuzumab: 9 of 13 patients had a ≥50% PSA decline154 Single-agent lapatinib in advanced-stage hormone-naive PC: no antitumor activity155 PI3K/Akt/mTOR Everolimus, temsirolimus and OSI‑027: undergoing clinical trials in CRPC33 PKC-β Phase II trial of enzastaurin: very limited activity, will be tested with docetaxel156 IGF pathway Phase II trials of cixutumumab: ongoing157 Phase II trial of preoperative figitumumab in localized prostate cancer: 31% of patients had >50% PSA decline158 Phase II trials of figitumumab and docetaxel in solid tumors: 3 of 18 patients with CRPC showed PR, 41% (9/22) patients had ≥50% PSA response159 Phase II trial with figitumumab and docetaxel in CRPC ongoing33 IL-6R/JAK/STAT3 Phase II trial of siltuximab in post-chemotherapy CRPC: PSA response rate of 3.8% and stable disease in 23%160 MET/VEGFR2/RET Phase II trial of cabozantinib in CRPC with measurable soft-tissue disease: 56 of 65 patients with bone metastasis from CRPC achieved either complete or partial resolution of lesions on bone scan; evidence of tumor shrinkage in 84% of patients with measurable soft-tissue disease161 Phase I trials of specific MET inhibitor ARQ 197: CTC declines and RECIST PR in CRPC162,163 Abbreviations: CRPC, castration-resistant prostate cancer; CTC, circulating tumor cell; HDAC, histone deacetylase; IGF, insulin-like growth factor; OS, overall survival; PARP, poly(ADP) ribose polymerase; PC, prostate cancer; PDGFR, platelet-derived growth factor receptor; PFS, progression-free survival; PR, partial response; PSA, prostate-specific antigen. 604 | OCTOBER 2011 | VOLUME 8 www.nature.com/nrclinonc © 2011 Macmillan Publishers Limited. All rights reserved REVIEWS Extracellular space VEGFR P P P P P P EGFR P P P HER2 P P P P P P P P P MET IGF-1R P P P P P P P P P P P P P P P P P P P P P ETA IL-6 PDGFR P P P P P P Cytoplasm P P P P P P JAK/STAT3 Ras P P P Angiogenesis Survival PI3K AR Raf Clusterin MEK Treatment resistance ERK Src AR Akt p53 BIM BCL2 Survival mTOR NF-κB Angiogenesis Proliferation Differentiation Therapy resistance Ribosomal protein synthesis Apoptosis Hsp90 AR PKC DNA repair Methylation PARP DNMTs Deacetylation Survivin Cell-cycle progression Proliferation Differentiation AR ER ARE Nucleus ERE AR TMPRSS2 ER ligand HDACs ER ERG AR ligand P Phosphorylation Figure 1 | Key signaling cascades involved in prostate cancer. A wide range of agents, both approved and under development, target pathways that are involved in prostate cancer (Table 3). Abbreviations: AR, androgen receptor; BIM, BLC2-interacting mediator of cell death; DNMT, DNA methyl transferase; ER, estrogen receptor; ET A, endothelin receptor type A; HDAC, histone deacetylase; HSP, heat-shock protein; IGF-1R, insulin-like growth factor receptor 1; IL, interleukin; mTOR, mammalian target of rapamycin; NF‑κB, nuclear factor κB; PARP, poly(ADP) ribose polymerase; PDGFR, platelet derived growth factor receptor; STAT, signal transducers and activators of transcription. with improved technologies and reduced costs, it is likely that the use of novel analytically validated and clinically qualified intermediate end point biomarkers will become more commonplace. These are likely to include the use of CTCs and functional imaging, such as diffusion‑weighted MRI techniques.87,96 With multiple novel agents for CRPC, new approaches for clinical trials are also essential. Overall survival is the only robust end point, but this means greater chances of treatment crossover as multiple new drugs are being evaluated, which can jeopardize successful trial outcomes. PFS is a poor surrogate for overall survival in prostate cancer, with overall associations between PFS and overall survival at best moderate (0.4 for radiographic PFS and 0.33 for PSA PFS).95 Therefore, it is essential that inter mediate end point biomarkers that are robust surrogates of overall survival are developed to accurately reflect treatment benefit at earlier time points.98 Historically, the biomarker associated with prostate cancer for screening, and patient stratification at diagnosis and following primary local therapy is PSA. 99 To improve the specificity and sensitivity of this biomarker, several PSA algorithms have been described (such as PSA doubling time);100 however, PSA level is not always representative of the disease, especially in the advancedstage phases when CRPC may modify its phenotype.101 In addition, PSA fluctuations during the first 12 weeks of treatment for CRPC are not indicative of early therapy failure.95 Several studies have been conducted or are ongoing to evaluate potential new markers that are able to better represent the complexity of CRPC, including intact CTCs, CTC fragments or exosomes, circu lating plasma DNA, protein multiplex plasma assays and metabolomics.102,103 The FDA has approved the CellSearch® CTC System as a prognostic indicator for patients with metastatic breast, colorectal and prostate cancers.104 The molecular characterization of CTCs may potentially offer a ‘liquid biopsy’ for patient selection, monitoring of treatment efficacy and the identification of drug-resistant mechanisms. Recently, the relationship between post-therapy CTC counts and overall survival was demonstrated in patients with CRPC.98 A total of 231 patients were stratified into predetermined ‘favorable’ or ‘unfavorable’ groups, based on the number of CTCs (<5 and ≥5 CTCs/7.5ml of blood). Patients with unfavorable pre-treatment CTC levels had a shorter overall survival than those in the favorable group (11.5 months versus 21.7 months; HR = 3.3; P <0.0001). CTC counts were better at predicting overall survival than PSA algorithms at all time points assessed (P = 0.0218). The prognosis for patients with unfavorable baseline CTC counts who converted to favorable CTC counts improved (6.8 months to 21.3 months), while patients with favorable baseline CTC count who converted to an unfavorable count worsened (>26 months to 9.3 months). Based on these data, CTCs NATURE REVIEWS | CLINICAL ONCOLOGY VOLUME 8 | OCTOBER 2011 | 605 © 2011 Macmillan Publishers Limited. All rights reserved REVIEWS Treatment paradigm in 2011 and beyond 2011 Beyond 2011 Gonadotropin-releasing hormone agonist Gonadotropin-releasing hormone agonist Gonadotropin-releasing hormone agonist + bicalutamide Sipuleucel-T? Sipuleucel-T? Gonadotropin-releasing hormone agonist + abiraterone + low-dose steroids Low-dose steroids Stilbestrol? Stilbestrol? Docetaxel Docetaxel Cabazitaxel Abiraterone ■ Reassessment with conventional imaging and intermediate end point biomarkers (e.g. CTCs and functional imaging) ■ Patient molecular stratification with analytically validated biomarkers Cabazitaxel ■ Reassessment with PSA and CT or bone scans Figure 2 | Treatment paradigm for CRPC in 2011 and beyond. The gold standard for CRPC remains docetaxel; however, positive results with cabazitaxel, sipuleucel‑T and abiraterone provide a range of agents, and stilbestrol and low-dose steroids should also be considered. In the current treatment pathway, cabazitaxel and abiraterone are in the post-docetaxel setting and sipuleucel‑T is in the pre-docetaxel setting in line with FDA approval. In the future, this pathway will inevitably change substantially, as factors including resistance to prior therapies and drug availability determine the sequence of drugs. In addition, efforts should be made to molecularly stratify patients to match targeted therapies (Figure 1 and Table 3). The decision for treatment transition should incorporate standard clinicopathological measures, novel biomarkers (such as CTCs and circulating plasma DNA) and imaging modalities (such as diffusion weighted-MRI and F18 PET). Abbreviations: CRPC, castration-resistant prostate cancer; CTCs, circulating tumor cells; PSA, prostate-specific antigen. are an accurate and independent predictor of overall survival in CRPC and are likely to predict prognosis and monitor the antitumor effects of treatment in CRPC in the future (Figure 2).98 Using CTCs as an intermediate end point for overall survival is being assessed in ongoing clinical trials (NCT00638690; NCT01084655).33 New CRPC therapeutic landscape First-line therapy for CRPC is docetaxel; however, with positive results now available from phase III trials of cabazitaxel, sipuleucel‑T and abiraterone, and data for MDV‑3100 expected soon, we now have a cocktail of agents to choose from. Although survival gains are measured in months for each agent, careful deliberation must be given to the rational use of these agents to optimize their administration (Figure 2). Factors such as drug-related toxicities and the acquired cross resistance to individual agents after exposure to a prior therapy have to be considered. For example, it was 606 | OCTOBER 2011 | VOLUME 8 recently shown that chemotherapies such as docetaxel not only inhibit cell division, but also impair AR signaling through significant AR translocation.62,105 Therefore, it might be possible that by affecting the AR with docetaxel, cross resistance to other AR antagonists may arise. It is likely that the novel agents currently approved or being assessed for use following docetaxel treatment will have an eventual role in the pre-docetaxel setting. Since taxanes modulate AR signaling, it will be important to consider if taxanes are as active in patients with CRPC following treatment with agents such as abiraterone or MDV‑3100, or if these agents will negatively impact taxane benefit. Transition from one treatment to the next should be initiated based not just on a combination of clinical, biochemical and radiological measures, but also on novel biomarkers and functional imaging modalities.87,96 It is crucial that such biomarkers are analytically validated and clinically qualified, before their wider use as decision end points.87 Key questions about the biology of prostate cancer remain; for example, does advanced-stage CRPC ever truly become nuclear-steroid receptor independent? The reality is that unless we start seeing patients developing disease progression without a rising PSA, we should not assume this to be the case. Conclusions These are exciting times for the treatment of advancedstage prostate cancer, but much remains to be done, particularly in the introduction of novel treatments in the adjuvant setting where it is envisioned higher cure rates may be achievable. Overall, we are entering a new era in CRPC management surrounded by a very different treatment landscape. In 2010 and 2011, there were four positive phase III trials for CRPC—although the alpharadin data have not yet been fully reported; along with docetaxel, these therapeutics have demonstrated survival benefits in CRPC, with three obtaining FDA approval (Figure 2). It is now critical that these agents are appropriately applied to the CRPC treatment pathway to maximize benefits for patients with advanced-stage prostate cancer. Such an approach will require the incorporation of novel functional imaging modalities and predictive and intermediate end point biomarkers. Despite these recent advances, efforts should continue to develop novel agents through intelli gent trial designs that involve molecular therapeutics in selected patient populations. Review criteria Data for this review was compiled using the PubMed, ASCO abstract and ESMO abstract databases published before 30 June 2011. 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