Challenges in the sequencing of therapies for the management of metastatic castrationresistant

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1 See discussions, stats, and author profiles for this publication at: Challenges in the sequencing of therapies for the management of metastatic castrationresistant prostate cancer Article in Asia-Pacific Journal of Clinical Oncology May 2014 Impact Factor: 1.54 DOI: /ajco CITATIONS 3 READS 70 3 authors: Phillip Parente Monash University (Australia) 45 PUBLICATIONS 880 CITATIONS Francis X Parnis Adelaide Cancer Centre 24 PUBLICATIONS 400 CITATIONS SEE PROFILE SEE PROFILE Howard Gurney Macquarie University 113 PUBLICATIONS 2,552 CITATIONS SEE PROFILE Available from: Howard Gurney Retrieved on: 09 May 2016

2 bs_bs_banner Asia-Pacific Journal of Clinical Oncology 2014; 10: doi: /ajco REVIEW ARTICLE Challenges in the sequencing of therapies for the management of metastatic castration-resistant prostate cancer Phillip PARENTE, 1,2 Francis PARNIS 3 and Howard GURNEY 4 1 Medical Oncology, Box Hill Hospital, Box Hill, Victoria, Australia, 2 Faculty of Medicine, Monash University, Melbourne, Victoria, Australia, 3 Adelaide Cancer Centre, Adelaide, South Australia, Australia, and 4 Clinical Research, Medical Oncology, Westmead Hospital, Sydney, New South Wales, Australia Abstract Prior to 2010, was the standard option for chemotherapy in men with metastatic castrationresistant prostate cancer (). Today, the picture is vastly different: several additional therapies have each demonstrated a survival benefit such that we now have chemotherapy (cabazitaxel), androgen suppressive agents (abiraterone acetate and enzalutamide), a cellular vaccine (sipuleucel-t) and radium-233 (for symptomatic bone metastases). With several other agents in the pipeline for late-stage disease, the future looks promising for. As the available data are not able to inform as to the optimum sequencing of therapy, this remains a challenge. This paper draws on insights from published and ongoing clinical studies to provide a practical patient-focused approach to maximize the benefits of the current therapeutic armamentarium. Preliminary sequencing suggestions are made based on clinical trial criteria. But until more data become available, clinical gestalt, experience, cost and individual patient preferences will continue to drive choices. Key words: abiraterone acetate, cabazitaxel, enzalutamide, innovative therapy, prostate cancer. INTRODUCTION Prostate cancer is the most common cancer diagnosed in Australian men, accounting for 30% of all cancer cases, and recent projections out to 2020 suggest that it will remain the leading cause of cancer in men for many years to come. 1 Early detection and improved local therapies mean that a large number of men with prostate cancer will be cured. 2 However, for those individuals who are diagnosed with, or who go on to develop, metastatic castration-resistant disease (), the treatment options have until recently been limited. In 2004, demonstrated a significant 21% reduction in the risk of death; it was quickly established Correspondence: Dr Phillip Parente MBBS (Hons) FRACP, Cancer Services Eastern Health, Box Hill Hospital, Nelson Road, Box Hill, Vic. 3128, Australia. phillip.parente@med.monash.edu.au Conflicts of interest: none Accepted for publication 17 February as first-line chemotherapy significantly changing the management of. 3,4 In the intervening 8 years, five additional therapies have each demonstrated a survival benefit for patients with (Table 1). The management of has undergone a significant and positive change; we now have chemotherapy, androgen suppressive agents and a cellular vaccine. Sipuleucel-T (for asymptomatic and minimally symptomatic disease), cabazitaxel, abiraterone acetate, enzalutamide (formerly called MDV3100) and radium-223 (for symptomatic bone metastases) are all approved for use by the US FDA (Food and Drug Administration). Although, currently, only cabazitaxel and abiraterone acetate are registered in Australia, it is still important to consider the role each of these new treatment options in managing prostate cancer. This paper builds on our previous overview of these and other pipeline therapies. 12 It draws on insights from published and ongoing clinical studies with the aim of providing a more practical patient-focused article to aid in maximizing the benefits of the current therapeutic armamentarium Wiley Publishing Asia Pty Ltd

3 206 P Parente et al. Table 1 Phase III trials in with a survival benefit Median survival Trial Design Patients characteristics N HR (95% CI) P-value (months) TAX (0.62, 0.94) versus 16.5 IMPACT 5 TROPIC 6 COU-AA AFFIRM 9 ALSYMPCA 10 COU-AA Docetaxel/ versus mitoxantrone/ Sipuleucel-T versus control Cabazitaxel/ versus mitoxantrone/ Abiraterone/ versus placebo/ Enzalutamide versus placebo Radium-223/best standard of care versus placebo/best standard of care Abiraterone/ versus placebo/ (0.61, 0.98) versus (0.61, 0.84) 7 < versus (0.64, 0.86) < versus (0.53, 0.75) < versus (0.58, 0.83) versus 11.3 Mixture of chemotherapy naïve and prior treatment with (0.61, 0.93) 0.01* NR versus 27.2 *Did not reach the prespecified boundary for significance (P 0.001) at the observed number of events. CI, confidence interval; HR, hazard ratio; NR, not reached. UPDATE ON NEWLY ESTABLISHED TREATMENTS The efficacy of sipuleucel-t has recently come under scrutiny after reanalysis of the IMPACT study results and previously unpublished data showing an 11-month difference in median survival in older versus younger patients in the placebo groups. 13 Age has not previously been a prognostic factor in this group of patients and it has been hypothesized that the repeated leukapheresis in the placebo group may have had a detrimental effect on survival, especially in older patients. However, this supposition was refuted by the investigators of the IMPACT trial who argued that leukapheresis removed only % of the total body pool of lymphocytes. In addition, the age effect on survival was similar in both control and sipuleucel-t arms indicating it was unlikely an effect of the therapy. 14 A post hoc analysis of the IMPACT study has shown a trend toward greater benefit in patients with more favorable baseline prognostic factors, in particular low baseline prostate-specific antigen (PSA), suggesting that its use may be of more value in earlier stage disease when the disease burden is lower. 15 The TROPIC trial demonstrated an overall survival benefit of cabazitaxel versus mitoxantrone, 6 and an updated efficacy analysis (at the final cutoff date) has supported the robustness of these data (Table 1). 7 Interim analysis of data from a compassionate use program and an early access program 16 demonstrates that the adverse event profile is manageable in the routine practice clinical setting and that there is a low rate of febrile neutropenia supporting the value of patient monitoring and careful dose selection The final results of the COU-AA-301 study have now been published, ratifying the 4-month improvement in overall survival benefit (Table 1). Despite the longer follow-up, the safety profile remained similar to that reported in the interim analysis; as was expected mineralocorticoid-related adverse events were reported in a higher proportion in the abiraterone group. 8 The currently available data do not support a benefit in survival beyond 2 years in most patients. The second phase III study, COU-AA-302, evaluating abiraterone in chemotherapy-naïve patients was halted early after a planned second interim analysis after 43% of expected deaths had occurred; median follow-up for all patients 2014 Wiley Publishing Asia Pty Ltd Asia-Pac J Clin Oncol 2014; 10:

4 Management of 207 was 22.2 months. 11 The data demonstrate a statistically significant improvement in radiographic progressionfree survival (16.5 vs 8.3 months; hazard ratio [HR] = 0.53; 95% CI ; P < ) and a strong trend toward increased overall survival (Table 1). A substantial proportion of the patients in the -alone arm was crossed over to abiraterone treatment which may affect the final survival figures. The incidence of mineralocorticoid-related adverse events, including hypertension, hypokalemia and fluid retention/edema, was higher in the abiraterone arm. Grade 3/4 hepatotoxicity adverse events, primarily reversible elevations in aminotransferase levels, were reported in 8% of abiraterone-treated patients versus 3% of those on alone. The final results of the AFFIRM study have also been published demonstrating a prolonged overall survival benefit (Table 1) and the superiority of enzalutamide over placebo in each of the trial s secondary endpoints. 9 Comprehensive safety data are presented. Although rates of fatigue, diarrhea and hot flashes were higher in the enzalutamide group, the median time to any initial adverse event was longer in the enzalutamide group (12.6 vs 4.2 months). Seizure has previously been reported as a potential barrier to the development of enzalutamide, having been observed in preclinical 20 and early phase I/II 21 studies. In AFFIRM, seizures were reported in five (0.6%) of patients receiving enzalutamide compared with none in the placebo group, and the drug was discontinued in patients who were reported to have had a seizure. Caution is warranted in patients with a history of seizure or other predisposing factors that may lower seizure threshold. The ALYMPCA trial 22 evaluating radium-223 combined with best standard of care in CRPC patients with bone metastases was stopped early due to evidence of significant treatment benefit. In an updated analysis, the median overall survival benefit for radium-223 increased from 2.8 to 3.6 months (Table 1). Time to first skeletal-related event also remained significantly prolonged (14.9 vs 11.3 months; HR = 0.658; 95% CI ; P = ). 10 Ongoing phase III trials (Table 2) with these newly established treatments aim to further refine their utility at different stages in the treatment pathway. OTHER EMERGING THERAPIES A number of other emerging therapies each with positive outcome data from phase II studies are currently being evaluated in phase III trials (Table 3). Primary outcome data for these trials have not yet been presented. The ELM-PC 5 phase III study of orteronel in patients previously treated with 29 was unblinded in July 2013 after a preplanned interim analysis suggested that the study would likely not meet its primary endpoint of improved overall survival (HR 0.894, P = 0.226). The phase II data for ipilimumab and orteronel (TAK-700) have been summarized previously. 12 The first phase III results for ipilimumab in patients previously treated with failed to meet its primary endpoint of overall survival (11.2 vs 10 months with placebo; HR = 0.85; 95% CI ; P = 0.053). 34 Some secondary endpoints (progression-free survival, PSA reduction greater than 50%) were favored in the ipilimumab group, with a prespecified subset analysis suggesting most benefit in those patients with lower disease burden. The PROSTVAC-VF vaccine induces a specific targeted immune response that attacks the cancerous cells in the prostate. It combines two different poxviruses (vaccinia and fowlpox), each designed to encode PSA as well as multiple immune enhancing co-stimulatory molecules (B7.1, ICAM-1 and Lfa-3; collectively called TRICOM). 35,36 The vaccine is designed to be given as monthly subcutaneous injection starting with an immune priming dose of Vaccinia-PSA-TRICOM for and followed by six monthly Fowlpox-PSA-TRICOM for repetitive immune boosts. This dosing schedule was employed in a randomized phase II study which demonstrated an overall survival benefit of 8.5 months (HR 0.56, 95% CI , P = ) but no benefit in progression-free survival (HR 0.88, 95% CI , P = 0.60). 37 A phase III study in chemotherapy-naïve patients (PROSPECT) is now underway (Table 3). 31 Unlike abiraterone acetate and enzalutamide, which target the androgen receptor, cabozantinib is an inhibitor of multiple kinase signaling pathways, including met proto-oncogene (c-met) and vascular endothelial growth factor receptor. 38 A phase II discontinuation trial has reported a median progression-free survival of 23.9 weeks (vs 5.9 weeks with placebo; HR 0.12, P < 0.001), high rates of bone scan improvement (68% improved, 12% resolved at week 12) and a 67% reduction in pain with cabozantinib 100 mg/day. 39 Toxicity was high, with 62% of patients experiencing adverse events that required dose reductions. Two phase III trials are currently planned to evaluate cabozantinib (60 mg/day) in patients with and prior treatment with and abiraterone/enzalutamide (Table 3). The first of these studies (COMET-1 32 ) has overall survival as the primary endpoint whereas the second (COMET-2 33 ) will assess relief of bone pain. Asia-Pac J Clin Oncol 2014; 10: Wiley Publishing Asia Pty Ltd

5 208 P Parente et al. Table 2 Newly established therapies undergoing further clinical trials in prostate cancer Trial ID Interventions Trial design Patient characteristics Primary outcome Status start and end date Cabazitaxel NCT mg/m 2 cabazitaxel + (FIRSTANA) mg/m 2 cabazitaxel + + NCT mg/m 2 cabazitaxel + (PROSELICA ) mg/m 2 cabazitaxel + NCT Cabazitaxel,, (AFFINITY) 25 custirsen cabazitaxel, Enzalutamide NCT Enzalutamide (PREVAIL) 26 Placebo Abiraterone NCT Abiraterone Placebo Randomized, open-label, parallel group Randomized, open-label, parallel group Randomized, open-label, parallel group parallel group, double blind, placebo controlled, multicenter parallel group, double blind, placebo controlled, multicenter Overall survival Follow-up Start: May 2011 End: January 2016 Overall survival Follow-up Start: April 2011 End: September 2017 Overall survival Recruiting Start: August 2012 End: December 2015 Overall survival, progression-free survival Progression-free survival, overall survival Follow-up Start: September 2010 End: September 2014 Recruiting Start: March 2012 End: February 2014 End date is estimated primary completion date and denotes final data collection date for primary outcome measure Wiley Publishing Asia Pty Ltd Asia-Pac J Clin Oncol 2014; 10:

6 Management of 209 Table 3 Emerging therapies undergoing phase III clinical trials in prostate cancer Trial ID Interventions Trial design Patient characteristics Primary outcome Status start and end date Androgen synthesis inhibitors (CYP17 inhibitor) NCT Orteronel + vs (ELM-PC 4) 28 placebo + NCT Orteronel + (ELM-PC 5) 29 versus placebo + parallel group, double blind, placebo controlled, multicenter parallel group, double blind, placebo controlled, multicenter Immunotherapy (CLTA4 inhibitor) NCT Ipilimumab versus placebo Randomized, parallel group, double blind, placebo controlled Immunotherapy (vaccine) NCT PROSTVAC alone versus (PROSPECT) 31 PROSTVAC in combination with GM-CSF versus placebo Inhibitor of MET, VEGFR2 and RET NCT Cabozantinib (XL184) (COMET-1) 32 versus NCT Cabozantinib (XL184) (COMET-2) 33 versus MTX + parallel group, double blind, placebo controlled double blind, controlled study double blind, controlled study and prior abiraterone or enzalutamide and prior abiraterone or enzalutamide Overall survival, progression-free survival Follow-up Start: October 2010 End: January 2013 Overall survival Follow-up Start: November 2010 End: September 2013 Overall Survival Follow-up Start: July 2010 End: January 2015 Overall survival Recruiting Start: November 2011 End: December 2014 Overall survival Follow-up Start: May 2012 End: March 2014 Pain response at week 12 Recruiting Start: January 2012 End: June 2014 End date is estimated primary completion date and denotes final data collection date for primary outcome measure. Asia-Pac J Clin Oncol 2014; 10: Wiley Publishing Asia Pty Ltd

7 210 P Parente et al. Figure 1 Therapies are currently approved for on both sides of a wall based on the populations included in their respective clinical trials. (?) Denotes whether new therapies will emerge in this group over time. (*) For bone metastases only, includes patients unfit for. ( ) Preventative treatment for skeletal-related events. Other promising novel therapies targeting the androgen-androgen receptor pathway are on the horizon. CYP17, the target of abiraterone, regulates androgen physiology. However, related inhibition of 17-alpha hydroxylase results in decreased cortisol and a compensatory rise in adrenocorticotropic hormone, leading to secondary mineralocorticoid excess. 40 These effects can be attenuated by coadministration with. However, has a poor tolerability profile and the potential to activate androgen receptor mutations. 41 As a consequence, considerable interest has emerged in more selective CYP17 lyase inhibitors, such as galeterone. Galeterone (TOK-001), a CYP17 inhibitor that disrupts multiple androgen signaling pathways, demonstrated a favorable biochemical response in a proof of concept study (AMOR1). 42 A two-part phase II study opened in December ARN-509, like enzalutamide, works via competitive androgen receptor inhibition. Pharmacodynamic evidence of androgen receptor antagonism was demonstrated in a phase I/II study. 44 In phase II of the same trial, ARN-509 was shown to be well tolerated with promising preliminary activity based on high PSA response rates in men with high-risk non-metastatic CRPC 45 and in those with chemotherapy-naïve. 46 Full results from phase II of the study are expected by mid IMPROVING SURVIVAL IN Current, new and emerging treatments not only have the potential to extend survival (Table 1), but are reshaping the management pathway for men with. To maximize the likely benefit for each individual patient, careful consideration must be given to the timing of treatment and the sequence in which the various agents are used. The wall Since the establishment of as first-line chemotherapy in, clinical trials have been designed to assess overall survival in the context of either chemotherapy-naïve patients or those patients who have progressed despite therapy. This categorization of patients as pre- or post-, and the creation of a wall (Fig. 1), is based primarily on clinical trial inclusion criteria rather than a biological rationale. How can we use trial eligibility data to inform treatment choice and timing post-? Although the timing of chemotherapy initiation has often been debated in, the decision to start treatment is currently based largely on signs of disease progression combined with consideration of the patient s overall performance status and the likelihood of treatment complications. With a growing number of treatment options, it will be more important than ever to identify the right treatment for the right patient after progression on. The new therapeutic options have not been subjected to direct head-to-head comparisons. Moreover, the available trial data reveal no compelling efficacy reason for using one over the other in the post- setting. Key driving factors regarding timing and choice of these newer therapeutic options are likely to include extent of disease, rate of progression, prior hormonal response, performance status and patient preference. Until more data become available, it is reasonable to consider a variety of additional factors in the decisionmaking process, including availability, cost benefits, and the perceived relative toxicity and effectiveness of the available treatment option agents. It has been suggested that optimal outcomes will be achieved by sequential administration of all active drugs in accordance with the eligibility criteria from their respective clinical trials. 48 Table 4 provides a summary of relevant data from the key published trials in. A closer analysis of these data highlights some differences between the trials. Compared with the 2014 Wiley Publishing Asia Pty Ltd Asia-Pac J Clin Oncol 2014; 10:

8 Management of 211 Table 4 Baseline patient characteristics in key published trials Trial characteristic IMPACT 5 COU-AA TAX COU-AA-301 8,49 TROPIC 7 AFFIRM 9 ALSYMPCA 10 Treatment arm Sipuleucel = T (q2w) 3 infusions Abiraterone acetate (1000 mg OD) Docetaxel (q3w) max 10 cycles Abiraterone acetate (1000 mg OD) Cabazitaxel (q3w) max 10 cycles Enzalutamide (160 mg OD) Radium-223 Age, median (range) 72 (49 91) 71 (44 95) 68 (42 92) 69 (42 95) 68 (62 73) 69 (41 92) Mean = 70.2 ECOG performance status 0 or 1 (%) Extent of disease Bone metastases (%) Visceral metastases (%) Gleason score 7 (%) Serum PSA at baseline Median (ng/ml) Previous therapy Surgery (%) Radiation (%) Hormonal (%) Chemotherapy (%) Docetaxel (%) Biological agent (%) prior chemotherapy regimens (%) Total previous NA dose (mg/m 2 ) Medium time from last dose to disease progression (months) NA 0.8, data not available; OD, once daily; PSA, prostate-specific antigen; q2w, every second week; q3w, every third week. Asia-Pac J Clin Oncol 2014; 10: Wiley Publishing Asia Pty Ltd

9 212 P Parente et al. TROPIC (cabazitaxel) and AFFIRM (enzalutamide) trials, fewer patients in the COU-AA-301 (abiraterone) trial had visceral metastases and none had received more than two prior chemotherapy regimens. It is also of note that two-thirds of the patients included in the radium- 223 (ALSYMPCA) study had previously been treated with, 10 suggesting that radium-223 may be suitable for use, post-, in patients with bone metastases only and whose performance status suggests they are not suitable for further chemotherapy cycles. In the TROPIC study, subset analyses of overall survival favored cabazitaxel in all age groups, with significant benefit in patients 65 years (n = 460, HR = 0.62, 95% CI ) and a trend for benefit in those aged <65 years (n = 295, HR = 0.81, 95% CI ), 6 whereas all age groups seemed to benefit equally from both abiraterone (COU-AA-301) 8 and enzalutamide (AFFIRM). 9 In subset analyses, both enzalutamide and abiraterone showed a trend for improvement in overall survival among patients with visceral metastases at baseline but the HRs crossed unity. Subset analysis for visceral metastases at baseline has not been reported for cabazitaxel. Although different patients can have different treatment goals, many patients with still desire further treatment after failure. The new therapeutic options can help furnish that desire, although careful and active monitoring clearly underpins the decision for the next stage of intervention. Based on subset analysis of overall survival from the TROPIC, COU- AA-301 and AFFIRM trials, no patient group stands out as potentially benefitting more from one drug or the other. Patients of older age, those with visceral metastases and those with higher pain scores at baseline seem to obtain benefit from all three drugs when compared with the control arm of the studies. Until more specific markers of response become available, the sequence of drug use in the post- setting still relies on the assessment of the patient by an experienced clinician. It is up to the clinician to ensure that his patient gets exposure to as many of these effective agents as possible within the limits of toxicity and while maintaining or improving quality of life. Can any of these newer agents be combined for greater efficacy? The growth of CRPC is complex, and with many different pathways implicated in its development, it is likely that a combination of drugs could lead to better outcomes than any single agent. While androgen receptor antagonists have demonstrated efficacy, it is yet to be determined whether synergy exists when they are used in combination with each other or with chemotherapy. 50 Similarly, emerging data supporting the use of immunotherapeutic agents combined or sequenced with each other and with other standard therapies are being explored in an effort to maximize their benefits and further improve patient outcomes. 51,52 How can we identify men who will respond to different forms of therapy? While much research is focusing on new treatment modalities, there is a need to consider the development of predictive tools. The ability to identify predictive biomarkers for risk stratifying and subgrouping patients represents the next step forward in improving our ability to guide treatment choices in. To date, the biomarkers in clinical use provide information regarding prognosis but no predictive biomarkers have been validated in. 53 Enumeration of circulating tumor cells has been FDA approved for monitoring progression and prognosis in ; however, its value as a predictive biomarker to aid therapeutic decision making still requires confirmation. 54 What about future predictions? We are now moving into an era in which the wall will disappear providing more fluidity of treatment options. The natural progression is for the less toxic novel hormonal agents to be moved forward in the treatment schema and some of these may even supersede the standard anti-androgens such as bicalutamide. The clinical benefit of radiographic progression-free survival as an endpoint is not yet established, 53 and treatment with abiraterone in the chemotherapy-naïve setting has shown a trend toward improved overall survival. 11 Abiraterone s emerging position as the preferred treatment before may be challenged when the results of ongoing studies with enzalutamide (PREVAIL) 26 and future studies with radium-223 in the same setting become available. With more treatment options now available in the post- setting, one option would be to use earlier. The survival benefits shown for cabazitaxel and radium-223 have secured their role in the treatment of men with and we wait to see whether one or both will supersede the current standard of as first line after hormone therapy failure. The primary endpoint of the FIRSTANA trial 23 (overall survival) will directly inform as to the utility of cabazitaxel as first-line treatment compared with 2014 Wiley Publishing Asia Pty Ltd Asia-Pac J Clin Oncol 2014; 10:

10 Management of 213 and better enable us to optimize its use in patients with. The overarching goal is to ensure that patients are exposed to as many active therapies as possible during the course of their diseases. Although the actual sequencing of agents will be determined largely by the results of current trials, choice will be governed to some extent by drug availability (regulatory approvals and indications) and government subsidy. Guidelines developed by the American Urological Association offer a basis for the use of different treatment options based on clinical data and drug registration status in the United States; sequencing has been dictated by disease stage, prior treatment, symptoms and performance status. 55 CONCLUSIONS The future looks promising for. There has been rapid increase in the number of new treatments with demonstrated survival benefit. To maximize the utility of these new options and provide a chance of extended survival for each individual patient, careful consideration must be given to the timing, sequencing and potential combination of treatment options. At present, this remains a challenge because available data are not able to inform as to the optimum sequencing of therapy. Current trials exploring treatment options in chemotherapy-naïve patients have the potential to reframe the position of ; their results are eagerly awaited. Until more data become available and validated predictive biomarkers established, clinical gestalt, experience, cost and individual patient preferences will continue to drive choices. In general, if a patient displays signs and symptoms indicative of progression, then it is important to reevaluate his treatment before it becomes too late and his performance status deteriorates. The overall aim is to be able to expose the patient to as many treatment options as possible to extend survival time while being mindful of the need to carefully balance the cost, availability, benefits and burdens of treatment. ACKNOWLEDGMENTS This work has been carried out with financial support from Sanofi Australia Pty Ltd. The authors acknowledge the editorial assistance provided by Hazel Palmer of Scius Solutions Pty Ltd; Ms Palmer s contribution was funded by Sanofi Australia Pty Ltd. All three authors report receiving reimbursement from Sanofi for participation in an Australian Advisory Board and have previously been, or are currently, involved in clinical trials with Sanofi oncology products. REFERENCES 1 Australian Institute of Health and Welfare. Cancer Incidence Projections: Australia, 2011 to AIHW, Canberra Cat. No. CAN Walczak JR, Carducci MA. Prostate cancer: a practical approach to current management of recurrent disease. Mayo Clin Proc 2007; 82: Petrylak DP, Tangen CM, Hussain MH et al. Docetaxel and estramustine compared with mitoxantrone and for advanced refractory prostate cancer. N Engl J Med 2004; 351: Tannock IF, de Wit R, Berry WR et al. Docetaxel plus or mitoxantrone plus for advanced prostate cancer. N Engl J Med 2004; 351: Kantoff PW, Higano CS, Shore ND et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med 2010; 363: de Bono JS, Oudard S, Ozguroglu M et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castrationresistant prostate cancer progressing after treatment: a randomised open-label trial. Lancet 2010; 376 (9747): Oudard S, de Bono JS, Ozguroglu M et al. Cabazitaxel plus /prednisolone significantly increases overall survival compared to mitoxantrone plus / prednisolone in patients with metastatic castrationresistant prostate cancer () previously treated with : final results with updated overall survival of a multinational phase iii trial (TROPIC). Ann Oncol 2010; 21 (Suppl 8): 272. Abstract 871PD. 8 Fizazi K, Scher HI, Molina A et al. Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: final overall survival analysis of the COU-AA-301 randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol 2012; 13: Scher HI, Fizazi K, Saad F et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med 2012; 367: Parker C, Nilsson S, Heinrich D et al. Updated analysis of the phase III, double-blind, randomized, multinational study of radium-223 chloride in castration-resistant prostate cancer (CRPC) patients with bone metastases (ALSYMPCA). J Clin Oncol 2012; 30 (Suppl 18): Abstract LBA Ryan CJ, Smith MR, de Bono JS et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med 2013; 368: Parente P, Parnis F, Gurney H. Emerging and second line therapies for the management of metastatic castrationresistant prostate cancer: the Australian perspective. Asia Pac J Clin Oncol 2012; 8: Asia-Pac J Clin Oncol 2014; 10: Wiley Publishing Asia Pty Ltd

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