Lincolnshire Knowledge and Resource Service

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1 Lincolnshire Knowledge and Resource Service This search summary contains the results of a literature search undertaken by the Lincolnshire Knowledge and Resource Service librarians in August All of the literature searches we complete are tailored to the specific needs of the individual requester. If you would like this search re-run with a different focus, or updated to accommodate papers published since the search was completed, please let us know. We hope that you find the information useful. If you would like the full text of any of the abstracts listed, please let us know. Alison Price Janet Badcock alison.price@lpct.nhs.uk janet.badcock@lpct.nhs.uk Librarians, Lincolnshire Knowledge and Resource Service NHS Lincolnshire Beech House, Waterside South Lincoln LN5 7JH

2 Lincolnshire Knowledge and Resource Service Literature Search Results Trials and Reviews Abiraterone and Cabazitaxel Completed by: Alison Price Completion date: 5 th August 2011

3 Overviews of Research Cancer Research UK Abiraterone Abiraterone is still being looked at in clinical trials. The results from a phase 1 trial were published in July 2008 in the Journal of Clinical Oncology. There were only 21 men in this trial. All the men had prostate cancer that had spread and were taking hormone therapy, but it was no longer working. The men started taking abiraterone acetate once a day. When the men started taking abiraterone, most of them (80%) had a fall in the level of prostate specific antigen (PSA) in their blood and their tumours shrank. A fall in PSA level usually means that the number of cancer cells has gone down. Some of the men who had pain were able to take lower doses of painkillers. The reduction in PSA level lasted from just over 2 months in some men to up to 18 months in other men. The researchers then carried out a phase 2 trial and the results were published in the Journal of Clinical Oncology in May The trial included 54 men all together. All the men had been having hormone therapy, but it was no longer working. In the trial, they started taking abiraterone and when abiraterone was no longer working, the men started taking a steroid called dexamethasone as well. When the men were taking abiraterone alone, most had a fall in their PSA levels. This meant that the treatment was stopping the cancer from growing or developing. In just over a third of the men (37%) whose tumours could be measured on a scan, the cancer got smaller. And the PSA level went down by at least a half in about two thirds of the men (67%) taking part. After some time though the men s PSA level started to rise again. When this happened, the men could start taking dexamethasone as well as abiraterone. When the results were published in May 2009, 39 of the men had taken both drugs together. In some of these men, the level of PSA went down again, but levels started to rise once more after a few months. It is encouraging that the two drugs seemed able to lower the PSA once more. But do remember, these results are only for a very small number of men. So we will need more research with larger trials to confirm them. Results of another phase 2 trial were published early in The men in the trial had already had hormone treatment and chemotherapy called docetaxel for prostate cancer that had spread. When the men started taking abiraterone, nearly three quarters (75%) had a fall in their level of PSA. A phase 3 trial called COU-AA-301 started in May It stopped recruiting patients in April The aim of the trial was to find out how well abiraterone worked for men who had already had hormone therapy and chemotherapy for prostate cancer that had spread. It was a randomised trial. The men taking part were put into treatment groups by a computer. One group of men had abiraterone once a day and a steroid called prednisolone twice a day. The other group took a dummy (placebo) tablet once a day and prednisolone twice a day. Results presented at a conference in October 2010 showed that on average, the men who had abiraterone lived about 4 months longer than the men who had the dummy tablet. They also found that the PSA levels in the men who had abiraterone were more likely to fall and on average it took longer for their prostate cancer to start growing again. These results are promising and seem to show that abiraterone may help to control advanced prostate cancer for a time in some men. At the moment though, the studies

4 have been on a small number of men with very advanced disease. So it is too early to say exactly how helpful this drug may be in treating men with earlier stage prostate cancer. Larger studies are planned. Another phase 3 trial called COU-AA-302 aims to find out how well the combination of abiraterone and prednisolone works for men who have previously had hormone therapy, but not chemotherapy. This trial has finished recruiting patients, but the results are not known yet. Cabazitaxel A new drug researchers are looking at is XRP6258 or cabazitaxel. It is also called Jevtana. The international TROPIC trial compared cabazitaxel with mitoxantrone for men who had advanced prostate cancer that had continued to grow, despite hormone therapy and chemotherapy with docetaxel. Men in the trial had prednisolone and either mitoxantrone or cabazitaxel. The results showed that the men who had cabazitaxel lived an average of 3 months longer than the men who had mitoxantrone. The men who had cabazitaxel were more likely to get infections because their white blood cell count was low. More trials are looking at combining cabazitaxel with other types of chemotherapy. Cabazitaxel is now approved for use in the UK and Europe by the European Medicines Agency. NICE are reviewing its use within the NHS in England and Wales at the moment and should make a decision in late

5 Ongoing Research Abiraterone Acetate in Castration-Resistant Prostate Cancer Previously Treated With Docetaxel-Based Chemotherapy This study is ongoing, but not recruiting participants. First Received on March 13, Last Updated on July 27, 2011 ClinicalTrials.gov Identifier: NCT Purpose This is a phase 3 study to compare the clinical benefit of abiraterone acetate plus prednisone with placebo plus prednisone in patients with metastatic castration-resistant prostate cancer (CRPC) who have failed one or two chemotherapy regimens. At least one of the previous chemotherapies must have contained docetaxel Abiraterone Acetate in Asymptomatic or Mildly Symptomatic Patients With Metastatic Castration-Resistant Prostate Cancer This study is ongoing, but not recruiting participants. First Received on April 18, Last Updated on May 21, 2010 ClinicalTrials.gov Identifier: NCT Purpose This is a phase 3 study to compare the clinical benefit of abiraterone acetate plus prednisone with placebo plus prednisone in patients with asymptomatic or mildly symptomatic patients with metastatic castration-resistant prostate cancer.

6 Drug Approval, Assessment & Evaluation Cabazitaxel National Prescribing Centre: Positive opinions for new medicines adopted: Cabazitaxel (Jevtana) used in combination with prednisone or prednisolone for the treatment of patients with hormone refractory metastatic prostate cancer NHS Regional Drug and Therapeutics Centre: The Use of Cabazitaxel for the Treatment of Metastatic Hormone-Refractory Prostate Cancer Evaluation Report This is one of a series of evaluations prepared by the Regional Drug and Therapeutics Centre (Newcastle). The aim is to give objective information and guidance to commissioners of health services, prescribers and others both on clinical aspects of the subject and on arrangements for prescribing. The reports are prepared by a multidisciplinary team within the Centre and reviewed by local NHS personnel and appropriate external specialists. SUMMARY Prostate cancer is the most common cancer in men in the UK, and the second most common cause of male cancer deaths. It has an age-standardised incidence of 97.5/100,000, increasing to 744/100,000 in men aged over 85. Most deaths are due to hormone-refractory prostate cancer, also known as castration-resistant prostate cancer (CRPC). Cabazitaxel is a tubulin-binding taxane, which brings about cell death by inhibiting cell division. The Committee for Medicinal Products for Human Use issued a positive opinion in January 2011, and NICE has proposed a technology appraisal of the use of cabazitaxel for the second-line treatment of CRPC, although there is currently no date set for publication. A randomised, open-label, active comparator phase III study in 755 patients comparing cabazitaxel with the unlicensed comparator mitoxantrone, both plus prednisone (10 mg daily) has been published. Patients had prostate cancer which had shown disease progression during or after treatment with docetaxel. The primary endpoint was overall survival (OS), as calculated from the time of randomisation to death. Median OS with cabazitaxel treatment was 15.1 months (95% confidence interval [CI]: 14.1 to 16.3) compared to 12.7 months with mitoxantrone (95% CI: 11.6 to 13.7). Treatment with cabazitaxel resulted in a 30% reduction in relative risk of death (hazard ratio [HR]: 0.70; 95% CI: 0.59 to 0.83; p < ). The main toxicities experienced by patients were haematological. Neutropenia of grade 3/4 was experienced in 82% of cabazitaxel patients, compared to 58% of those treated with mitoxantrone. Leukopenia, anaemia and thrombocytopenia were also reported. Non-haematological adverse effects of any grade experienced in 20% of patients receiving cabazitaxel were: diarrhoea (47%), fatigue (37%), asthenia (20%), nausea (34%), vomiting (23%) and constipation (20%). Eighteen patients (5%) in the cabazitaxel group died within 30 days after the last infusion, 17 of whom due to an adverse event. Seven patients died due to neutropenia or its clinical consequences. No information on cost is available in the UK, however in the USA cabazitaxel costs $8,000 per 60mg single-use vial, which is sufficient for one infusion. In the TROPIC study patients underwent a mean of six cycles of treatment, totalling $48,000. Further trial data is required before cabazitaxel s place in therapy can be determined, but the side effect profile may limit its use in clinical practice. If licensed, it may compete with the novel drug abiraterone, which is also awaiting marketing authorisation. Several phase I studies are in progress to investigate the efficacy of cabazitaxel in combination with gemcitabine and cisplatin, and to further investigate the safety of cabazitaxel.

7 EMA approves cabazitaxel (Jevtana ) for prostate cancer The European Medicines Agency has approved cabazitaxel (Jevtana) in combination with prednisone or prednisolone for the treatment of patients with hormone refractory metastatic prostate cancer previously treated with a docetaxel-containing regimen. Please see the link below for further information, including the European Public Assessment Report (EPAR). How has Jevtana been studied? The effects of Jevtana were first tested in experimental models before being studied in humans. Jevtana was investigated in one main study involving 755 men with hormone refractory metastatic prostate cancer who had previously been treated with docetaxel. The effects of Jevtana were compared with another anticancer medicine, mitoxantrone. Both medicines were given in combination with daily prednisone or prednisolone. The main measure of effectiveness was overall survival (the average length of time the patients lived). What benefit has Jevtana shown during the studies? In the main study, Jevtana prolonged overall survival compared with the comparator medicine mitoxantrone. The average overall survival for patients treated with Jevtana was 15.1 months compared with 12.7 months for patients given mitoxantrone. What is the risk associated with Jevtana? The most common side effects with Jevtana (seen in more than 1 patient in 10) are anaemia (low red blood cell counts), leucopenia (low white blood cell counts), neutropenia (low counts of neutrophils, a type of white blood cell), thrombocytopenia (low blood platelet counts) and diarrhoea. Jevtana should not be used in people who may be hypersensitive (allergic) to cabazitaxel, to any other taxane, or to any of the other ingredients. It must not be given to patients whose blood neutrophil count is below 1,500/mm3, who have abnormal liver test results indicating liver problems or who recently received or are about to receive a yellow fever vaccine. Why has Jevtana been approved? The CHMP considered that the ability of Jevtana to prolong overall survival in hormone refractory metastatic prostate cancer patients was clinically important. It decided that Jevtana s benefits are greater than its risks and recommended that it be given marketing authorisation. 18/human_med_ jsp EMA Assessment Report For Jevtana (cabazitaxel) Please contact library Service for Full Text

8 Abiraterone European Medicines Agency (EMA): Meeting highlights from the Committee for Medicinal Products for Human Use (CHMP) July Positive opinions for new medicines adopted: Abiraterone acetate (Zytiga) intended in combination with prednisone or prednisolone for the treatment of metastatic castration resistant prostate cancer in adult men whose disease has progressed on or after a docetaxel-based chemotherapy regimen. Zytiga Key facts Questions & Answers On 21 July 2011 the Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion, recommending the granting of a marketing authorisation for the medicinal product Zytiga 250mg tablet, intended for the treatment of metastatic castration resistant prostate cancer. The applicant for this medicinal product is Janssen- Cilag International N.V. They may request a re-examination of any CHMP opinion, provided they notify the European Medicines Agency in writing of their intention within 15 days of receipt of the opinion. The active substance of Zytiga is abiraterone acetate, a hormone antagonist and related agent (L02BX03) that inhibits the production of androgens in the testes, adrenal glands and overall. The benefits with Zytiga are its ability to improve the survival of patients and to delay the progression of disease. The most common side effects are peripheral oedema, hypokalaemia, hypertension and urinary tract infection. A pharmacovigilance plan for Zytiga will be implemented as part of the marketing authorisation. The approved indication is: Zytiga is indicated with prednisone or prednisolone for the treatment of metastatic castration resistant prostate cancer in adult men whose disease has progressed on or after a docetaxel-based chemotherapy regimen. Detailed recommendations for the use of this product will be described in the summary of product characteristics (SmPC), which will be published in the European public assessment report (EPAR), and will be available in all official European Union languages after the marketing authorisation has been granted by the European Commission. The CHMP, on the basis of quality, safety and efficacy data submitted, considers there to be a favourable benefit to risk balance for Zytiga and therefore recommends the granting of the marketing authorisation. 21/smops/Positive/human_smop_ jsp

9 NHS Regional Drug and Therapeutics Centre: The Use of Abiratone for the Treatment of Castration-Resistant Prostate Cancer Evaluation Report This is one of a series of evaluations prepared by the Regional Drug and Therapeutics Centre (Newcastle). The aim is to give objective information and guidance to commissioners of health services, prescribers and others both on clinical aspects of the subject and on arrangements for prescribing. The reports are prepared by a multidisciplinary team within the Centre and reviewed by local NHS personnel and appropriate external specialists. SUMMARY Prostate cancer is the most common cancer in men in the UK, and the second most common cause of male cancer deaths. It has an age-standardised incidence of 97.5/100,000, increasing to 744/100,000 in men aged over 85. Most deaths are due to hormone-refractory prostate cancer, also known as castration-resistant prostate cancer (CRPC). Abiraterone is a potent, oral, specific inhibitor of CYP17, which is a key enzyme in the biosynthesis of androgens including testosterone and dihydroxytestosterone. Androgens play a role in prostate cancer growth and survival. AA does not currently have a marketing authorisation. A phase III trial (published in abstract form only) found that AA increased survival in docetaxel-treated men with castration-resistant prostate cancer (CRPC) to 14.8 months, compared with 10.9 months in the placebo group (hazard ratio 0.65, 95% confidence interval , p<0.0001). The secondary endpoints of time to PSA progression, radiographic progression-free survival and PSA response were all significantly improved in patients taking abiraterone. Three phase II trials have investigated the use of AA to treat CRPC. All were small, single-arm, open-label studies, and a total of 147 men with CRPC were enrolled. Two trials examined men who had been previously treated with docetaxel-based chemotherapy, while the third enrolled men who were chemotherapy-naïve. The phase II trials showed a 50% decrease in prostate-specific antigen (PSA) levels in 36% and 51% of docetaxel-treated patients following treatment with AA. Attard et al observed a 50% decrease in 67% of chemotherapy-naïve patients. Common adverse events (AEs) included hypokalaemia, hypertension and oedema, all which were expected symptoms of secondary mineralocorticoid excess and easily managed. Fatigue, headache, gastrointestinal upsets, and altered liver function tests were also reported. Grade 3 or 4 AEs were rare. Reid et al reported three deaths during their study. Two were considered not to be related to treatment, while the third was attributed to a myocardial infarction or pulmonary embolus. If licensed, AA will initially be indicated in combination with prednisone or prednisolone for the treatment CRPC in men who have previously received docetaxel-based chemotherapy. It may compete with the current options (further docetaxel treatment, estramustine, dexamethasone, or mitoxantrone plus prednisone) or with the novel taxane cabazitaxel, which has recently received a positive opinion for marketing authorisation. No information on the cost of abiraterone is currently available. A second phase III trial is currently underway in chemotherapy-naïve men with metastatic CRPC, and an interim analysis is expected in The manufacturers expect to receive marketing authorisation in quarter

10 Poster Presentations The prostate cancer clinical trials working group (PCCTWG) consensus for phase II trials in metastatic castration-resistant prostate cancer. The prostate cancer clinical trials working group (PCCTWG) consensus for phase II trials in metastatic castration-resistant prostate cancer. Print this page Meeting: 2007 Prostate Cancer Symposium Session Type and Session Title: General Poster Session B H. I. Scher, S. Halabi, I. Tannock, M. Morris, C. Higano, T. Beer, C. Sternberg, M. Eisenberger, A. Martin, H. Maha Introduction: The clinical manifestations of castration-resistant metastatic prostate cancer pose significant challenges to phase II trial design. The first consensus to standardize phase II design and endpoint definitions was published in A thorough reassessment is reported. Methods: PCCTWG convened in 4 meetings over 2 years. Criteria were updated or revised based on experience with the original Criteria and emerging trial data. Results: PCCTWG recommends distinct designs for cytotoxic and non-cytotoxic agents, and defines clinical subtypes based on patterns of spread. The independent reporting of biochemical, radiographic, and clinical outcome measures are retained, using RECIST for changes in measurable soft tissue spread, separating nodal and visceral disease. Bone scans should be reported as "new lesions" or "no new lesions", and confirmated with a second scan. PCCTWG recommends that trial endpoints not rely exclusively on post-treatment PSA declines or measurable disease regression, but should increasingly adopt time-to-event endpoints based on radiographic and clinical progression in preference to PSA elevations. Delaying or preventing time-toevents is a recommended objective, with attention to defining eligibility by an estimated event frequency, and/or randomization to a control group, and incorporating standardized criteria for bone progression. Conclusions: The recommendations are evolving as more data are generated from randomized trials. The Criteria focus on measuring treatment effects that can meaningfully inform definitive phase 3 trials of promising agents for further development. Supported by the SPORE, DOD and PCF.

11 Improved survival outcomes in clinically relevant patient subgroups from COU- AA-301, a phase III study of abiraterone acetate (AA) plus prednisone (P) in patients with metastatic castration-resistant prostate cancer (mcrpc) progressing after docetaxel-based chemotherapy Meeting:2011 Genitourinary Cancers Symposium General Session II: Prostate Cancer Therapy for Recurrent Disease Abstract No:4 Citation: J Clin Oncol 29: 2011 (suppl 7; abstr 4) H. I. Scher, C. Logothetis, A. Molina, O. B. Goodman, C. N. Sternberg, K. N. Chi, T. S. Kheoh, C. M. Haqq, K. Fizazi, J. S. De Bono, on behalf of the COU-AA-301 Study Group; Memorial Sloan-Kettering Cancer Center, New York, NY; University of Texas M. D. Anderson Cancer Center, Houston, TX; Ortho Biotech Oncology Research and Development, Los Angeles, CA; Nevada Cancer Institute Medical Group, Las Vegas, NV; San Camillo and Forlanini Hospitals, Rome, Italy; British Columbia Cancer Agency, Vancouver, BC, Canada; Cougar Biotechnology, Los Angeles, CA; Institut Gustave Roussy, Villejuif, France; The Royal Marsden Hospital, Sutton, United Kingdom Background: AA is a selective androgen biosynthesis inhibitor that blocks the action of CYP17. Preclinical and early clinical studies suggest that AA potently inhibits persistent androgen synthesis from adrenal and intratumoral sources, thus suppressing an important growth stimulus for mcrpc. Methods: COU-AA-301 (NCT ) is an international, randomized, double blind study of AA (1,000 mg + P 5 mg po BID) vs placebo + P administered to men with mcrpc progressing after docetaxel-based chemo. OS is the primary endpoint. Patients treated with previous ketoconazole or > 2 prior chemo regimens were excluded. Results: Data are drawn from a planned, stratified interim analysis, unblinded in August 2010, based on significant OS improvement in the AA + P treatment group compared to the placebo + P group [median OS 14.8 vs.10.9 months; HR = ( ), P < ]. A subgroup analysis for OS is presented in the table. Mineralocorticoid- related AEs were more common in the AA arm vs placebo: fluid retention 30.5% vs 22.3%, hypokalemia 17.1% vs 8.4%; but grade 3/4 hypokalemia (3.8% vs 0.8%), and grade 3/4 hypertension (1.3% vs 0.3%) were infrequent. LFT abnormalities were observed in 10.4% AA vs 8.1% placebo; and cardiac disorders were observed in 13.3% AA vs 10.4% placebo. Conclusions: AA significantly prolongs OS in patients with mcrpc who have progressed after docetaxel-based chemo. AA's favorable treatment effect on OS, observed across multiple patient subgroups (HR range vs placebo + P), was consistent with the survival benefit for the overall study population. Research from Medline and Embase follows

12 Table of Contents Search Results 1. New therapies for castration-resistant prostate cancer: Efficacy and safety... page 3 2. The role of abiraterone acetate in the management of prostate cancer: A critical analysis of the literature... page 3 3. Translating scientific advancement into clinical benefit for castration-resistant prostate cancer patients... page 4 4. Broadening horizons in medical management of prostate cancer... page 4 5. Current clinical trials in castrate-resistant prostate cancer... page 5 6. Contemporary management of metastatic castration-resistant prostate cancer.... page 5 7. Evolving therapeutic paradigms for advanced prostate cancer.... page 6 8. Abiraterone and increased survival in metastatic prostate cancer.... page 6 9. Cabazitaxel for the treatment of prostate cancer.... page Abiraterone acetate, a novel adrenal inhibitor in metastatic castration-resistant prostate cancer.... page New strategies in metastatic prostate cancer: targeting the androgen receptor signaling pathway.... page TROPIC: Phase III trial of cabazitaxel for the treatment of metastatic castration-resistant prostate cancer... page Cabazitaxel for the treatment of prostate cancer... page EAU guidelines on prostate cancer. Part II: Treatment of advanced, relapsing, and castration-resistant prostate cancer... page Novel therapeutic strategies for castration resistant prostate cancer: inhibition of persistent androgen production and androgen receptor mediated signaling.... page Role of second-line systemic treatment post-docetaxel in metastatic castrate resistant prostate cancer- current strategies and future directions.... page Cabazitaxel: a novel second-line treatment for metastatic castration-resistant prostate cancer.... page Cabazitaxel for the treatment of castration-resistant prostate cancer... page Cabazitaxel: A novel microtubule inhibitor... page Pharmacotherapeutic management of locally advanced prostate cancer: Current status... page Practice changing data and new developments in the management of prostate cancer - ASCO page Improving outcomes with recent advances in chemotherapy for castrate-resistant prostate cancer.... page Changing therapeutic paradigms in castrate-resistant prostate cancer.... page Cabazitaxel, a new taxane with favorable properties.... page Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial.... page Abiraterone acetate (AA) plus low dose prednisone (P) improves overall survival (OS) in patients (PTS) with metastatic castrationresistant prostate cancer (mcrpc) who have progressed after docetaxel-based chemotherapy (chemo): Results of cou-aa-301 a randomized double-blind placebo-controlled phase III study... page New agents and strategies for the hormonal treatment of castration-resistant prostate cancer... page Castration-resistant prostate cancer: current and emerging treatment strategies.... page Abiraterone acetate: a promising drug for the treatment of castration-resistant prostate cancer.... page Abiraterone acetate for castration resistant prostate cancer.... page Critical appraisal of cabazitaxel in the management of advanced prostate cancer.... page Abiraterone acetate... page Hormonal therapy for prostate cancer: toward further unraveling of androgen receptor function.... page 18 Page 1

13 34. Abiraterone acetate: CYP17 inhibitor oncolytic... page Selective inhibition of CYP17 with abiraterone acetate is highly active in the treatment of castration-resistant prostate cancer... page Antitumor activity with CYP17 blockade indicates that castration-resistant prostate cancer frequently remains hormone driven.... page Emerging therapies in castrate-resistant prostate cancer.... page A multicenter phase II study of abiraterone acetate (AA) in docetaxel pretreated castration-resistant prostate cancer (CRPC) patients (pts)... page CYP17 blockade by abiraterone: further evidence for frequent continued hormone-dependence in castration-resistant prostate cancer.... page Is abiraterone acetate well tolerated and effective in the treatment of castration-resistant prostate cancer?... page Phase I clinical trial of a selective inhibitor of CYP17, abiraterone acetate, confirms that castration-resistant prostate cancer commonly remains hormone driven... page 22 Page 2

14 1. New therapies for castration-resistant prostate cancer: Efficacy and safety Citation: European Urology, August 2011, vol./is. 60/2( ), ; (August 2011) Beltran H.; Beer T.M.; Carducci M.A.; De Bono J.; Gleave M.; Hussain M.; Kelly W.K.; Saad F.; Sternberg C.; Tagawa S.T.; Tannock I.F. Context: Prostate cancer (PCa) is the most common noncutaneous malignancy and the second leading cause of cancer mortality amongst men in the Western world. Up to 40% of men diagnosed with PCa will eventually develop metastatic disease, and although most respond to initial medical or surgical castration, progression to castration resistance is universal. The average survival for patients with castration-resistant prostate cancer (CRPC) is 2-3 yr. Objective: To discuss the biologic rationale and evidence supporting current management of patients with CRPC and to review promising novel agents. Evidence acquisition: Electronic databases (PubMed, ClinicalTrials.gov), relevant journals, and conference proceedings were searched manually for preclinical studies, clinical trials, and biomarker analyses focused on the treatment of CRPC. Keywords included castrate resistant prostate cancer and: targeted therapy, novel therapy, immunotherapy, androgen therapy, bone therapy, mechanisms, biomarkers, and trial endpoints; no time range was specified. Information pertaining to current studies was discussed with key opinion leaders. Evidence synthesis: We focus on the efficacy and safety of approved agents, promising therapies that have proceeded to phase 3 evaluation, and those that have enhanced our understanding of the biology of CRPC. Biomarkers are considered in the context of novel targeted agents and immunotherapy. Conclusions: CRPC has many targets. Four new agents with different mechanisms of action have recently been shown to have positive results in large phase 3 randomized trials, and have already been approved in the United States for CRPC: cabazitaxel, sipuleucel-t, denosumab, and abiraterone acetate. With our improved understanding of tumor biology and the incorporation of new prognostic and molecular biomarkers into clinical trials, we are making progress in the management of patients with CRPC European Association of Urology. Journal: Review 2. The role of abiraterone acetate in the management of prostate cancer: A critical analysis of the literature Citation: European Urology, August 2011, vol./is. 60/2( ), ; (August 2011) Sonpavde G.; Attard G.; Bellmunt J.; Mason M.D.; Malavaud B.; Tombal B.; Sternberg C.N. Context: The development of agents targeting androgen signalling holds promise for men with castration-resistant prostate cancer (CRPC). Objective: The emerging role of abiraterone acetate (AA), a novel, orally administered androgen synthesis inhibitor, is critically analysed. Evidence acquisition: Data were acquired from critically important original research published in peer-reviewed literature or presented at conferences conducted by the American Society of Clinical Oncology and the European Society of Medical Oncology. Evidence synthesis: The major findings are addressed in an evidence-based, objective, and balanced fashion. Conclusions: AA specifically inhibits CYP17 and substantially reduces serum androgen levels without inducing significant adrenal insufficiency. A phase 3 trial reported a significant extension of survival in metastatic CRPC with AA plus prednisone compared to prednisone alone following docetaxel. The primary toxicity of mineralocorticoid excess is manageable. The addition of low-dose corticosteroids to AA may be necessary for controlling symptoms of mineralocorticoid excess European Association of Urology. Journal: Review Page 3

15 3. Translating scientific advancement into clinical benefit for castration-resistant prostate cancer patients Citation: Clinical Cancer Research, June 2011, vol./is. 17/12( ), ; (15 Jun 2011) Attard G.; De Bono J.S. In the past 12 months, three novel therapeutics - sipuleucel-t, cabazitaxel, and abiraterone acetate - were granted Food and Drug Administration regulatory approval for the treatment of metastatic castration-resistant prostate cancer (CRPC) patients based on phase III studies that showed a survival advantage. Other agents, including the novel antiandrogen MDV3100, are at an advanced stage of clinical phase III evaluation. The treatment paradigm for CRPC has now changed significantly, and this has introduced new challenges for physicians, including selecting patients for specific therapies, developing the best sequencing and combination regimens for the several new effective agents that have recently been approved or are in development, and dissecting mechanisms of resistance that will inform the development of a new generation of therapeutics. This Focus issue reviews the results obtained with immunotherapies, taxane cytotoxics, and androgen receptor targeting therapeutics for CRPC, as well as the postulated mechanisms of resistance to these protocols and proposed strategies for improvement. The use of biomarkers for patient selection, monitoring of treatment activity, and acceleration of drug approval will be critical for achieving further improvements in the treatment for CRPC, and is also discussed in detail AACR. Journal: Review 4. Broadening horizons in medical management of prostate cancer Citation: Acta Oncologica, June 2011, vol./is. 50/SUPPL. 1( ), X; X (June 2011) Niraula S.; Tannock I.F. Hormonal therapy. Testosterone suppression achieved either medically or surgically is the standard initial treatment for men with advanced prostate cancer. Most men respond but the disease progresses after a median of 12 years. Clinical trials suggest that intermittent androgen deprivation therapy (ADT) provides equal or longer time to castration-independence than continuous ADT, and is preferred, especially since there are subtle long-term toxicities associated with ADT. Further hormonal manipulations (including addition and withdrawal of peripheral antiandrogens, steroid synthesis inhibitors such as ketoconazole, and estrogens) can be transiently effective in selected patients with castration-resistant prostate cancer (CRPC). Androgen-dependent signalling pathways remain active in most men with CRPC and are associated with mutation, changes in expression or modulation of the androgen receptor (AR); abiraterone acetate and MDV3100 are promising drugs being evaluated in clinical trials that may lead to further hormonal response. Chemotherapy. Eventually men who progress rapidly, are symptomatic, and/or develop metastasis to visceral organs require chemotherapy. Three-weekly docetaxel with prednisone has been shown to improve survival and relieve symptoms but eventually men develop progressive disease or become intolerant to docetaxel. Multiple trials are evaluating new drugs (mainly molecular targeted agents) either given first line with docetaxel chemotherapy, or to men who have progressive disease after receiving docetaxel. Cabazitaxel was shown recently to improve survival as compared to mitoxantrone when used second line and has been approved by the United States Food and Drug Administration (FDA). Conclusion. Despite major advances, treatment of men with advanced CRPC remains a challenge both for the seeker and giver of care Informa Healthcare. Page 4

16 Journal: Review 5. Current clinical trials in castrate-resistant prostate cancer Citation: Current Urology Reports, June 2011, vol./is. 12/3( ), ; (June 2011) Petrylak D.P. Seven years passed since docetaxel/prednisone demonstrated and overall survival benefit, leading to its approval by the FDA for metastatic castration resistant prostate cancer. In 2010, two new treatments, sipuleucel-t and cabazitaxel, were approved by the United States Food and Drug Administration for men with castration-resistant prostate cancer, based upon improvement in overall survival. The progress that has been made in understanding the biological basis of disease progression, particularly the role of the continued activation of the androgen receptor, have led to new treatments that will further improve survival in these patients. Abiraterone, a drug that depletes both intracellular and extracellular sources of testosterone, demonstrated a 3.9-month improvement in survival in patients who failed docetaxel-based chemotherapy. Other drugs targeting the androgen-receptor axis, such as TAK-700 and MDV3100, have demonstrated significant activity in phase 1 and 2 studies, and are currently in phase 3. Agents that target angiogenesis, bone, and novel apoptotic proteins currently are under investigation, either as single agents or in combination with chemotherapy. The challenge for the development of clinical trials will be how these compounds will be sequenced in the future Springer Science+Business Media, LLC. Journal: Article 6. Contemporary management of metastatic castration-resistant prostate cancer. Citation: Current Opinion in Urology, May 2011, vol./is. 21/3(241-7), ; (2011 May) Sonpavde G; Sternberg CN PURPOSE OF REVIEW: This review will describe the contemporary management of castration-resistant prostate cancer in the context of multiple recent advances.recent FINDINGS: Two novel agents have been added to the therapeutic armamentarium including cabazitaxel and sipuleucel-t. Cabazitaxel, a novel taxane extended survival in men with progressive metastatic CRPC following conventional docetaxel-based chemotherapy. Sipuleucel-T, an autologous dendritic cell based vaccine extended survival in men with relatively asymptomatic metastatic CRPC without visceral metastasis. A third agent, abiraterone acetate, an orally administered CYP17 inhibitor, which suppresses androgen synthesis has been preliminarily reported to significantly prolong survival following prior docetaxel and approval by regulatory agencies is anticipated. Baseline and early changes in circulating tumor cells appear useful as a prognostic factor. Additionally, data demonstrated the superiority of denosumab, a RANK-ligand antagonist, compared to zoledronic acid in the prevention of skeletal related events in men with bone metastases.summary: Cabazitaxel, sipuleucel-t and denosumab were approved in 2010 by regulatory agencies in the USA for men with metastatic CRPC, and approval of abiraterone acetate is anticipated based on the results of a phase III trial. The evaluation of circulating tumor cells assists in determining prognosis, although its utility for clinical decision-making entails validation. Journal Article; Research Support, Non-U.S. Gov't; Review Page 5

17 7. Evolving therapeutic paradigms for advanced prostate cancer. Citation: Oncology (Williston Park), May 2011, vol./is. 25/6( , 508), ; (2011 May) Ruch JM; Hussain MH Improving survival in metastatic castration-resistant prostate cancer (CRPC) is no longer an elusive goal. With the expansion of knowledge regarding the biology of the disease, we are witnessing a plethora of novel therapeutics that are undergoing testing in clinical trials. Since the approval of docetaxel for metastatic CRPC in 2004, three additional agents have demonstrated improvements in overall survival in randomized phase III trials: two agents (cabazitaxel and sipuleucel-t) were approved by the FDA in 2010, and a third (abiraterone) was approved in April of A threshold has clearly been crossed in the management of advanced prostate cancer; however, the impact on survival has been relatively modest, and efforts at personalized therapy have lagged behind those for other solid tumors. Further meaningful advances are needed, and the foundation for future clinical trials must be high-quality, high-impact translational science that focuses on disease biology, the defining of relevant pathways and validated predictive biomarkers, and adequate preclinical characterization of agents and combinations that will facilitate more personalized therapy. Journal Article; Review 8. Abiraterone and increased survival in metastatic prostate cancer. Citation: New England Journal of Medicine, May 2011, vol./is. 364/21( ), ; (2011 May 26) de Bono JS; Logothetis CJ; Molina A; Fizazi K; North S; Chu L; Chi KN; Jones RJ; Goodman OB Jr; Saad F; Staffurth JN; Mainwaring P; Harland S; Flaig TW; Hutson TE; Cheng T; Patterson H; Hainsworth JD; Ryan CJ; Sternberg CN; Ellard SL; Flechon A; Saleh M; Scholz M; Efstathiou E; Zivi A; Bianchini D; Loriot Y; Chieffo N; Kheoh T; Haqq CM; Scher HI; COU-AA-301 Investigators BACKGROUND: Biosynthesis of extragonadal androgen may contribute to the progression of castration-resistant prostate cancer. We evaluated whether abiraterone acetate, an inhibitor of androgen biosynthesis, prolongs overall survival among patients with metastatic castration-resistant prostate cancer who have received chemotherapy.methods: We randomly assigned, in a 2:1 ratio, 1195 patients who had previously received docetaxel to receive 5 mg of prednisone twice daily with either 1000 mg of abiraterone acetate (797 patients) or placebo (398 patients). The primary end point was overall survival. The secondary end points included time to prostate-specific antigen (PSA) progression (elevation in the PSA level according to prespecified criteria), progression-free survival according to radiologic findings based on prespecified criteria, and the PSA response rate.results: After a median follow-up of 12.8 months, overall survival was longer in the abiraterone acetate-prednisone group than in the placebo-prednisone group (14.8 months vs months; hazard ratio, 0.65; 95% confidence interval, 0.54 to 0.77; P<0.001). Data were unblinded at the interim analysis, since these results exceeded the preplanned criteria for study termination. All secondary end points, including time to PSA progression (10.2 vs. 6.6 months; P<0.001), progression-free survival (5.6 months vs. 3.6 months; P<0.001), and PSA response rate (29% vs. 6%, P<0.001), favored the treatment group. Mineralocorticoid-related adverse events, including fluid retention, hypertension, and hypokalemia, were more frequently reported in the abiraterone acetate-prednisone group than in the placebo-prednisone group.conclusions: The inhibition of androgen biosynthesis by abiraterone acetate prolonged overall survival among patients with metastatic castration-resistant prostate Page 6

18 Full Text: cancer who previously received chemotherapy. (Funded by Cougar Biotechnology; COU-AA-301 ClinicalTrials.gov number, NCT ). Clinical Trial, Phase III; Journal Article; Multicenter Study; Randomized Controlled Trial; Research Support, Non-U.S. Gov't Available in fulltext at EBSCO Host 9. Cabazitaxel for the treatment of prostate cancer. Citation: Expert Opinion on Pharmacotherapy, April 2011, vol./is. 12/6(977-82), ; (2011 Apr) Michielsen DP; Braeckman JG; Denis L INTRODUCTION: Prostate cancer is a frequently diagnosed male cancer. In men presenting locally advanced or metastatic disease, the mainstay of treatment is hormonal suppression. Despite the castrate levels of testosterone, with time, prostate cancer gradually evolves into a castration-refractory state. Chemotherapeutic agents are able to influence the natural history of metastatic castration-resistant prostate cancer. Docetaxel is a clinically relevant, FDA-approved taxane. Today, it is the first-line chemotherapeutic agent in castration-refractory prostate cancer (CRPC). There is no standard second-line chemotherapeutic regimen. AREAS COVERED: This review provides information on the efficacy of cabazitaxel as a second-line treatment for CRPC. The medline database was searched for clinical trials on chemotherapeutical treatment options of castration-resistant prostate cancer. All available data on the efficacy of cabazitaxel are summarized. EXPERT OPINION: New treatment strategies for castration-resistant prostate cancer should primarily focus on quality of life. In this view, vaccination therapy seems promising because of the acceptable level of toxicity. However, more research is needed to prove their efficacy in the treatment of castration-resistant prostate cancer. Cabazitaxel seems to be a promising second-line therapy in CRPC. Journal Article; Review 10. Abiraterone acetate, a novel adrenal inhibitor in metastatic castration-resistant prostate cancer. Citation: Current Oncology Reports, April 2011, vol./is. 13/2(92-6), ; (2011 Apr) Salem M; Garcia JA The androgen receptor remains the key player in patients with castration-resistant prostate cancer (CRPC). Available agents capable of blocking early adrenal androgen production have limited activity and can lead to significant toxicities. Abiraterone acetate, a pregnenolone analog, is a small molecule that irreversibly inhibits CYP17, a rate-limiting enzyme in androgen biosynthesis. Several clinical trials have demonstrated the safety and efficacy of this compound in men with metastatic CRPC. Recently, a randomized phase 3 trial evaluating abiraterone acetate in docetaxel-refractory CRPC patients demonstrated a survival improvement over placebo-treated patients (14.8 vs 10.9[NON-BREAKING SPACE]months; HR 0.646; P[THIN SPACE]<[THIN SPACE]0.0001). A similar trial in the pre-chemotherapy setting has completed accrual and is undergoing analysis. Here we review the rationale and clinical development of abiraterone acetate in men with CRPC. Journal Article; Review 11. New strategies in metastatic prostate cancer: targeting the androgen receptor signaling pathway. Page 7

19 Citation: Clinical Cancer Research, April 2011, vol./is. 17/7( ), ; (2011 Apr 1) Attard G; Richards J; de Bono JS Recent data report that abiraterone acetate, a specific inhibitor of CYP17 that is key to androgen and estrogen synthesis, improves survival in metastatic castration-resistant prostate cancer (CRPC), confirming the continued dependency of CRPC on the androgen receptor (AR) signaling pathway. MDV3100 is a novel antagonist of AR that is also in phase III clinical trials. In addition, several other agents targeting the AR axis are undergoing evaluation in early clinical studies. CRPC patients progress on these therapies with an increasing prostate specific antigen (PSA), suggesting that repeated therapeutic interventions targeting the AR signaling axis could induce secondary responses and achieve prolonged clinical benefit for a subgroup of patients. These exciting results are good news for patients but introduce a number of treatment paradigm dilemmas for physicians. Clinical studies evaluating the ideal sequence of administration of these new agents, best timing for initiation, combination strategies, discontinuation beyond progression and after commencement of subsequent therapies, and coordination with other treatments have not been done. Predictive biomarkers could allow patient selection for a specific treatment, but in their absence, most physicians will rely on a trial of treatment with a preferred agent and substitute for an alternative therapy on objective progression. Current data suggest that the response rate to drugs targeting the AR ligand-binding domain decreases with each treatment, but we hypothesize that a significant proportion of CRPC remains dependent on the AR axis and, therefore, novel strategies for disrupting AR signaling merit evaluation. Journal Article; Research Support, Non-U.S. Gov't; Review 12. TROPIC: Phase III trial of cabazitaxel for the treatment of metastatic castration-resistant prostate cancer Citation: Future Oncology, April 2011, vol./is. 7/4( ), ; (April 2011) Oudard S. For patients with metastatic castration-resistant prostate cancer (mcrpc), the current standard of care is chemotherapy involving the tubulin-binding taxane docetaxel. However, as the tumor cells become resistant to docetaxel-based therapy, disease progression is inevitable, and until recently there was no further available treatment beyond palliative care. In June 2010, cabazitaxel, a next-generation taxane, was approved by the US FDA for the treatment of mcrpc that has progressed after docetaxel therapy. This article describes the background and rationale of cabazitaxel's development and the clinical study program that led to its FDA approval, focusing on the Phase III TROPIC trial that demonstrated the efficacy of cabazitaxel plus prednisone in the treatment of mcrpc. Future development of this therapy and others under investigation is discussed Future Medicine Ltd. Journal: Article 13. Cabazitaxel for the treatment of prostate cancer Citation: Expert Opinion on Pharmacotherapy, April 2011, vol./is. 12/6( ), (April 2011) Michielsen D.P.J.; Braeckman J.G.; Denis L. Introduction: Prostate cancer is a frequently diagnosed male cancer. In men presenting locally advanced or metastatic disease, the mainstay of treatment is hormonal Page 8