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Critical Reviews in Oncology/Hematology 90 (2014) 36–48
Metastatic castration resistant prostate cancer: Current strategies ofmanagement in the Middle East
Shouki Bazarbashi a, Marwan Bachour b, Muhammad Bulbul c, Mohammed Alotaibi d,Mohamed Jaloudi e, Hassan Jaafar e, Deborah Mukherji f, Naim Farah g,
Tahseen Alrubai h, Ali Shamseddine f,∗a Section of Medical Oncology, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia
b Department of Medical Oncology, El Beyrouni University Hospital, Damascus, Syriac Division of Urology, Department of Surgery, American University of Beirut Medical Center, Beirut, Lebanon
d Department of Urology, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabiae Department of Oncology, Tawam Hospital/Johns Hopkin Medicine, Al Ain, United Arab Emirates
f Division of Hematology & Oncology, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanong Division of Uro-Oncology, King Hussein Cancer Center, Amman, Jordan
h Al-Amal National Hospital, Baghdad, Iraq
Accepted 1 November 2013
ontents
. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
. Castration resistant prostate cancer (CRPC): management options . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
. Second-line hormonal treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 383.1. Antiandrogens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 383.2. Antiandrogen withdrawal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 383.3. Ketoconazole/aminoglutethimide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 383.4. Estrogens. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 393.5. Glucocorticoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
. More novel agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 394.1. Abiraterone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 394.2. Enzalutamide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
. Chemotherapy for CRPC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 405.1. The Pre-Taxane Era . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 405.2. Taxanes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 405.3. Cabazitaxel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
. Febrile neutropenia and growth-factor support for patients with CRPC treated with chemotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 416.1. Primary CSF prophylaxis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 416.2. Secondary CSF prophylaxis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
6.3. Recommended approach and GCSF dosing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41. Bone-targeted therapy in advanced prostate cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 427.1. Zoledronic acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 427.2. Radium-223 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 427.3. Denosumab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
. Treatment sequencing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
∗ Corresponding author at: Division of Hematology/Oncology, Department of Internal Medicine, American University of Beirut Medical Center,.O. Box: 113-6044, Beirut 1107 2802, Lebanon. Tel.: +961 1 350000; fax: +961 1744464.
E-mail address: [email protected] (A. Shamseddine).
040-8428/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved.ttp://dx.doi.org/10.1016/j.critrevonc.2013.11.001
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S. Bazarbashi et al. / Critical Reviews in Oncology/Hematology 90 (2014) 36–48 37
8.1. Metastatic CRPC pre-docetaxel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 438.2. Timing of docetaxel chemotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 438.3. Can we improve on docetaxel for first-line chemotherapy?. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 438.4. Metastatic CRPC post-docetaxel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
. Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45Reviewers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45Biography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
bstract
Although most patients with prostate cancer respond to initial androgen-deprivation therapy, progression to castration-resistant prostateancer (CRPC) is almost inevitable. In 2004, the docetaxel/prednisone regimen was approved for the management of patients with metastaticRPC, becoming the standard first-line therapy. Recent advances have also led to an unprecedented number of approved new drugs; thus,roviding several treatment options for patients with metastatic CRPC. Five new drugs have received US Food and Drug Administration-pproval between 2010 and 2012: sipuleucel-T, an immunotherapeutic agent; cabazitaxel, a novel microtubule inhibitor; abiraterone acetate, aew androgen biosynthesis inhibitor; enzalutamide, a novel androgen receptor inhibitor; and denosumab, a bone-targeting agent. Such drugsre either already marketed or about to be marketed in the Middle East. Data supporting the approval of each of these agents are described inhis review, as are recent approaches to the treatment of metastatic CRPC.
2013 Elsevier Ireland Ltd. All rights reserved.
l; Abira
Smlnc1occM(piwThis is likely due to more common use of PSA screening com-pared with the rest of the region. Out of the six Gulf CountriesCouncil (GCC) states, Bahrain has the highest incidence with
Table 1Age standardized rate (ASR) of prostate cancer in some Middle Easterncountries. Data presented per 100,000 individuals.
Country ASR
Lebanon 27.6Turkey 13.7–19.1Bahrain 13.3Kuwait 12.6Jordan 11.5Qatar 10.3Egypt 6.6Saudi Arabia 6.1
eywords: Prostate cancer; Castration-resistance; Sipuleucel-T; Cabazitaxe
. Introduction
Prostate cancer is the second most common cancer inen worldwide, with an estimated 900,000 new cases diag-
osed and 258,000 deaths in 2008 and with the highestates recorded primarily in the developed countries of Asia,urope, and North America [1]. The American Cancer Soci-ty estimated that 241,740 American men were diagnosedith the disease and 28,170 men died of it in 2012 [2].ates of prostate cancer differ by over 50-fold between dif-
erent international populations [2]. Interpretation of theseata is complicated by dramatic changes in the incidence ofrostate cancer in the United States (US) and other Westernountries that have taken place over the past two decades.hese changes have been primarily driven by the increased
requency of prostate biopsies performed in asymptomaticen because of an elevated serum prostate-specific antigen
PSA) level. In the US, the incidence of prostate cancerramatically rose in the early 1990s concomitant with thencreased utilization of PSA testing [3]. After an initial peak,ncidence rates fell, but they have persisted at a rate nearlywice that recorded in the pre-PSA era [3]. Countries that doot utilize PSA testing typically have a much lower rate ofrostate cancer compared to those that do. However, unlesstudies control for the number of prostate biopsies performed,t is difficult if not impossible to be definitive in making suchonclusions. Prostate cancer is the most common cancer in
ales in 24 of 40 European countries with estimated agetandardized rate (ASR) of 96/100,000 in 2012 [4].Countries in the Middle East and North Africa exhibit
ower rates of prostate cancer compared to global rates [5,6].
OUI
terone; Enzalutamide; Denosumab
ome countries such as Lebanon [7,8] and Libya exhibit auch higher rate than their neighboring countries. Due to the
ack of continuous reporting over time, temporal trends can-ot be examined. Even in countries that have an establishedancer registry, mortality rates and incidence rates prior to990 are not available making it difficult to examine the effectf screening tests on incidence and mortality of prostate can-er. Lower median age may represent an additional factorontributing to the low incidence of prostate cancer in theiddle Eastern population. Table 1 represents the incidence
age standardized rate; ASR) of prostate cancer according toublished data in several Middle Eastern countries [8–12]. Its notable that Lebanon represents the Middle Eastern countryith the highest recorded incidence rate at 27.6/100,000 [8].
man 5.8nited Arab Emirates 5.3
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n ASR of 13.3/100,000 while United Arab Emirates hashe lowest incidence at 4.2/100,000 [12]. In addition, unlike
estern countries, prostate cancer ranks lower in incidencemong other cancers in men. For example, prostate canceranks 4th in Jordan, 3rd in Lebanon, 6th in Egypt, and 5th inCC nationals [8–12].In this review, we highlight the most notable advances in
he management of patients with advanced prostate cancer.e will focus on those approaches and management options
vailable and utilized in the Middle East region.
. Castration resistant prostate cancer (CRPC):anagement options
Advanced prostate cancer has been known by severalames over the years, including hormone-resistant/refractoryrostate cancer (HRPC) and androgen-insensitive prostateancer. Most recently, the term ‘castrate/castration-esistant/recurrent’ prostate cancer (CRPC) was introducedlong the realization that intracrine and paracrine androgenroduction plays a significant role in the resistance ofrostate cancer cells to gonadal androgen-deprivation ther-py (ADT). Thus, CRCP is defined by disease progressionespite ADT and may present as one or any combinationf: a continuous rise in serum levels of PSA, progression ofre-existing disease, or appearance of new metastases.
In their second publication, the Prostate Cancer Workingroup 2 (PCWG2) defined CRPC as a continuum on theasis of whether metastases are detectable (clinically or onmaging) and whether serum testosterone is in the castrateange because of a surgical orchiectomy or medical therapy13]. The resulting clinical-states model was recommendedo classify patients. Within the rising PSA states (castrate andon-castrate), no detectable (measurable or non-measurable)isease is found. Alternatively, in the clinical metastasestates (castrate and non-castrate), disease has to have beenetectable at some point in the past, regardless of whether its currently detectable [13].
The European Association of Urology defines CRPC asollows: serum castrate levels of testosterone, three consec-tive rises of PSA two weeks apart resulting in two 50%ncreases over the nadir, anti-androgen withdrawal for ateast four weeks, PSA progression despite secondary hor-
onal manipulations, and progression of osseous or softissue lesions. Anti-androgen withdrawal or one secondaryormonal manipulation should have failed in order to fulfillhe criteria for CRPC [14].
Thus, it is agreed that CRPC presents a spectrum of dis-ase ranging from rising PSA levels without metastases orymptoms and despite ADT, to metastases and significantebilitation from cancer symptoms. Prognosis is associated
ith several factors, including performance status, presencef bone pain, extent of disease on bone scan, and serumevels of alkaline phosphatase [15]. Bone metastases willccur in 90% of men with CRPC and can produce significantaaol
ology/Hematology 90 (2014) 36–48
orbidity, including pain, pathologic fractures, spinal cordompression, and bone marrow failure. Paraneoplastic effectsre also common, including anemia, weight loss, fatigue,ypercoagulability, and increased susceptibility to infection15].
. Second-line hormonal treatment
One-third of patients with prostate cancer will ultimatelyevelop metastatic disease. Hormonal therapy (HT), medi-al or surgical, is the standard initial therapy for advancedisease. Luteinizing Hormone Releasing Hormone (LHRH)gonists as well as antagonists with or without anti-androgensre used for medical castration. Despite initial profoundesponses in the majority of patients, responses are noturable and patients will progress biochemically then radio-ogically as they develop CRPC [16]. Therapeutic optionst this stage depend on the patient’s performance status,SA doubling time, Gleason score, extent of metastasis,nd patient’s expectations [17,18]. As previously discussed,RPC is not hormone refractory and suppression of gonadalndrogens needs to be continued in the form of LHRHgonists or antagonists if the patient has not undergone pre-ious orchiectomy [19]. Since a great number of patientsresent with asymptomatic, non-metastatic, biochemicalRPC, second-line hormonal therapy seems a logical next
tep to delay progression before recommending cytotoxichemotherapy. Second-line hormonal manipulations include:
.1. Antiandrogens
For patients progressing on LHRH agonists/antagonistslone, the addition of low-dose or high-dose antiandrogenould result in a 50% decrease in PSA in 54% of patientsith advanced disease [20]. However, median response to
his combined androgen blockade is only between 4 and 11onths [21–23].
.2. Antiandrogen withdrawal
A significant but short duration biochemical and clinicalesponse has been observed in patients progressing on com-ined androgen blockade when the antiandrogen is stopped24,25].
.3. Ketoconazole/aminoglutethimide
Both inhibit the first step of steroid biosynthesis fromholesterol to pregnenolone. Ketocanozole, an antifungal
gent, when used in high doses (800–1200 mg) has shownctivity in 30–60% of CRPC patients with a median responsef 7 months [26,27]. Side effects, mainly hepatic toxicity,imit its use.
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.4. Estrogens
Diethylstilbestrol reduces testosterone production bynhibiting LHRH and LH production. Around 50% PSAecrease has been observed in 20–40% of patients [28,29].ardiovascular side effects limit its use and concomitant anti-oagulation or antiplatelet agents should be given due to anncreased risk of venous thromboembolism.
.5. Glucocorticoids
Prednisone, dexamethasone, and hydrocortisone haveeen used alone or in combination with other medications.iological effects are unknown but palliation is always noted.
. More novel agents
.1. Abiraterone
Abiraterone acetate (Zytiga, Janssen) is an oral inhibitorf CYP17A1, a key enzyme in the testosterone biosynthe-is pathway. Inhibition of CYP17A1 results in reduction ofestosterone both from adrenal steroid precursors and intratu-
oral production. The use of single-agent abiraterone leadso a rebound increase in LH, hence the development of abi-aterone for use in combination with medical or surgicalastration [30]. The observation that the addition of low-doselucocorticoid resulted in normalization of mineralocorti-oid levels and an improvement in blood pressure control inarly-phase studies led the investigators to recommend thatbiraterone acetate should be used with prednisone in furtherlinical trials.
In the pivotal phase III study published in 2011 (COU-A-301), abiraterone plus prednisone was shown to prolong
urvival in men with CRPC who had progressive diseaseollowing docetaxel chemotherapy [31]. Approval from theS Food and Drug Administration (FDA) for the use of
biraterone in the post-docetaxel setting followed in April011 [32]. The primary endpoint of COU-AA-301 wasverall survival (OS), and the study was halted when thelanned interim analysis met pre-specified criteria for effi-acy. The initial analysis reported a 3.9 month improvementn median OS, but at the final analysis the benefit hadxtended to 4.6 months [33]. All secondary efficacy end-oints favored the experimental arm at the time of studynblinding, including time to PSA progression (10.2 vs. 6.6onths; p < 0.001), progression-free survival (PFS; 5.6 vs.
.6 months; p < 0.001), and PSA response rate (29% vs. 6%; < 0.001). Abiraterone was generally well tolerated; how-ver, mineralocorticoid-related adverse events were reported
ore frequently in the group of patients receiving abiraterone31]. Significant improvements in patient-reported fatigue,ain relief, delayed pain progression, and prevention ofkeletal-related events were also noted [34,35].
toew
ology/Hematology 90 (2014) 36–48 39
Abiraterone has also been tested in chemotherapy-naïveatients in the phase III COU-AA-302 study which random-zed 1088 patients to receive abiraterone plus prednisone orlacebo plus prednisone. The co-primary endpoints of thistudy were radiographic PFS (rPFS) and OS. The study wasnblinded and patients receiving placebo offered abirateronehen a planned interim analysis showed a statistically signif-
cant improvement in rPFS and a strong trend for increasedS in the abiraterone arm. Median rPFS was 8.3 months in
he placebo arm and had not been reached in the abirateronerm; median OS was 27.2 months in the placebo arm andgain had not been reached in the abiraterone arm [36]. Inecember 2012, The US FDA has expanded the approvedse of abiraterone acetate to treat men with metastatic CRPCrior to receiving chemotherapy. This was shortly followedy its approval pre chemotherapy by the European Medicinesgency (EMA). Thus, abiraterone may offer an attractive
herapeutic option for patients reluctant or unable to tolerateoxicities associated with cytotoxic chemotherapy.
.2. Enzalutamide
Enzalutamide (MDV3100, Xtandi, Medivation) is an oralovel androgen receptor antagonist that binds to the andro-en receptor more avidly than first generation anti-androgens.nzalutamide prevents DNA binding, induces apoptosis andas no agonist activity when the androgen receptor is overex-ressed [37]. The phase III AFFIRM study of enzalutamide60 mg daily vs. placebo for patients with metastatic CRPCho had progressed after docetaxel chemotherapy showed
significant survival benefit associated enzalutamide treat-ent. A planned interim analysis of the study showed a 4.8onth improvement in median OS with enzalutamide com-
ared to placebo (18.4 months vs. 13.6 months; hazard ratioHR] = 0.631; p < 0.0001). Enzalutamide was generally well-olerated; however, five seizures were documented in patientseceiving enzalutamide, including two patients with intracra-ial metastases, whereas no seizures were observed in thelacebo arm [38]. A potential advantage of enzalutamidever androgen biosynthesis inhibitors such as abiraterones the fact that concurrent steroids are not required; how-ver, approximately 30% of patients in each arm of theFFIRM study received concurrent corticosteroid treatment
38]. According to its insert package, seizures might occur in.9% of patients on enzalutamide; patients should be advisedf the risk of engaging in any activity where sudden loss ofonsciousness could cause serious harm to themselves or oth-rs. In September 2012, the US FDA approved enzalutamides a once-daily oral therapy for men with metastatic CRPChat has either spread to other organs or recurred, despiterior surgical or medical treatment. However, it is expected
hat enzalutamide will also benefit patients at earlier stagesf disease. The phase III PREVAIL study is examining theffect of enzalutamide on OS and PFS benefits in patientsith progressive metastatic prostate cancer after androgen
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eprivation therapy who have not yet received chemotherapyClinicalTrials.gov identifier: NCT01212991).
Following a trend of selectivity in cancer treatment ineneral, CRPC is witnessing a new surge of second-lineormonal manipulation drugs affecting both the ligand andeceptor for improved effectiveness.
. Chemotherapy for CRPC
Prior to 2004, few options were available for men withRPC, and no single agent or combination chemotherapyad been proven to prolong survival in these patients. How-ver, data derived from the TAX327, SWOG 99-16 andecent TROPIC studies (featured in subsequent sections)ave demonstrated that patients with CRPC may have a sur-ival benefit from chemotherapy. These results have changedxpectations although while introducing new sequencingilemmas.
.1. The Pre-Taxane Era
In the early 1990s PSA assays became available, andesponse to agents in clinical trials began to be measured andeported in terms of PSA response [39–41]. Two consecutiverials in the late 1990s demonstrated that the combinationf mitoxantrone plus corticosteroids could relieve pain andmprove quality of life more frequently than corticosteroidslone, but neither demonstrated a survival benefit [42,43].
.2. Taxanes
Taxanes have significant antitumor activity in men withRPC, when administered either as single agents or inombination with estramustine. Initial studies using single-gent paclitaxel administered as a 24-h infusion at a dosef 135–170 mg/m2 every 3 weeks were disappointing withnly a response rate of only 4% [44]. In contrast, when doce-axel was evaluated in men with CRPC at 75 mg/m2 every
weeks, a greater than 50% decline in PSA was observedn 46% of treated patients, while 28% of patients with mea-urable disease had a partial response [45]. The promisingctivity of docetaxel administered either as a single agent orn combination with estramustine [46–51] provided the basisor two multi-institutional phase III trials, SWOG 99-16 andAX327 [17,18].
In the TAX327 trial, 1006 patients with CRPC werenrolled in a three-arm study comparing two dosing schedulesf docetaxel plus prednisone with the standard mitoxantronelus prednisone therapy. Patients in the control arm werereated with mitoxantrone 12 mg/m2 every 3 weeks plusrednisone 5 mg orally twice-daily continuously. The exper-
2
mental arms consisted of docetaxel 75 mg/m every 3 weekr docetaxel 30 mg/m2 weekly for 5 of every 6 weeks. Pred-isone 5 mg orally twice-daily continuously was given in bothxperimental arms. In an intent-to-treat analysis, at a medianm1fw
ology/Hematology 90 (2014) 36–48
ollow-up of 28 months, the median OS for patients treatedith docetaxel every 3 weeks was 18.9 months, comparedith 16.4 months for patients in the control arm (p = 0.009).eekly docetaxel did not result in a significant survival bene-
t. Most importantly, the every 3-week schedule of docetaxelas associated with a 24% reduction in the risk of death
p = 0.009), compared with the control regimen. An updatedurvival analysis confirmed these findings [52]. Docetaxelherapy was also associated with significant improvement inain relief and in PSA decline. There were no significant dif-erences between the docetaxel arms in terms of response rate.he most common toxicity was neutropenia, which occurredore frequently in the every 3-week docetaxel regimen (32%
s. 21.7%) [18].In the SWOG 99-16 trial, 770 patients were randomized
o treatment with docetaxel plus estramustine or with mitox-ntrone plus prednisone. The experimental arm was docetaxel0 mg/m2 every 3 weeks and estramustine 280 mg orally 3imes per day on days 1–5. The control arm was mitoxantrone2 mg/m2 every 3 weeks plus prednisone 5 mg orally twice-aily continuously. The trial was designed to detect a 33%mprovement in median OS by using a one-sided log-rankest at a p level of 0.025. Secondary end-points were PFS,esponse rate, and rate of PSA decline. Patients treated withhe combination of docetaxel and estramustine had a signifi-ant improvement in median OS (18 months vs. 16 months,
= 0.01), longer PFS (6 months vs. 3 months, p < 0.0001),uperior median PSA decline, and a 20% reduction in theisk of death [17].
On the basis of the statistically significant improvementn survival observed in patients receiving the doce-axel/prednisone combination in the TAX327 trial, the FDAranted in May 2004 approval for docetaxel 75 mg/m2 every
week in combination with prednisone as front-line therapyor CRPC. This combination has widely become the standardf care as first-line chemotherapy in CRPC worldwide.
.3. Cabazitaxel
Cabazitaxel (Jevtana, Sanofi-Aventis) is a novel taxanehich has antitumor activity following the development of
esistance to paclitaxel and docetaxel. Cabazitaxel has alsoemonstrated the ability to cross the blood–brain barrier,hus making it potentially effective in patients with cere-ral or spinal cord metastases. In June 2010, cabazitaxelas licensed by the US FDA for the treatment of metastaticrostate cancer for patients with progressive disease follow-ng docetaxel-based chemotherapy on the basis of the phaseII TROPIC study.
The TROPIC study randomized 755 men to receive cabaz-taxel 25 mg/m2 or mitoxantrone 12 mg/m2 on a 3-weeklyasis. All patients received prednisone 10 mg daily. The
edian OS was 15.1 months in the cabazitaxel group and2.7 months in the mitoxantrone group. The HR for deathor men treated with cabazitaxel compared to those treatedith mitoxantrone was 0.70 (95% CI: 0.59–0.83; p < 0.0001).
s in Oncology/Hematology 90 (2014) 36–48 41
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Age over 65 years (most important risk factor for developing severeneutropenia)
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here were relatively high rates of grade 3 or 4 neutrope-ia in both the cabazitaxel (82%) and mitoxantrone (58%)roups. The rates of febrile neutropenia were 8% and 1%,espectively [53]. The use of gold-standard supportive man-gement including growth-factor support and standardizedathways for the management of febrile neutropenia is likelyo improve treatment-related morbidity; however, patientelection remains important.
Data from 68 patients treated within the expanded accessrogram in the UK showed improvements in pain control andealth status associated with cabazitaxel treatment as mea-ured by the EQ-5D quality of life questionnaire and healthtatus visual analog scale (VAS). The proportion of patientseporting no pain or discomfort increased from 22.6% at base-ine to 50% at cycle 4 [54]. Data from 111 patients treated withabazitaxel under the German compassionate-use programas recently been published. Seventy-one patients (64%)ere above the age of 65 with 20 patients (18%) above the agef 75. Grade 3/4 treatment-emergent adverse events occurredn 27.5% of patients under 65 and 32.4% of patients above5 with no statistically significant difference between thewo groups. The use of granulocyte colony-stimulating factorGCSF) was used in 17.1% of patients; however, the rate ofebrile neutropenia was significantly lower than that observedn the TROPIC study at 1.8% for the whole cohort. Fourreatment-related deaths occurred due to sepsis, two patientsnder 65 years and two patients over 65 years [55]. A largeandomized phase III trial (PROSELICA) is now investigat-ng a lower cabazitaxel dose of 20 mg/m2 vs. the licensedose of 25 mg/m2 in CRPC (ClinicalTrials.gov Identifier:CT01308580).
. Febrile neutropenia and growth-factor support foratients with CRPC treated with chemotherapy
Occurrence of febrile neutropenia may delay subsequenthemotherapy courses or result in dose reduction that mayompromise treatment outcomes. Development of febrileeutropenia also increases diagnostic and treatment costs andften leads to longer hospital stays [56]. Studies have demon-trated that prophylactic use of GCSFs can reduce the risk,everity, and duration of febrile neutropenia, but its cost hasrevented its routine use for all patients receiving myelosup-ressive chemotherapy. Selective use of GCSFs in patientst increased risk for neutropenic complications may, how-ver, enhance the cost-effectiveness. The GCSFs filgrastimnd pegfilgrastim currently have the approval for use in therevention of chemotherapy-induced neutropenia. In a meta-nalysis of 17 randomized trials including 3493 adult patientsith solid tumors and lymphoma, showed that G-CSF use asrimary prophylaxis reduces the risk of febrile neutropenia
RR = 0.54; 95% CI: 0.43–0.67; p < 0.001) and improves rel-tive dose-intensity of the chemotherapy delivered (averageifference between study arms 8.4%; p = 0.001). For the firstime, this analysis also reported a substantial reduction in riskslpm
istory of invasive fungal infection or other clinically-documentedinfections
f infection-related mortality (RR = 0.55; 95% CI: 0.33–0.90; = 0.018) and all early deaths during chemotherapy [57].
.1. Primary CSF prophylaxis
The indication for prophylactic CSF use depends on theisk of febrile neutropenia or other neutropenic events thatan potentially compromise treatment. Febrile neutropeniaisk is assigned to a high-risk group (>20% risk of febrileeutropenia), an intermediate group (10–20% risk), and aow risk group (<10% risk). The NCCN, ASCO and EORTCuidelines recommended prophylactic use of CSF if the riskf febrile neutropenia is 20% or greater [58]. Patient risk fac-ors are an important consideration in estimating the overallisk of febrile neutropenia, particularly when chemotherapyegimens are considered an intermediate risk (reviewed byyman et al. [59]). Patient risk factors may elevate the over-ll risk to a high-risk category, where prophylactic CSFs areore routinely recommended. These factors are illustrated
n Table 2. Most of these factors have been confirmed asndependent risk factors for neutropenic complications in aisk model developed by Lyman and colleagues that was vali-ated in a study population of 3760 cancer patients beginninghemotherapy [60].
.2. Secondary CSF prophylaxis
After the first cycle, patient evaluation should be per-ormed prior to each subsequent cycle to determine the riskategorization. If the patient experienced a previous episodef febrile neutropenia or a dose-limiting neutropenic eventa nadir or a day-of-treatment count impacting the plannedose of chemotherapy), this patient is now considered in theigh-risk group.
.3. Recommended approach and GCSF dosing
Patients with CRPC receiving docetaxel or cabazitaxelave to be assessed for overall febrile neutropenia riskincluding patient risk factors). High risk (>20% risk) patientshould receive primary prophylaxis, while secondary prophy-
axis is given for those who develop febrile neutropenia orrolonged nadir. In second-line treatment with cabazitaxelost of patients in our region fit in the category of high risk
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or febrile neutropenia because of the aforementioned patientisk factors and primary prophylaxis is advised.
When treatment with GCSF is indicated, initial doses oflgrastim should be initiated within 1–3 days after comple-
ion of chemotherapy in a daily dose of �g/kg until post-nadirbsolute neutrophil count recovery is to normal or near-ormal levels by laboratory standards. The dose may beounded to the nearest vial size by institution-defined weightimits. Because pegfilgrastim is longer-acting than filgrastim,
single injection of 6 mg, given 1–3 days after administra-ion of chemotherapy, is sufficient per chemotherapy cycle.here is evidence to support use of pegfilgrastim 1 day afterompletion of chemotherapy given every 2–3 weeks [61,62].ose reduction should be considered if CSF support did not
chieve the goal.
. Bone-targeted therapy in advanced prostateancer
Bone metastases are a major cause of prostate cancer-pecific morbidity and mortality. The treatment andrevention of skeletal related events (SREs) in prostate can-er has the potential to impact both symptoms and survivaln advanced disease. Bisphosphonates such as zoledroniccid [63] and bone-targeted radiopharmaceuticals such asamarium-153 and strontium-89 are used as monotherapynd in combination with chemotherapy (zoledronic acid)64,65]. Novel approaches to bone-targeted therapy includen alpha-emitting radiopharmaceutical (radium-223) and aeceptor activation of nuclear factor kappa-B ligand (RANK-) inhibitor (denosumab).
.1. Zoledronic acid
In men with CRPC and bone metastases, bisphosphonateslow the progression of SREs. Bisphosphonates also protectgainst the bone loss associated with androgen deprivationherapy. The FDA has approved only one bisphosphonate,oledronic acid for use in castrate-resistant prostate with boneetastases.The benefit of zoledronic acid in men with bone metas-
ases and CRPC was demonstrated in a trial in 643 men whoseisease was progressing while on ADT [66]. Men were ran-omly assigned to one of two doses of zoledronic acid (4 mgr 8 mg) or placebo, each given every three weeks. The 8 mgose of zoledronic acid was reduced to 4 mg early in the trialecause of an increased risk of renal toxicity. At an averageollow-up of 24 months, there was a significant reductionn the frequency of SREs in men receiving zoledronic acidompared to placebo (38% vs. 49%), and the median time to
evelop an SRE was significantly longer with zoledronic acid488 vs. 321 days) [63]. Pain and analgesic scores were sig-ificantly higher in men who received placebo than in thoseho received zoledronic acid, but there were no differencesava
ology/Hematology 90 (2014) 36–48
n disease progression, performance status, or quality-of-lifecores among the groups.
.2. Radium-223
Radium-223 chloride (Xofigo, Alpharadin, Bayer) is aovel bone-targeting alpha-emitting agent that has recentlyeen reported to improve pain as well as survival in patientsith CRPC and symptomatic bone metastasis [67–69]. Thehase III ALSYMPCA study enrolled men with prostateancer with symptomatic bone metastasis, no evidencef visceral disease or significant lymphadenopathy andither post-docetaxel or unfit for docetaxel chemotherapy.
planned interim analysis showed median OS of 14onths with alpharadin compared to 11.2 months with
lacebo (p = 0.0033, HR = 0.699), so the trial was haltednd placebo patients were offered treatment with alpharadin70]. Alpharadin appeared to be well tolerated; however,hrombocytopenia and diarrhea were seen more frequentlyith alpharadin compared to placebo. On May 2013, theDA approved Xofigo for the treatment of patients withRPC, symptomatic bone metastases, and no known vis-eral metastatic disease. Whether alpharadin can be safelyombined with chemotherapy or novel androgen receptorathway targeting agents has yet to be determined.
.3. Denosumab
RANK signaling is a potent stimulus for osteoclast prolif-ration and bone resorption. Denosumab (Xgeva®, Amgen)s a fully humanized monoclonal antibody targeting RANK-igand that has recently been shown to be superior tooledronic acid in preventing or delaying SREs in patientsith bone metastases from CRPC [71]. A large double-blindhase III non-inferiority study randomized 1904 patients toenosumab 120 mg subcutaneously monthly or zoledroniccid 4 mg intravenously monthly. The primary end-point wasime to SRE as defined by pathological fracture, radiothe-apy to bone, surgery to bone or spinal cord compression.he adverse event profile was similar in both arms. Deno-umab was shown to be superior to zoledronic acid forrevention of SRE (median time to SRE 20.7 monthss. 17.1 months; HR = 0.82; p = 0.008) [71]. A phase IIIlacebo-controlled study also demonstrated that denosumabignificantly improved bone metastasis-free survival in menith CRPC (29.5 vs. 25.2 months; HR = 0.85; 95% CI:.73–0.98; p = 0.028); however there was no improvementn OS [72].
. Treatment sequencing
With four novel therapies (cabazitaxel, abirateronecetate, enzalutamide, and alpharadin) shown to improve sur-ival in patients with advanced prostate cancer who progressfter docetaxel chemotherapy, the pace of clinical drug
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Table 3Summary of the most important trials using docetaxel in combination withnovel therapies.
Design Results
DN-101 ± docetaxel [89] NegativeBevacizumab ± docetaxel [86] NegativeGVAX ± docetaxel [90] Negative
S. Bazarbashi et al. / Critical Review
evelopment in this field has been unprecedented. Medianurvival from a diagnosis of CRPC was 13–19 months inhe pre-docetaxel era and is now exceeding 30 months withovel treatments [73,74]. With so many therapeutic optionsow in the clinic and under investigation in clinical trials,trategies for treatment selection, combination and sequenc-ng are urgently required. Since docetaxel became standardf care for symptomatic patients with CRPC following theAX327 study [18], three artificial ‘spaces’ have emerged.hese form the basis of current prostate cancer drug develop-ent strategies and are divided into: pre-docetaxel, docetaxel
ombination therapy, and post-docetaxel spaces. Treatmentf metastatic CRPC is nowadays a rapidly changing field andccordingly the treatment options described below may soonhange in the near future [75].
.1. Metastatic CRPC pre-docetaxel
Several options exist for patients with metastatic CRPCefore they go on chemotherapy. Sipuleucel-T, a dendriticell vaccine, has shown in randomized trials prolonged OSompared with placebo in men with minimally symptomatic,etastatic prostate cancer [76]. There are no data on the
ffectiveness of sipuleucel-T in men whose only evidencef disease is an elevated PSA or in those with symptomaticetastatic disease. Although sipuleucel-T prolonged overall
urvival, it did not significantly increase progression-free sur-ival or affect the serum PSA. However, due to its high cost,ontraindication to the use of corticosteroids for 6 months fol-owing treatment, and some controversy regarding the studyesign [77], the use of sipuleucel-T is likely to be limited.
As previously mentioned, abiraterone plus prednisonean prolong rPFS pre-chemotherapy compared to prednisonelone, however the COU-AA-302 study was unblinded prioro the co-primary end-point of OS showing a significantifference between the two arms [78]. Despite this, abi-aterone is FDA approved now for use pre-docetaxel and isn attractive option for patients who wish to avoid the tox-city of chemotherapy. Another option for patients unfit forocetaxel is radium-223 (alpharadin). In the ALSYMPCAtudy, 42% were chemotherapy naïve [79]. Another drugurrently in phase III clinical trials in the pre-docetaxel set-ing aside from enzalutamide (ClinicalTrials.gov identifier:CT01212991) is tasquinimod (ClinicalTrials.gov identifier:CT01234311). Although many of the above mentionedptions are presently used in the castrate resistant phase ofhe disease, ongoing studies are being conducted to assess thefficacy of many of the above agents in the 1st line setting oformone naive disease with encouraging results [80].
.2. Timing of docetaxel chemotherapy
Strict guidelines for the role of docetaxel chemotherapy insymptomatic metastatic CRPC do not exist. In the TAX 327rial, those patients without baseline pain were able to receivehemotherapy for a significantly greater duration compared
OAZ
ology/Hematology 90 (2014) 36–48 43
ith those with baseline pain (median 27 vs. 21 weeks; = 0.0017) [52]. Moreover, those without baseline pain hadignificantly greater overall survival than those with painHR 0.73 vs. 0.85; 95% CI: 0.57–0.93; p = 0.01) [52]. Takenogether, these data point to the potential benefits of earlierhemotherapy. Despite this NCCN guidelines require thathemotherapy only be given to patients with symptomaticetastatic disease [81]. On the other hand the European Asso-
iation of Urology (EAU) guidelines state that patients withsymptomatic metastatic CRPC who have elevated PSA lev-ls or PSA doubling time < 6 months should be started onytotoxic therapy early in order to increase the opportunityor extended survival [82].
A prognostic nomogram developed by Armstrong et al.83] and based on results from TAX 327 demonstrated thatatients with lower PSA (<114 ng ml−1) and slower PSAoubling time (≥55 days) had significantly greater survivalhan patients with higher PSA or faster PSA doubling time.he analysis of clinical trial data by Hussain et al. [84] also
evealed that PSA progression, defined as an increase in PSAf at least 25% over nadir, or an absolute increase of 2 ng ml−1
based on the Prostate Cancer Working Group 2008 defi-ition), was predictive of OS in both patients with CRPCn chemotherapy. Based on this data, the predictive valid-ty of PSA kinetics regarding response to chemotherapy andhe threshold for initiation of chemotherapy in asymptomaticatients may, in some cases, be appropriate if their PSA-elated values support it regardless if they are metastatic orot [85]; the latter is though discouraged by most treatmentuidelines. The availability of other therapeutic options at thisnterim period, such as immunotherapy or hormonal therapydiscussed above), may be seen as preferable at this stage.
.3. Can we improve on docetaxel for first-linehemotherapy?
Several large phase III studies investigating the com-ination of docetaxel with novel therapies for CRPCncluding bevacizumab (CALGB 90401 trial), lenalidomideMAINSAIL trial), and Dasatinib (READY trial) have beenisappointingly negative [86–88]. So far, despite promisinghase II results, no combination treatments have been shown
blimersen ± docetaxel [91] Negativetrasentan ± docetaxel [92] Negativeibotentan ± docetaxel [93] Negative
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.4. Metastatic CRPC post-docetaxel
In the post-docetaxel space we now have three drugshown to improve survival in phase III studies and this isrguably the area of most debate due to the lack of head-o-head data. Cabazitaxel, abiraterone, and enzalutamidere all now licensed for use in CRPC following docetaxel31,38,53]. Pending prospective sequencing studies, onean examine the patient characteristics of the pivotal phaseII trials and retrospective data from institutions treatingatients with these drugs within serial clinical trial proto-ols.
One essential question remains, are the results of theivotal phase III trials in the post-docetaxel space for cabaz-taxel, abiraterone, and enzalutamide comparable? The firstoint to note is that in the TROPIC study, cabazitaxel wasompared to the active comparator of mitoxantrone plusrednisone; in the COU-AA-301 study abiraterone plus pred-isone were compared to prednisone alone; while in theFFRIM study, enzalutamide was compared to placebo
31,38,53]. Furthermore in the TROPIC study, PFS wasoubled in the cabazitaxel arm compared to mitoxantrone2.8 months vs. 1.4 months; HR = 0.74; p < 0.0001). Thebserved PFS is somewhat shorter than what has beeneported with the COU-AA-301 trial for abiraterone acetatePFS: 5.6 months vs. 3.6 months; p < 0.001) [31,53]. Oneontributing factor to this difference is the definition ofFS, which in the COU-AA-301 trial was a compositend-point defined as time to disease progression includingadiographic progression plus symptomatic/clinical progres-ion plus PSA progression. In the TROPIC trial, PFS wasefined as time from randomization to PSA progression,umor progression, pain progression, or death. PSA ele-ation alone often predates clinical tumor progression by–4 months; thus, such a definition may result in a shorterFS.
Patients recruited in these three trials had progressedollowing docetaxel with approximately 30% of patientseceiving two or more lines of chemotherapy prior totudy entry. In the TROPIC trial, nearly two-thirds ofatients had progressed on or within 3 months of doce-axel. Prior response to docetaxel was not reported in theOU-301 or AFFIRM trials; however, some retrospectiveata are available. In an exploratory analysis of the COU-A-301 trial, approximately 45% discontinued docetaxelue to disease progression in each arm. The OS bene-t of abiraterone was maintained when calculated from
he first or last dose of prior docetaxel and whether orot patients discontinued docetaxel for progressive disease94].
When selecting second-line therapy, the potential for crossesistance should also be considered. In vitro studies sug-
est that one mechanism of action for taxanes is inhibitionf microtubule-dependent, androgen receptor translocationo the nucleus, impairing androgen receptor signaling andeducing PSA expression. Abiraterone impairs such signalingobpa
ology/Hematology 90 (2014) 36–48
y reducing CYP17-dependent androgen production, as wells directly binding to the androgen receptor and reducingts signaling in a dose-dependent manner. This raises con-erns regarding the potential for cross resistance betweenicrotubule inhibitors and hormonal therapies such as abi-
aterone, based on the hypothesis that use of androgeneceptor signaling inhibitors may impair the ability of tax-nes to subsequently inhibit this pathway [95]. There is aistinction to be made, however, regarding truly docetaxel-efractory CRPC (no response to docetaxel) and those whoave an initial response to treatment yet develop progres-ive disease while still receiving chemotherapy. In a smalletrospective series of 44 patients treated with abirateroneost-docetaxel, seven patients were defined as docetaxel-efractory (no PSA response, PSA or radiological progressionn treatment). None of these docetaxel-refractory patientsad a subsequent response to abiraterone raising questionsegarding cross-resistance [96]. In a separate retrospectivetudy looking at the activity of docetaxel post-abiraterone,o responses to docetaxel were observed in abiraterone-efractory patients [97].
Apart from prior response to chemotherapy, other fac-ors such as prior response to endocrine therapy may beaken in to consideration for treatment selection. Loriott al. reported that duration of sensitivity of ADT ≥16onths is a significant predictive factor for efficacy of subse-
uent endocrine manipulations in patients with CRPC [98].lthough abiraterone has antitumor activity in patients pre-
reated with docetaxel and enzalutamide [99], two recenttudies showed reduced efficacy of abiraterone acetate inatients who previously received enzalutamide despite theirifferent mechanisms of action indicating the presence ofross resistance [100,101]. There is no doubt that novel treat-ents are prolonging survival for patients with CRPC withedian OS in placebo arm of the AFFIRM study of over 13onths. The majority of these patients went on to receive sub-
equent therapy including cabazitaxel and abiraterone [38].n the absence of randomized data on which to base the deci-ion regarding which drug to use first following docetaxelailure in CRPC, clinical criteria to select cabazitaxel includeood performance status, aggressive disease trajectory withisceral metastasis and resistance to prior docetaxel and/orhort duration of response to ADT. Abiraterone or enzalu-amide may be more appropriate options for patients whoish to avoid the toxicity of chemotherapy, particularly thoseith poorer performance status, medical co-morbidities, andoor bone marrow reserve. In summary, selection of second-ine therapy beyond docetaxel and sequencing of therapies inatients with progressive metastatic CRPC should be basedn careful evaluation of disease characteristics. In patientsikely to poorly respond to abiraterone (e.g., high Glea-on score, rapid progression to CRPC with primary ADT,
r progression during docetaxel therapy), cabazitaxel mighte the preferred first-option in the second-line setting. Foratients with less-aggressive metastatic CRPC, cabazitaxelnd abiraterone are reasonable treatment options. Treatment
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aradigms for advanced prostate cancer are changing rapidlys more data emerges.
. Conclusions
Men with advanced prostate cancer now have hope whenittle existed before. While there is no formal sequence toreating CRPC, men have increasing options to help dealith a complex problem. Further, going from one therapy
o another may have cumulative benefits and can further pro-ong survival. Several options have recently demonstratedctivity, providing survival improvement, in patients withrostate cancer progressing while on androgen deprivationherapy: chemotherapy (docetaxel, cabazitaxel), sipuleucel-, abiraterone, and enzalutamide. The availability of newpproved agents with different mechanisms of action high-ight the need for the coordinated multidisciplinary carepproach between different specialities especially urologistsnd oncologists. It is important to understand that this is aontinuously changing field and it is likely that we will seeormonal therapy move from the post-docetaxel phase to there-docetaxel phase or even to the hormone naïve phase. Theptions of chemotherapy among the emerging large numberf hormonal therapies need to be clearly defined. There isow emerging data that can help in defining patients whoight benefit from chemotherapy beyond symptomatic andetastatic CRPC. There is presently an urgent need to iden-
ify predictive factors of efficacy for each of these treatmentso assist decision-making in patients with CRPC.
onflict of interest statement
Shouki Bazarbashi: Honoraria and travel from Sanofi,ravel support from Ferring.
Marwan Bachour: No conflicts of interest.Muhammad Bulbul: No conflicts of interest.Mohammed Alotaibi: Honoraria and travel expenses from
anofi.Mohamed Jaloudi: Honoraria from Sanofi and Roche,
rial grants from Bayer.Hassan Jaafar: Honoraria and travel from Sanofi.Deborah Mukherji: Honoraria from Janssen and travel
upport from Sanofi.Naim Farah: No conflicts of interest.Tahseen Alrubai: Travel expenses from Sanofi.Ali Shamseddine: 1) Advisory board: Sanofi, Roche,
fizer, Pharmamed, Amgen and GSK; 2) Honoraria: Sanofi,oche, Amgen, GSK, and Merck; and 3) Research grants:oche, Sanofi, GSK and Novartis.
unding
No source of funding.
ology/Hematology 90 (2014) 36–48 45
eviewers
Professor Cora Sternberg, San Camillo and Forlanini Hos-itals, Department of Medical Oncology, Nuovi Padiglioni,irconvallazione Gianicolense 87, Rome 00152, Italy.
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iography
Dr. Shamseddine is Professor of Clinical Medicine andead of Hematology–Oncology Division at the American
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ology/Hematology 90 (2014) 36–48
niversity of Beirut and Medical Center. He is the formalhair of the hospital committee on cancer as well as the direc-or of the Tumor Registry at the Medical Center (1997–2012).e is also the V/P of the National Cancer Registry (NCR)
ince 2005. Starting October 2012, he is appointed as direc-or of data base & clinical research unit at NK Basile Cancernstitution at AUBMC. He published more than 150 papers ineer review journals. His research focuses on several issuesncluding: Epidemiology of cancer in Lebanon, Breast can-er, Gastro-intestinal and Prostatic cancers. He also published
book dealing with the trends of cancer at the Americanniversity of Beirut over 20 years (1983–2003) and recently
May 2010) cancer report 2010 (APOCP). Dr. Shamseddines an active member in the society. He is a formal presidentf the Lebanese Society of Medical Oncology as well as theice-President of the National Cancer Registry. He is alsoell known internationally in the field of oncology and he is
n active member of the American Society of Clinical oncol-gy (ASCO) and over the last two years he was the chairf the Best of ASCO meeting in Beirut. He is also mem-er of the European Society of Medical Oncology (ESMO)nd the European Association of Hematology (EHA). He is
co-founder and chair of the advisory board of the Arabollaborative Hematology–Oncology Group (ACHOG). Dr.hamseddine chairs the EASO (European Arab School of
ncology) prostatic committee in Lebanon. On May 1st,012, Dr. Shamseddine was elected as a fellow of the Royalollege of Physician in London (FRCP).
