In Focus: Prostate Cancer
`
`ECOG 3805: CHAARTED—-
`
`ChemoHormonal Therapy versus
`Androgen Ablation Randomized
`Trial for Extensive Disease in
`
`Prostate Cancer
`
`Christopher]. Sweeney, MBBS
`Associate Professor, Department of Medicine
`lndiana Uruversny
`
`Background
`
`Although testing for prostate—specific antigen (PSA) has
`enabled earlier diagnosis of prostate cancer, it is unclear
`whether the overall incidence and mortality rates have
`declined as a result;
`the most recent data indicate an
`
`incidence of approximately 230,000 cases per year with
`30,000 deaths per year.‘
`The current treatment for individuals presenting with
`hormone-naive metastatic prostate cancer
`is hormone
`ablation either alone or in combination with antiandro-
`
`times varying depending on
`gen therapy, with survival
`the extent of disease at treatment initiation. PSA testing
`has resulted in identifying earlier disease that has relapsed
`after surgery or radiation therapy (ie, prior to disease
`being seen by imaging modalities). However, it is unclear
`whether the use of androgen deprivation prior to iden-
`tification of overt metastatic disease is advantageous. If
`androgen deprivation is instituted for PSA-only relapse,
`the earlier diagnosis results in a longer exposure to the
`toxic effects of androgen ablation, which include osteopo-
`rosis. Moreover, the median time from PSA relapse after
`definitive local therapy to development of overt metastatic
`disease is approximately 8 years among patients who are
`observed (ie, if androgen deprivation is delayed)? Once
`hormonal therapy is instituted at the time of development
`of metastatic disease, the median time to progression is
`2—3 years?
`Patients with overt metastases are currently treated
`with androgen ablation therapy alone and followed
`until disease progression; most patients continue to
`
`Broadcast
`
`those
`receive androgen deprivation indefinitely. Of
`with metastatic disease, patients with a high metastatic
`burden (“extensive disease") have a poorer prognosis,
`with a median time to PSA progression of approximately
`10 months and a median time to clinical progression (eg,
`worsening ofbone metastases) of about 14 months.“ The
`median overall survival among patients with extensive
`disease is about 24 months, compared to 5 years among
`patients with minimal disease. Clearly, improved thera-
`peutic options are needed.
`Currently, chemotherapy is employed only after
`hormonal
`therapy is no longer effective. At this stage,
`chemotherapy is palliative, and prolongs survival of
`patients with hormone—refractory disease slightly. Many
`agents have been evaluated for the treatment ofhormone—
`refractory prostate cancer (HRPC) and only recently has
`a clear survival advantage been realized with the use of
`docetaxel (Taxotere, Sanofi-Aventis). Two large phase III
`trials—Southwest Oncology Group 9916 and TAX327—
`found that patients with HRPC treated with a docetaxel-
`based chemotherapy regimen experienced a statistically
`significantly improved serologic response and overall
`survival compared to patients treated with mitoxantrone
`plus prednisone."'7
`Eastern Cooperative Oncology Group (ECOG)
`trial 3805 will determine whether starting chemotherapy
`simultaneously with hormonal therapy can delay the time
`to progression without detriment to quality of life in
`men with extensive disease (defined as four or more bony
`metastases with at least one involving the appendicular
`skeleton and/or visceral metastases). All patients will be
`treated with androgen ablation but daily prednisone will
`not be administered with doeetaxel in order to minimize
`
`the toxicity associated with chronic low—dose steroid
`exposure. It is intended that this approach will not only
`make the treatment regimen more tolerable, but will also
`remove prednisone as a confounding variable.
`The rationale for this approach is that starting che-
`motherapy simultaneously with hormonal therapy may
`be rnore effective for treating small—volun1e disease not
`eradicated by androgen deprivation than it generally is for
`treating later—stage disease (ie, HRPC), and, additionally,
`it may prolong the time to progression and thus disease
`control. However,
`it may be that early chemotherapy
`is made less effective by androgen deprivation, which
`removes cells outside the cell cycle. This issue can only be
`addressed through a randomized phase Ill study.
`
`fa.J
`>525
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`Clinical Advances in Hematology & Oncology Volume 4, Issue 8 August 2006
`Th is material was mpied
`at the NLMaN:l may be
`§Ll.bj~EsE11 US{.t3p'yv'ight Laws
`
`JANSSEN EXHIBIT 2157
`Wockhardt v. Janssen IPR2016-01582
`
`

`

`trial evaluating
`A previottsly conducted clinical
`androgen deprivation versus androgen deprivation plus
`docetaxel-based chemotherapy found a longer time to PSA
`progression among patients receiving chemohot'monal
`therapy compared with hormonal therapy alone (19 vs 10
`months, respectively) among patients with high-volume
`disease (11:64). At the time of data analysis, there was no
`improvement in time to PSA progression among patients
`with low-volume disease (11:50) and no improvement in
`overall survival in either patient group (personal c0mmt1—
`nication, Randall Millikan).
`
`References
`
`1. Jemal A, Tiwari RC, Murray'l', et al. Cancer statistics, 2004. CA Czmcer] Clin.
`2001l;5/1:8-2‘).
`2. Pound CR. l’artin /NV, Eisenlverger MA. et :11. Natural history ofprogtession alter
`1’SA elevation following radical prostatectomy.j/1/ll/1. 1999;281:1591-1597.
`3. Maximum androgen blockade in atlvancetl prostate cancer: an overview of
`the randomised trials. Prostate Cancer iliialists’ Collaborative Group. Lrmeet.
`2000;355:1491-1498.
`Ii.
`liisenberger MA, liltnnenstein BA. Crawford E1), or al. 13ilateral orchieetomy
`with or without llutamide for metastatic prostate cancer [see comments]. Nflnglf
`/Wet/. 1998;339:1036-1042.
`5. Crawford ED, Eixenberger MA, McLeod DG, er al. A controlled trial of leu-
`prolide with and without llutamitle in prostatic carcinoma [published erratum
`appears in Nlfnglj/VIM’. 1989;321:1420]. NEng[] Mal. 1989;321:419-/124.
`6.
`l’etrylal< D1’, Tangen CM, Hussain MH. et al. Docetaxel and estramustine com-
`pared with mitoxantrone and prednisone for advanced refractory prostate cancer.
`NE7Ig[] /Wed. 2004;351:1513-1520.
`7. Tannock 117, de Wit R. lierry W/R. et al. Docetaxel plus prednisone or mitoxantrone
`plus prcdnisone for advanced prostate cancer. Nfnglj/We//. 2004;351:1502-1512.
`
`Objectives
`
`Primzzry
`To evaluate the ability of early chemotherapy to improve
`overall survival in men commencing androgen depriva-
`tion therapy for metastatic prostate cancer
`
`Secondary
`° To determine whether early chemotherapy can increase
`any of the following compared to hormonal therapy
`alone:
`time to clinical progression;
`time to develop-
`ment of hormone—refractory disease; time to serologic
`progression
`
`To determine rates of biochemical response at 6 and
`12 months in the chemohormonal therapy versus hor-
`monal monotherapy arms
`
`To determine the frequency of adverse events and the
`tolerability of chemotherapy combined with hormonal
`therapy versus hormonal therapy alone
`
`the postulated clinically
`determine whether
`To
`meaningful increase in disease control is associated with
`an alteration in overall quality of life
`
`To determine if PSA changes can serve as a surrogate for
`clinical benefit from therapy and overall survival
`
`Basic Eligibility Criteria
`
`° Histologically or cytologically confirmed prostate can-
`cer with extensive metastatic disease with plans to start
`androgen deprivation therapy
`
`platelet
`count 21,500/mmz;
`0 Absolute neutrophil
`total bilirubin S upper limit
`count 2100,000/mmz;
`of normal (ULN); alanine aminotransferase S 2.0 x
`
`ULN; creatinine clearance 230 ml/min; prothrombin
`time,
`international normalized ratio 51.5 x ULN
`
`if on therapeutic anticoagulation); partial
`(except
`thromboplastin time $1.5 x ULN (except if on thera-
`peutic anticoagulation)
`
`More than 4 weeks since major surgery and recovered
`from all toxicity prior to beginning protocol therapy
`
`° No adjuvant or neoadjuvant hormonal therapy within
`12 months prior to starting protocol therapy; no more
`than 24 months of hormonal therapy total; no evidence
`of disease at least 12 months after completing adjuvant
`or neoadjuvant hormonal therapy
`
`° No prior adjuvant or neoadjuvant chemotherapy
`
`Clinical Advances in Hematology & Oncology Volume 4, Issue 8 August 2006
`
`589
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`

`

`Schema
`
`Stratification:
`
`0 Age (270 yr vs <70 yr)
`- ECOG PS (0-1 vs 2)
`0 CAB > 30 d (yes vs no)
`- Prior adjuvant hormonal therapy (>12 mo vs :12 mo)
`0 Bisphosphonates (yes vs no)
`
`Randomization
`
`A
`
`Arm B:
`
`Androgen deprivation alone
`
`V
`lirvaluate q1f28wk
`
`' 1
`
`Y
`
`0 Follow for time to progression
`and overall survival
`
`0 Chemotherapy at
`investigator's discretion at
`progression
`
`Arm A:
`
`Androgen deprivation +
`docetaxei 75 mg/m2 q21d x 6
`
`‘V
`
`7* WA
`
`Evaluate q3wk while receiving
`docetaxei and at wk 24, then
`q12wk
`
`l V
`
`A
`
`"
`‘” ‘
`- Follow for time to progression
`and overall survival
`
`0 Chemotherapy at
`investigator's discretion at
`progression
`
`' ECOG performance status (PS) 0-2
`
`Targeted Accrual
`
`568 patients.
`
`Contact Information
`
`Chairperson: Christopher J. Sweeney, MBBS
`317-2746515
`
`chsweene@iupui.edu
`
`Patient enrollment: Cancer Trial Support Unit Data Operations Center,
`888-691-8039.
`
`5
`
`90
`
`Clinical Advances in Hematology & Oncology Volume 4, Issue 8 August 2006
`
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