Original Article
`
`Gemcitabine and Docetaxel in Metastatic,
`Castrate-Resistant Prostate Cancer
`
`Results From a Phase 2 Trial
`
`Jorge A. Garcia, MD, FACP1; Thomas E. Hutson, MD2; Dale Shepard, MD1; Paul Elson, ScD3; and Robert Dreicer, MD1
`
`BACKGROUND: Docetaxel
`is the standard of care for patients with metastatic, castrate-resistant prostate cancer
`(CRPC). Gemcitabine is a nucleoside analogue with broad antitumor activity. In a phase 2 study of combined doce-
`taxel and gemcitabine, the authors assessed its safety and activity in patients with chemotherapy-naive, metastatic
`CRPC. METHODS: Eligible patients had untreated, metastatic CRPC with radiologic and/or biochemical evidence of
`progression after antiandrogen withdrawal with castrate testosterone levels, an Eastern Cooperative Oncology per-
`formance status (ECOG PS) of 0 to 2, and adequate organ function; no previous chemotherapy was permitted.
`Patients received gemcitabine (800 mg/m2) Days 1 and 8 and docetaxel (75 mg/m2) on Day 8 every 21 days for a
`maximum of 6 cycles. Response was evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) for
`measurable disease. A prostate-specific antigen (PSA) response was defined as a decline 50% in baseline PSA level.
`RESULTS: Thirty-five patients with chemotherapy-naive, metastatic CRPC were enrolled. The median age was 67
`years, and 60% of patients had an ECOG PS of 0. PSA responses were observed in 49% of patients. Among
`the patients who had measurable disease (n ¼ 25), 3 patients (12%) had a confirmed, RECIST-defined partial response
`(PR); 4 patients (16%) had an unconfirmed PR; and 15 patients (60%) achieved stable disease. The most
`common adverse events included grade 1 and 2 fatigue (69%), alopecia (80%), and nausea/vomiting (54%). No treat-
`ment-related deaths were noted, but an unusually high incidence of grade 3 and 4 neutropenia was observed.
`CONCLUSIONS: The efficacy of combined gemcitabine and docetaxel
`in metastatic CRPC was similar to that
`observed with single-agent docetaxel. In contrast to single-agent docetaxel, the combination was moderately toxic
`and had an impact primarily on bone marrow reserve. Cancer 2011;117:752–7. VC 2010 American Cancer Society.
`
`KEYWORDS: castrate-resistant prostate cancer, chemotherapy, gemcitabine, docetaxel, prostate-specific antigen.
`
`Prostate cancer is the second leading cause of death among men in the United States, and >192,280 new cases were
`diagnosed in 2009.1 Although the majority of patients with advanced prostate cancer have an initial response to androgen-
`deprivation therapy, all patients eventually will progress to a castrate-resistant state, which is manifested by rising levels of
`prostate-specific antigen (PSA), progressive disease on imaging studies, worsening of symptoms, and, ultimately, death.2
`Patients with progressive prostate cancer despite anorchid testosterone levels are considered ‘‘castrate resistant.’’ The treat-
`ment of patients with metastatic, castrate-resistant prostate cancer (CRPC) has evolved significantly in the last several
`years. Chemotherapeutic options for patients with advanced disease, once considered a futile endeavor, have changed sig-
`nificantly with the understanding that docetaxel-based chemotherapy produces palliative benefits and leads to an overall
`survival improvement in patients with CRPC.3,4 Despite its clinical benefits, the response to docetaxel often is short lived,
`and all patients eventually develop progressive disease.
`Gemcitabine is a nucleoside analog that has activity against a broad spectrum of solid tumors.5 Although in vitro
`work has suggested significant activity in prostate cancer cell lines,6 existing clinical data suggest modest clinical activity
`when gemcitabine is used as a single agent in CRPC.7 A series of phase 1 and 2 trials that evaluated the combination of
`gemcitabine plus docetaxel provided some evidence of a potential synergistic or additive effect when these 2 agents are
`
`Corresponding author: Jorge A. Garcia, MD, FACP, Department of Solid Tumor Oncology, Cleveland Clinic Taussig Cancer Institute, 9500 Euclid Avenue/R35,
`Cleveland, OH 44195; Fax: (216) 444-9464; garciaj4@cff.org
`
`1Department of Solid Tumor Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland, Ohio; 2Urologic Oncology Program, Charles A. Sammons Cancer Cen-
`ter, Baylor University Medical Center, Dallas, Texas; 3Department of Biostatistics, Cleveland Clinic Taussig Cancer Institute, Cleveland, Ohio
`
`Presented at the 2006 American Society of Clinical Oncology Prostate Cancer Symposium; San Francisco, California; February 24-26, 2006.
`
`DOI: 10.1002/cncr.25457, Received: March 2, 2010; Revised: April 29, 2010; Accepted: May 3, 2010, Published online October 4, 2010 in Wiley Online Library
`(wileyonlinelibrary.com)
`
`752
`
`Cancer
`
`February 15, 2011
`
`AVENTIS EXHIBIT 2209
`Mylan v. Aventis IPR2016-00712
`
`

`
`used together.8-13 The objective of the current, multi-
`institutional, phase 2 trial was to evaluate the efficacy,
`safety, and tolerability of this combination in patients
`with previously untreated, metastatic CRPC.
`
`MATERIALS AND METHODS
`Eligible patients had histologically confirmed adenocarci-
`noma of the prostate with metastases and evidence of
`disease progression (worsening disease observed on bone
`scans, an increase in measurable disease, or a PSA >5 ng/
`mL and increasing on 2 consecutive measurements 1 week
`apart) despite at least 1 endocrine manipulation and tes-
`tosterone levels <50 ng/dL. Patients who had received
`antiandrogen therapy were required to demonstrate
`progressive disease after appropriate withdrawal from
`therapy. Androgen-deprivation therapy with a luteinizing
`hormone-releasing hormone (LHRH) agonist or orchiec-
`tomy was required for the duration of the study. Other
`inclusion criteria were a Eastern Cooperative Oncology
`Group (ECOG) performance status of 0 to 2 and
`adequate bone marrow, hepatic, and renal function (as
`defined by a white blood cell count 1500/lL, a platelet
`count 100,000/lL, hemoglobin 8.0 g/dL, aspartate
`and alanine aminotransferase levels 2 times the upper
`limit of normal [ULN], and serum bilirubin 1.5 times
`the ULN. Patients who had received previous chemother-
`apy for CRPC were excluded; however, the receipt of
`neoadjuvant or adjuvant (nontaxane) chemotherapy was
`allowed >1 year before study entry. Other exclusion crite-
`ria included previous radiation therapy within 4 weeks of
`study entry and a history of severe cardiovascular disease
`(class III/IV intra-abdominal hypertension), uncontrolled
`congestive heart failure, or ventricular arrhythmia. The
`Cleveland Clinic Institutional Review Board reviewed
`and approved this study in accordance with the Declara-
`tion of Helsinki and the International Conference on
`Harmonization Good Clinical Practice guidelines. All
`patients provided written informed consent before
`registration.
`Treatment consisted of Gemcitabine (Gemzar; Lilly
`Pharmaceuticals, Indianapolis, Ind) 800 mg/m2 adminis-
`tered intravenously over 30 to 60 minutes on Day 1 and 8
`of each treatment cycle and docetaxel (Taxotere; Sanofi-
`Aventis Pharmaceuticals, Bridgewater, NJ) 75 mg/m2
`administered intravenously over 30 to 60 minutes on Day
`8 followed the Day 8 infusion of gemcitabine. All patients
`received oral prednisone 5 mg twice daily with standard
`antiemetic and supportive care. Prophylactic use of white
`
`Gemcitabine and Docetaxel in CRPC/Garcia et al
`
`blood cell and erythrocyte growth factors was not
`permitted.
`All patients were required to have an absolute
`granulocyte count 1.5.109/L and/or a platelet count
`100.109/L on Day 1 and Day 8 of any cycle before they
`received treatment. Dose reductions of 25% and 50%
`were implemented for any initial and subsequent delay
`of Day-8 chemotherapy. Adverse events were graded
`according to version 3.0 of the National Cancer Institute
`Common Terminology Criteria for Adverse Events.
`Treatment was administered weekly for 2 consecutive
`weeks on a 21-day cycle for a maximum of 6 cycles or
`until disease progression was assessed by the investigators
`according to Response Evaluation Criteria in Solid
`Tumors (RECIST),14 unacceptable toxicity, or consent
`withdrawal.
`Baseline evaluations included medical history and
`physical examination, laboratory parameters (hematology
`and blood chemistry, including testosterone level and
`PSA), and tumor imaging (computed tomography [CT]
`scans or magnetic resonance imaging [MRI] studies of the
`chest, abdomen, and pelvis; bone scan; and brain CT or
`MRI scans). Tumor assessments were performed at base-
`line and every 8 weeks.
`
`Efficacy Assessment
`PSA values were obtained before each cycle of chemother-
`apy. A PSA response was defined as a decline >50% that
`was maintained for at least 4 weeks. PSA progression was
`defined as a 25% increase in PSA over the nadir value that
`was confirmed by a second PSA evaluation at least 1 week
`later. A complete PSA response required normalization
`of PSA (<4 ng/mL) for at least 21 days. Patients with
`measurable soft tissue disease were assessed according to
`RECIST. Complete responses required the complete dis-
`appearance of all evidence of all sites of measurable or os-
`seous disease with normalization of the PSA level (defined
`as PSA <4 ng/mL). A partial response was defined accord-
`ing to RECIST as a reduction 50% in PSA without the
`appearance of new osseous lesions, and worsening patho-
`logic findings. Progressive disease was defined as a pro-
`gression in the PSA level, an increase in the size of existent
`bone lesions, or the appearance of 1 or more new bone
`lesions identified on bone scan. The time to progression
`was measured from the first day of treatment to the time
`of disease progression. Overall survival was measured
`from the initiation of therapy to the date of death or last
`follow-up.
`
`Cancer
`
`February 15, 2011
`
`753
`
`

`
`Original Article
`
`Statistical Methods
`The primary endpoints of the study were to determine the
`safety and efficacy of combined gemcitabine plus doce-
`taxel in patients with untreated, metastatic CRPC. A 2-
`stage accrual design with a maximum goal of 34 eligible
`and evaluable patients was used to test the hypothesis that
`the underlying overall response rate (PSA for patients
`with nonmeasurable disease and RECIST-defined for
`patients with measurable disease) was essentially 20%
`versus 40%, respectively. The study was designed with
`a ¼ .11 and power of 0.90. Seventeen eligible and evalu-
`able patients were enrolled in the first accrual stage, and
`an additional 17 patients were enrolled in stage 2 if 4 of
`the 17 stage 1 patients responded. Survival was calculated
`from the date of study registration to the date of death or
`last follow-up; and was summarized using the method of
`Kaplan and Meier. Spearman rank correlations were used
`to assess associations, such as the relation between a PSA
`decrease and a measurable disease reduction.
`
`RESULTS
`Patient Characteristics
`Between July 2004 and October 2006, 35 patients with
`chemotherapy-naive, metastatic CRPC were enrolled.
`Baseline characteristics are summarized in Table 1. The
`median patient age was 67 years, and most patients (60%)
`had an ECOG performance status of 0. All patients had
`undergone either surgical or medical castration and dem-
`onstrated castrate levels of testosterone during study treat-
`ment. Similarly, all but 3 patients (9%) had received
`antiandrogen treatment either as part of their initial
`androgen-deprivation therapy or as a second-line hor-
`mone manipulation. Twenty-four patients (69%) had
`received previous radiation therapy, and 8 patients (23%)
`had undergone radical prostatectomy. Only 1 patient had
`received previous chemotherapy in the adjuvant setting.
`Pretreatment PSA levels ranged from 1.50 ng/mL to
`938.6 ng/mL. Although the vast majority of patients
`(71%) had RECIST-defined, measurable disease before
`study entry, 10 patients (29%) had documented bone dis-
`ease with either radiographic progression, a rising PSA, or
`worsening clinical symptoms.
`
`Efficacy Results
`All patients were evaluable for response. The vast majority
`of patients (29 of 35; 83%) experienced some PSA decline
`while they were receiving treatment. Seventeen patients
`(49%) achieved a PSA response. Among these, 6 patients
`
`Table 1. Patient Characteristics
`
`Variable
`
`No. of Patients (%)
`
`Median age [range], y
`
`67 [55-84]
`
`ECOG performance status
`0
`1
`2
`
`Previous adjuvant/neoadjuvant
`chemotherapy
`Previous RT
`Previous RP
`Median pretreatment PSA
`[range], ng/mL
`
`Measurable disease
`Soft tissue only
`Soft tissue and bone
`Bone disease only
`
`21 (60)
`12 (35)
`2 (6)
`1 (3)
`
`24 (69)
`8 (23)
`35.0 [1.50-938.6]
`
`17 (49)
`8 (23)
`10 (28)
`
`ECOG indicates Eastern Cooperative Oncology Group; RT, radiotherapy;
`RP, radical prostatectomy; PSA, prostate-specific antigen.
`
`(17%) had a PSA decrease 95%. The median time to
`PSA nadir in these patients was 3.4 months (range, from 3
`weeks to 5.4 months). Figure 1 summarizes the data as a
`waterfall plot. Of 25 patients who had measurable disease,
`3 patients (12%) had a confirmed, RECIST-defined par-
`tial response; 4 patients (16%) had an unconfirmed par-
`tial response; and 15 patients (60%) had stable disease,
`including reduced tumor burden in 12 patients. Figure 2
`illustrates the maximal change in tumor burden of the
`evaluable patients. The median reduction in tumor bur-
`den was a 26.5% decline (range, from a 72.1% decline to
`a 14.3% increase). At the time of this report, 26 patients
`had died, and the estimated median survival was 19.4
`months (Fig. 3). The median follow-up for the 9 patients
`who remained alive at the time of the current analysis was
`11.1 months (range, 0.9-48.5 months).
`
`Treatment Administration and
`Adverse Events
`the
`Twenty-two patients (63%) completed all 6 of
`planned treatment cycles. Thirty-two percent of the cycles
`were delayed at least by 1 week, primarily for neutropenia.
`Fourteen percent of patients required a dose reduction of
`gemcitabine by 25% (n ¼ 4; because of grade 3 neutrope-
`nia) and by 50% (n ¼ 1; because of grade 3 diarrhea).
`Docetaxel was reduced by 25% in 2 patients who devel-
`oped grade 3 neutropenia and by 50% in the same patient
`who developed grade 3 diarrhea and required a 50%
`reduction in the dose of gemcitabine. Four patients dis-
`continued therapy because of PSA progression. Other
`
`754
`
`Cancer
`
`February 15, 2011
`
`

`
`Gemcitabine and Docetaxel in CRPC/Garcia et al
`
`Figure 1. This waterfall plot illustrates the maximal prostate-specific antigen (PSA) change (%) from baseline. Negative values
`indicate a decrease in PSA compared with pretreatment levels, and positive values indicate an increase. PSA response was
`observed in 49% of patients, and 17% of patients achieved a PSA decline 90%.
`
`reasons for stopping treatment included adverse events
`(17%), consent withdrawal (3%), physician discretion
`(3%), and death secondary to progressive disease (3%).
`The most commonly reported treatment-related adverse
`events were constitutional in nature and included grade 1
`and 2 fatigue in 24 patients (69%), alopecia in 28 of 35
`patients (80%), nausea/vomiting in 19 of 35 patients
`(54%), edema in 15 of 35 patients (43%), and peripheral
`neuropathy in 9 of 35 patients (26%). The most common
`laboratory abnormalities included grade 1 or 2 anemia
`(40%), thrombocytopenia (9%), and elevated aspartate
`and alanine aminotransferase levels (14%) (Table 2). The
`most commonly reported, treatment-related, grade 3
`adverse events included neutropenia (34%) followed by
`fatigue (15%) and dyspnea (9%). Although there were no
`treatment-related deaths, 7 patients (20%) reported grade
`4 toxicities (neutropenia in 5 patients, febrile neutropenia
`in 1 patient, and neutropenia and thrombocytopenia in
`1 patient).
`
`DISCUSSION
`Metastatic, CRPC remains a therapeutic challenge.
`Although several novel agents are in late-stage develop-
`ment, there has been limited development beyond doce-
`
`Figure 2. This waterfall plot illustrates the maximal change
`(%) in size among tumors that were evaluable with Response
`Evaluation Criteria in Solid Tumors from baseline.11 The analy-
`sis excluded patients who had no follow-up measurements.
`Negative values indicate a decrease in measurable disease
`compared with pretreatment measurements, and positive val-
`ues indicate an increase or a new lesion. The overall response
`rate was 12% (confirmed partial responses), an additional 16%
`of patients had unconfirmed partial responses, and 60% of
`patients had stable disease.
`
`Cancer
`
`February 15, 2011
`
`755
`
`

`
`Original Article
`
`Figure 3. Overall survival is illustrated in months.
`
`taxel for patients with progressive, metastatic, CRPC.15-17
`Various phase 2 studies evaluating novel compounds
`administered in combination with docetaxel have been
`conducted.18 Challenges in terms of study design, clinical
`endpoints, and the relative significant activity of docetaxel
`have made the identification of active docetaxel-based
`regimens problematic.
`In our experience using gemcitabine combined with
`docetaxel-based chemotherapy in patients with untreated,
`metastatic CRPC, a high proportion of patients achieved
`significant PSA reductions. However, only 49% of
`patients demonstrated a PSA decline 50% compared
`with baseline. In addition, this PSA response did not
`differ substantially from that observed in the Southwest
`Oncology Group 9916 and TAX-327 studies.3,4 For the
`patients who had measurable soft tissue disease, the objec-
`tive response observed in our study was 28% (3 of 7
`patients had a confirmed partial response). Although this
`objective response rate is
`somewhat
`similar to that
`reported in previous phase 2 and 3 docetaxel-based stud-
`ies,3,4,18 the similarity is probably because of patient selec-
`tion and the inherent bias of phase 2 trial design.
`Our study results differ somewhat with the results
`from a recent phase 1/2 experience evaluating the same
`combination in patients with CRPC in which PSA and
`RECIST-defined responses were observed in 74% and
`48% of patients, respectively.19 In that study, the median
`time to progression and overall survival also were 7.9
`months and 13.9 months, respectively. These overall sur-
`vival data clearly are inferior to observations in previous
`docetaxel-based studies. Although the estimated median
`
`Table 2. Common Treatment-Related Adverse Events
`
`Adverse Event
`
`Percentage of Patients
`Grade 1 Grade 2 Grade 3 Grade 4
`
`43
`Nausea/vomiting
`37
`Taste changes
`31
`Anorexia
`26
`Diarrhea
`29
`Alopecia
`Dermatologic (nails/skin) 31
`Fatigue
`37
`Dyspnea
`20
`Edema
`34
`Neuropathy
`26
`Neutropenia
`—
`Neutropenia/fever
`3
`Infection/no neutropenia 3
`Thrombocytopenia
`6
`Anemia
`29
`Elevated AST/ALT
`17
`
`11
`6
`3
`—
`51
`11
`32
`6
`9
`—
`11
`—
`3
`3
`11
`3
`
`3
`—
`3
`1
`—
`—
`15
`9
`3
`—
`34
`—
`—
`3
`6
`—
`
`—
`—
`—
`—
`—
`—
`—
`—
`—
`—
`14
`3
`—
`3
`—
`—
`
`AST indicates aspartate aminotransferase; ALT, alanine aminotransferase.
`
`overall survival in our study was longer (19.1 months),
`our trial was limited by a lack of progression-free survival
`data, because follow-up measurements were not contin-
`ued once treatment stopped; thus, progression-free sur-
`vival based on measurable disease could not be estimated.
`In addition, ours was a single-arm, nonrandomized study,
`a design that has limitations in determining the relative
`benefit of the combination compared with other treat-
`ment strategies in this setting. In addition, we did not
`incorporate a pain or quality-of-life measurement tool,
`and the endpoints used in the study were developed before
`the Prostate Cancer Clinical Trials Working Group rec-
`ommendations of 2008.20
`Toxicity also appears to be a major limitation of this
`combination. Similar to the Danish study, we observed a
`higher incidence of myelosuppression (59%; grade 3 in
`34% of patients and grade 4 14% of patients) and fatigue
`(grade 3 only in 15% of patients) compared with other
`single-agent docetaxel trials. Similarly, a greater incidence
`of treatment delays was reported. In fact, approximately
`33% of planned cycles were delayed because of adverse
`events, and almost 15% of patients required a dose reduc-
`tion of 1 or both agents. Balancing treatment-related tox-
`icity versus clinical efficacy versus quality of life remains a
`challenge when treating patients with metastatic CRPC;
`thus, such factors should be taken into consideration
`when designing clinical trials.
`In conclusion, the current results suggest that the
`addition of gemcitabine to standard, docetaxel-based
`chemotherapy leads to significant toxicities without con-
`comitant clinical benefits over those observed with single-
`
`756
`
`Cancer
`
`February 15, 2011
`
`

`
`agent docetaxel. Current phase 3 studies evaluating the
`addition of novel targeted agents, such as bevacizumab
`and atrasentan, to standard docetaxel may provide evi-
`dence supporting the role of docetaxel-based combination
`regimens. The combination of gemcitabine and docetaxel
`has activity in metastatic CRPC but at a significant cost in
`terms of toxicity. Further development of this doublet in
`prostate cancer is not recommended.
`
`CONFLICT OF INTEREST DISCLOSURES
`Research grant support was provided by Bayer Pharmaceuticals
`(West Haven, Conn) and Onyx Pharmaceuticals (Emeryville,
`Calif).
`
`REFERENCES
`1. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ. Cancer
`statistics, 2009. CA Cancer J Clin. 2009;59:225-249.
`2. Oh WK, Kantoff PW. Management of hormone refractory
`prostate cancer: current
`standards and future prospects.
`J Urol. 1998;1160:1220-1229.
`3. Petrylak DP, Tangen CM, Hussain MH, et al. Docetaxel
`and estramustine compared with mitoxantrone and predni-
`sone for advance refractory prostate cancer. N Engl J Med.
`2004;351:1513-1520.
`4. Tannock IF, deWit R, Berry WR, et al. Docetaxel and
`prednisone or mitoxantrone and prednisone for advanced
`prostate cancer. N Engl J Med. 2004;351:1502-1512.
`5. Wong A, Soo RA, Yong WP, Innocenti F. Clinical pharma-
`cology and pharmacogenetics of gemcitabine. Drug Metab
`Rev. 2009;41:77-88.
`6. Muenchen H, Quigley M, Pilat M, et al. The study of gem-
`citabine in combination with other chemotherapeutic agents
`as an effective treatment for prostate cancer. Anticancer Res.
`2000;20:735-740.
`7. Morant R, Bernhard J, Maibach R, et al. Response and pal-
`liation in a phase II trial of gemcitabine in hormone-refrac-
`tory metastatic prostatic
`carcinoma. Swiss Group for
`Clinical Cancer Res. (SAKK). Ann Oncol. 2000;11:183-188.
`8. Mekhail T, Hutson T, Elson P, et al. Phase I trial of weekly
`docetaxel and gemcitabine in patients with refractory malig-
`nancies. Cancer. 2003;97:170-178.
`9. Poole M, Bernard S, Churchel M, et al. A phase I study of
`gemcitabine and docetaxel for advanced stage solid tumors.
`Cancer Invest. 2003;21:350-354.
`
`Gemcitabine and Docetaxel in CRPC/Garcia et al
`
`10. Dreicer R, Manola J, Schneider D, et al. Phase II trial
`of gemcitabine and docetaxel
`in patients with advanced
`carcinoma of
`the urothelium:
`a
`trial of
`the Eastern
`Cooperative Oncology Group. Cancer. 2003;97:2743-
`2747.
`11. Niho S, Kubota K, Goto K, et al. Combination second-
`line chemotherapy with gemcitabine and docetaxel
`for
`recurrent nonsmall-cell lung cancer after platinum-contain-
`trial. Cancer Chemother
`ing chemotherapy: a phase I/II
`Pharmacol. 2003;52:19-24.
`12. Pouessel D, Culine S, Becht C, et al. Gemcitabine and
`docetaxel after failure of cisplatin-based chemotherapy in
`patients with carcinoma of unknown primary site. Anti-
`cancer Res. 2003;23(3C):2801-2804.
`13. Skarlos D, Dimopoulos A, Kosmidis P, et al. Docetaxel and
`gemcitabine combination, as first-line treatment, in patients
`with extensive disease small-cell
`lung cancer. A phase II
`study of the Hellenic Cooperative Oncology Group. Lung
`Cancer. 2003;41:107-111.
`14. Therasse P, Arbuck SG, Eisenhauer EA, et al. New guide-
`lines to evaluate the response to treatment in solid tumors:
`European Organization for Research and Treatment of Can-
`cer, National Cancer Institute of the United States, National
`Cancer Institute of Canada. J Natl Cancer Inst. 2000;92:
`205-216.
`15. Attard G, Reid AH, A’Hern R, et al. Selective inhibition of
`CYP17 with abiraterone acetate is highly active in the treat-
`ment of castration-resistant prostate cancer. J Clin Oncol.
`2009;27:3742-3748.
`16. Chen Y, Clegg NJ, Scher HI. Anti-androgens and andro-
`gen-depleting therapies in prostate cancer: new agents for an
`established target. Lancet Oncol. 2009;10:981-991.
`17. Tran C, Ouk S, Clegg NJ, et al. Development of a second-
`generation antiandrogen for treatment of advanced prostate
`cancer. Science. 2009;324:787-790.
`in the manage-
`18. De Dosso S, Berthold DR. Docetaxel
`ment of prostate cancer: current
`standard of care and
`future directions. Exper Opin Pharmacother. 2008;9:1969-
`1979.
`19. Buch-Hansen TZ, Bentzen L, Hansen S, et al. Phase I/II
`study on docetaxel, gemcitabine and prednisone in castrate
`cancer. Cancer Chemother
`refractory metastatic prostate
`Pharmacol. 2010;66:295-301.
`20. Scher HI, Halabi S, Tannock I, et al. Design and endpoints
`of clinical trials for patients with progressive prostate cancer
`and castrate levels of testosterone: recommendations of the
`Prostate Cancer Clinical Trials Working Group. J Clin
`Oncol. 2008;26:1148-1159.
`
`Cancer
`
`February 15, 2011
`
`757