NIH Public Access
`Author Manuscript
`J Clin Oncol. Author manuscript; available in PMC 2014 May 05.
`
`Published in final edited form as:
`J Clin Oncol. 2008 March 1; 26(7): 1148–1159. doi:10.1200/JCO.2007.12.4487.
`
`Design and End Points of Clinical Trials for Patients With
`
`Progressive Prostate Cancer and Castrate Levels of
`
`Testosterone: Recommendations of the Prostate Cancer Clinical
`
`Trials Working Group
`
`Howard I. Scher, Susan Halabi, Ian Tannock, Michael Morris, Cora N. Sternberg, Michael A.
`
`Carducci, Mario A. Eisenberger, Celestia Higano, Glenn J. Bubley, Robert Dreicer, Daniel
`
`Petrylak, Philip Kantoff, Ethan Basch, William Kevin Kelly, William D. Figg, Eric J. Small,
`
`Tomasz M. Beer, George Wilding, Alison Martin, and Maha Hussain
`Sidney Kimmel Center for Prostate and Urologic Cancers, Memorial Sloan-Kettering Cancer
`Center, New York, NY; Duke University Medical Center, Durham, NC; Princess Margaret
`Hospital, Toronto, Ontario, Canada; Sam Camillo Forlanini Hospital, Rome, Italy; Beth Israel
`Deaconess Medical Center; Dana-Farber Cancer Center, Boston, MA; Sidney Kimmel
`Comprehensive Cancer Center at Johns Hopkins, Baltimore; National Cancer Institute, Bethesda,
`
`© 2008 by American Society of Clinical Oncology
`
`Corresponding author: Howard I. Scher, MD, Genitourinary Oncology Service, Department of Medicine, Sidney Kimmel Center for
`Prostate and Urologic Cancers, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10065;
`byczekb@mskcc.org.
`
`AUTHOR CONTRIBUTIONS
`Conception and design: Howard I. Scher, Susan Halabi, Ian Tannock, Michael Morris, Cora N. Sternberg, Michael A. Carducci,
`Mario A. Eisenberger, Celestia Higano, Glenn J. Bubley, Robert Dreicer, Daniel Petrylak, Philip Kantoff, Ethan Basch, William D.
`Figg, Eric J. Small, Alison Martin, Maha Hussain
`Provision of study materials or patients: Howard I. Scher
`Collection and assembly of data: Howard I. Scher, Mario A. Eisenberger, Celestia Higano, Tomasz M. Beer, Alison Martin
`Data analysis and interpretation: Howard I. Scher, Michael Morris, Michael A. Carducci, Mario A. Eisenberger, Glenn J. Bubley,
`Robert Dreicer, Philip Kantoff, William Kevin Kelly, William D. Figg, Tomasz M. Beer, George Wilding, Alison Martin, Susan
`Halabi, Maha Hussain
`Manuscript writing: Howard I. Scher, Susan Halabi, Ian Tannock, Michael Morris, Cora N. Sternberg, Michael A. Carducci, Mario
`A. Eisenberger, Celestia Higano, Glenn J. Bubley, Robert Dreicer, Ethan Basch, William Kevin Kelly, William D. Figg, Eric J. Small,
`Tomasz M. Beer, Alison Martin, Maha Hussain
`Final approval of manuscript: Howard I. Scher, Susan Halabi, Ian Tannock, Cora N. Sternberg, Michael A. Carducci, Mario A.
`Eisenberger, Celestia Higano, Glenn J. Bubley, Robert Dreicer, Daniel Petrylak, Philip Kantoff, Ethan Basch, William Kevin Kelly,
`William D. Figg, Eric J. Small, Tomasz M. Beer, George Wilding, Alison Martin, Maha Hussain
`
`AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
`Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant
`to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation
`was received; those relationships marked with a “C” were compensated. For a detailed description of the disclosure categories, or for
`more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of
`Potential Conflicts of Interest section in Information for Contributors.
`Employment or Leadership Position: None Consultant or Advisory Role: Ian Tannock, sanofi-aventis (U), Algeta ASA (U), GPC
`Biotech (U); Michael A. Carducci, Abbott Laboratories (C), sanofi-aventis (U), Methylgene (C), Cougar Biotech (C); Mario A.
`Eisenberger, sanofi-aventis (C), GPC (C), Celgene (C); Robert Dreicer, Merck (C), sanofi-aventis (C), Bristol-Myers Squibb (C);
`Daniel Petrylak, Aventis (C), GPC Biotech (C), Abbott Laboratories (C); Eric J. Small, Cougar Biotechnology (C), Poniard
`Pharmaceuticals (C); Tomasz M. Beer, Novacea (C) Stock Ownership: Tomasz M. Beer, Novacea Honoraria: Michael A. Carducci,
`sanofi-aventis, Abbott Laboratories; Mario A. Eisenberger, sanofi-aventis, Ipsen, GPC; Robert Dreicer, Berlex; Daniel Petrylak,
`Aventis, Celegene, Abbott; William Kevin Kelly, sanofi-aventis, Genetech; Tomasz M. Beer, sanofi-aventis Research Funding: Ian
`Tannock, sanofi-aventis, Novacea; Mario A. Eisenberger, sanofi-aventis, Clegene, Cytogen; Robert Dreicer, sanofi-aventis, Eli Lilly,
`Millenium; Daniel Petrylak, Aventis, Celegene, GPC Biotech; William Kevin Kelly, sanofi-aventis, Genetech, Curagen; Eric J. Small,
`Dendreon, Novartis; Tomasz M. Beer, sanofi-aventis Expert Testimony: None Other Remuneration: None
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`MD; University of Washington, Seattle, WA; Cleveland Clinic, Cleveland, OH; Columbia
`Presbyterian Medical Center, New York, NY; Yale Cancer Center, New Haven, CT; UCSF
`Comprehensive Cancer Center, San Francisco, CA; Oregon Health and Science Universeity,
`Portland, OR; University of Wisconsin Comprehensive Cancer Center, Madison, WI; and
`University of Michigan Comprehensive Cancer Center, Ann Arbor, MI
`
`Abstract
`
`Purpose—To update eligibility and outcome measures in trials that evaluate systemic treatment
`
`for patients with progressive prostate cancer and castrate levels of testosterone.
`
`Methods—A committee of investigators experienced in conducting trials for prostate cancer
`
`defined new consensus criteria by reviewing previous criteria, Response Evaluation Criteria in
`
`Solid Tumors (RECIST), and emerging trial data.
`
`Results—The Prostate Cancer Clinical Trials Working Group (PCWG2) recommends a two-
`
`objective paradigm: (1) controlling, relieving, or eliminating disease manifestations that are
`
`present when treatment is initiated and (2) preventing or delaying disease manifestations expected
`
`to occur. Prostate cancers progressing despite castrate levels of testosterone are considered
`
`castration resistant and not hormone refractory. Eligibility is defined using standard disease
`
`assessments to authenticate disease progression, prior treatment, distinct clinical subtypes, and
`
`predictive models. Outcomes are reported independently for prostate-specific antigen (PSA),
`
`imaging, and clinical measures, avoiding grouped categorizations such as complete or partial
`
`response. In most trials, early changes in PSA and/or pain are not acted on without other evidence
`
`of disease progression, and treatment should be continued for at least 12 weeks to ensure adequate
`
`drug exposure. Bone scans are reported as “new lesions” or “no new lesions,” changes in soft-
`
`tissue disease assessed by RECIST, and pain using validated scales. Defining eligibility for
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`prevent/delay end points requires attention to estimated event frequency and/or random
`
`assignment to a control group.
`
`Conclusion—PCWG2 recommends increasing emphasis on time-to-event end points (ie, failure
`
`to progress) as decision aids in proceeding from phase II to phase III trials. Recommendations will
`
`evolve as data are generated on the utility of intermediate end points to predict clinical benefit.
`
`INTRODUCTION
`
`Evaluating drugs to treat prostate cancer poses unique challenges. Measurable disease
`
`occurs infrequently, the natural history may be prolonged over decades, and because the
`
`treatment population is elderly, pursuing aggressive therapies may cause more harm than
`
`good. In 1999, the Prostate-Specific Antigen Working Group (PCWG1) addressed these
`challenges in their consensus recommendations for the conduct of clinical trials.1 They
`focused on trial development for patients with metastatic prostate cancer whose disease was
`
`progressing despite castrate levels of testosterone and defined eligibility and outcome
`
`measures based on clinically relevant end points, and proposed standards for the use of
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`prostate-specific antigen (PSA). In 2000, a broader collective of cancer researchers
`
`introduced New Guidelines to Evaluate the Response to Treatment in Solid Tumors
`(Response Evaluation Criteria in Solid Tumors [RECIST]).2 This international initiative
`sought to standardize criteria to assess tumor response in trials for all solid tumors. Although
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`RECIST served some cancer swell, its metrics did not capture some key characteristics of
`prostate cancer.3 For example, post-therapy changes in PSA, a routinely reported outcome in
`prostate cancer clinical trials and the primary focus of PCWG1, were not addressed by
`
`RECIST. In fact, none of the approved treatments for patients with prostate cancer would be
`
`available if trial outcomes were based solely on either the PCWG1 criteria or RECIST.
`
`Since these two initiatives were introduced, the biology and natural history of prostate
`
`cancer have become better understood, and diverse new therapies, including bone-targeted
`
`agents and signaling inhibitors, have become available for clinical testing. In 2004, the US
`
`Food and Drug Administration (FDA) challenged the prostate cancer clinical trials
`
`community to rework the eligibility and outcome measures from PCWG1 so they could be
`
`applied across the clinical spectrum of the disease. The subsequent process prompted the
`
`formation of the Prostate Cancer Clinical Trials Working Group (PCWG2), a collective of
`
`international investigators who developed this report through meetings and electronic
`
`communication.
`
`This article addresses clinical trials for patients with progressive prostate cancer despite
`
`castrate levels of testosterone and frames clinical trial questions for agents that act by
`
`diverse mechanisms. The consensus is that researchers should adopt a paradigm in which
`
`trial objectives are defined on the basis of controlling, relieving, or eliminating disease
`
`manifestations that are present when treatment is initiated, and/or of preventing or delaying
`
`disease manifestations expected to occur. This new paradigm expands the focus of prostate
`
`cancer clinical trials from traditional outcome measures such as early changes in PSA to
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`time-to-event end points that capture the impact of treatment on important clinical
`
`manifestations and indicate when a drug should be stopped as the measure of antitumor
`
`effect. It also recommends standardized criteria for assessing patients. A goal of these
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`recommendations is to ensure that a drug is not discontinued because of inappropriate
`
`outcome measures before it has had a chance to work.
`
`Although the intent of these guidelines is to maximize the ability of phase II trials to screen
`
`or select promising therapies, the eligibility and outcome measures have broad applicability
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`and are relevant to the design and conduct of phase III trials. Incorporation of similar
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`parameters into phase III trials assessing overall survival is encouraged to generate the
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`databases that will allow validation or refinement of the intermediate end points proposed
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`herein.
`
`I. CONCEPTUALIZING THE DISEASE
`
`Investigators need to adopt a common language to categorize the clinical spectrum of
`
`prostate cancer from diagnosis to metastasis. When PCWG1 was published, no common
`
`vocabulary was broadly accepted. PCWG2 categorizes the disease continuum of prostate
`
`cancer on the basis of whether metastases are detectable (clinically or by imaging) and
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`whether the serum testosterone level is in the castrate range by a surgical orchiectomy or
`medical therapy (Fig 1).3,4 Each state on this continuum represents a scenario encountered
`routinely in clinical practice.
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`The clinical-states model identifies patients with distinct prognoses who might benefit (or
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`not) from specific therapeutic approaches. The rising PSA states (castrate and noncastrate)
`
`signify that no detectable metastatic disease was found in the past or is now present. The
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`clinical metastases states (castrate and noncastrate) signify that disease was detectable at
`
`some point in the past, regardless of whether it is detectable now. Along this disease
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`continuum, a patient can only advance. For example, a patient with radiographically evident
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`bone metastases at diagnosis would be assigned to the clinical metastases–noncastrate
`
`disease state. If that patient is treated with androgen depletion, no longer has
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`radiographically evident disease, and has a PSA level that is not rising, he remains
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`categorized in the clinical metastases–noncastrate state.
`
`II. DEFINING THERAPEUTIC OBJECTIVES
`
`Since the publication of PCWG1 criteria, clinical investigators have used them to define the
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`primary end points for phase II trials for prostate cancer patients with progressive,
`
`castration-resistant disease. These trials are designed to demonstrate whether the therapeutic
`
`effects observed justify further evaluation in large-scale phase III trials. Phase III trials
`
`characterize the risk/benefit profile of the treatment in relation to either a placebo or
`
`established standards, such as time to clinically relevant progression, survival, or quality of
`
`life. The clinical-states model offers investigators a framework to standardize phase II end
`
`points to appropriately inform phase III end points.
`
`PCWG2 distinguishes two types of phase II trial objectives: (1) those based on controlling,
`
`relieving, or eliminating disease manifestations that are present when treatment is initiated,
`
`and (2) those based on preventing or delaying future disease manifestations. Traditional
`
`measures of response reflect when a treatment is working; measures of progression indicate
`
`when a drug should be stopped. Because of the uncertainties associated with assessing
`
`response in bone and the controversy surrounding the clinical significance of post-therapy
`
`changes in PSA, PCWG2 recommends expanding the focus of phase II trials from measures
`
`of response to measures of progression. For most agents, a reliably determined, clinically
`
`relevant improvement in time to progression provides the most useful way to assess whether
`
`to proceed from a phase II to a phase III trial and may, if reproduced in a randomized,
`
`controlled trial, be evidence of clinical benefit from a regulatory perspective.
`
`The drug evaluation pathways for cytotoxic and noncytotoxic agents need to be developed
`
`separately. Cytotoxic drugs typically produce a decline in PSA and regression of target
`
`lesions, whereas agents that act to slow tumor growth, inhibit destruction of bone, or inhibit
`
`angiogenesis may not. For example, a bone-directed therapy may prevent disease-related
`
`complications in the skeleton without influencing the growth of soft-tissue disease.
`
`Depending on the agent and the study, PCWG2 recommends that the effects of cytotoxic
`
`drugs be assessed with both control/relieve/eliminate or prevent/delay end points, and
`
`noncytotoxic drugs with prevent/delay end points.
`
`Changes in existing manifestations of disease provide signals whether or not a treatment has
`
`produced an antitumor effect at an early stage, even though such changes may not
`
`necessarily signify clinical benefit. For example, a declining PSA level may be useful to
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`screen for the activity of a cytotoxic agent, even though it does not mean that the patient will
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`live longer. However, when designing trials with control, relieve, or eliminate end points for
`
`patients with symptoms, it is often difficult to distinguish whether a symptom is related to
`
`the cancer, prior treatment, comorbidities, or a combination of factors.
`
`Patients who lack discernible disease manifestations (eg, symptomatic bone pain), may be
`
`enrolled onto trials with prevent or delay end points that seek to prevent symptoms from
`
`occurring in the future. Manifestations that may occur in the future include growth at an
`
`existing site of disease, spread to additional sites, an increase in markers, new disease-
`
`related symptoms (eg, pain or other skeletal events), and death resulting from disease. The
`
`success of trials evaluating prevent or delay end points depends on the ability to define a
`
`patient cohort with a defined probability of developing the manifestations that the treatment
`
`is designed to prevent and in what time frame. Biases in interpreting the significance of
`
`time-to-event end points in phase II trials have been well described and support the case for
`randomized trial designs.5 Regardless of the end point, it is essential that the trial be
`designed in a way that does not allow a drug to be discontinued prematurely on the basis of
`
`criteria that do not reflect that the treatment was ineffective or failed to benefit the patient.
`
`III. ESTABLISHING ELIGIBILITY FOR ENROLLMENT
`
`After defining the primary end points of efficacy (either control/relieve/eliminate or prevent/
`
`delay), investigators can effectively set eligibility criteria. PCWG1 restricted enrollment in
`
`trials to patients with progressive disease despite castrate levels of testosterone, based on
`
`changes in PSA, measurable disease, and bone scan, while controlling for antiandrogen
`
`withdrawal responses to avoid the potential erroneous misattribution of response to a study
`
`agent. PCWG2 modifies these eligibility criteria by authenticating disease with standardized
`
`assessments, considering the prior treatment history in more detail, defining distinct clinical
`
`subtypes, and highlighting the importance of predictive models for future clinical events.
`
`The demonstration of a survival benefit in a phase III trial and a confirmatory trial7 led to
`the approval of docetaxel in 2004.6 Since then, clinical trials for patients with castrate
`metastatic disease are being designed in three contexts: before receiving treatment with
`
`docetaxel, with agents in combination with docetaxel to improve first-line outcomes, and as
`
`second-line treatment for patients with disease that has progressed despite docetaxel.
`
`Independent of the context, PCWG2 recommends defining therapeutic objectives in relation
`
`to the mechanism of action of the agent under study, documenting disease manifestations at
`
`the time treatment is started (Table 1), and serially evaluating patients post-treatment using
`
`standard assessments that relate to the objectives of the trial.
`
`Authenticating Disease Progression
`
`Authenticating disease progression is achieved by establishing standard pretreatment
`
`assessments and identifying standard criteria for disease progression for entry.
`
`Pretreatment assessments—PCWG1 did not define a standard pretreatment
`
`evaluation, so PCWG2 builds on the standards for base-line evaluations recommended by
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`RECIST and provides guidelines for imaging and symptom assessment.
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`Baseline evaluations—Baseline evaluations should be tailored both to target outcome
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`measures and to contribute to the development of prognostic factors or other research
`
`questions. For the baseline evaluation, PCWG2 recommends documenting patient
`
`demographics, including age and performance status, clinical stage, PSA and Gleason score
`
`at the time of diagnosis, details and dates of the primary therapy (eg, pathologic stage and/or
`
`dose and type of radiation therapy as appropriate), and post-treatment PSA nadir. Details
`
`and dates of prior hormonal and nonhormonal therapies should be recorded, along with
`
`additional PSA measurements that can be used to estimate PSA doubling times (PSA-DTs).
`
`The presence or absence of disease in the primary site should also be documented.
`
`Imaging—PCWG2 pretreatment evaluations include imaging of the chest by plain
`
`radiograph or computed tomography (CT), a CT scan or magnetic resonance imaging (MRI)
`
`of the abdomen/pelvis, and radionuclide bone scan. To assess local disease, PCWG2
`
`suggests an endorectal MRI or ultrasound of the prostate or prostate bed. For those with
`
`symptoms of neurologic compromise, PCWG2 recommends MRI of the spine and base of
`
`the skull. PCWG2 also recognizes that detecting metastases will improve as more sensitive
`
`imaging tests become standard, but does not recommend positron emission tomography
`
`(PET) using fluorodeoxyglucose or other tracers and ProstaScint (Cytogen Corp, Princeton,
`
`NJ) scanning because they are considered investigational at this time.
`
`Symptoms and health-related quality of life—When enrolling a patient onto a
`
`clinical trial that incorporates symptoms and health-related quality of life, symptoms of
`
`disease should be characterized at baseline using validated instruments according to
`standards defined by the FDA in its guidance for patient-reported outcomes.8 The evaluation
`should include confirmation that patient input was included during development of the
`
`measure(s); that the content and the construct were validated; and that the measure(s) were
`
`reliable for the population being studied. A lead-in period of observation is advised to ensure
`
`adequate baseline assessments. Potentially relevant domains include pain, fatigue, anorexia/
`weight loss, constipation, and urinary symptoms.6,8
`
`The use of pain relief as a trial end point may be particularly valuable because the presence
`of pain is a known prognostic factor for survival,9 and palliation of symptoms is a
`therapeutic goal. An acceptable criterion for trial enrollment is new pain in an area of
`
`radiographically evident disease. Pain measures in particular should include assessments of
`
`intensity, frequency, and duration quantified (eg, on a five-point scale such as the McGill-
`
`Melzack Pain Questionnaire or IMMPACT [Initiative on Methods, Measurement, and Pain
`Assessment in Clinical Trials] recommendations).10 Level of bother, location(s), likely
`relationship to prostate cancer (v prior therapy or comorbidities), and analgesic requirements
`
`should also be recorded.
`
`Health-related quality of life can also be evaluated through patient self-reported instruments
`
`that have been developed in keeping with the FDA guidance. In addition to assessing
`
`selected symptoms, these instruments may emphasize the effects of disease on physical,
`
`social, psychological/emotional, and cognitive functioning. New instruments should also be
`
`developed, recognizing that validation is laborious and is generally outside the realm of a
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`phase II trial.
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`Criteria for disease progression—PCWG1 defined progression criteria for enrollment
`
`on the basis of changes in PSA, bone metastases, and measurable disease. PCWG2 retains
`
`most of the original recommendations with modifications (Table 2).
`
`PSA—For patients who manifested disease progression solely as a rising PSA level,
`
`PCWG1 required obtaining a sequence of rising values at least 1 week apart and made 5.0
`ng/mL the minimum starting level for trial entry (Table 2).1 PCWG2 keeps the timing of
`PSA testing at a minimum of 1-week intervals and recommends reducing the threshold PSA
`
`level from 5.0 ng/mL to 2.0 ng/mL because of the availability of more sensitive assays (Fig
`2). Given the prognostic significance of the rate of rise in PSA,11 PCWG2 advises
`estimating a pretreatment PSA-DT11a if at least three values are available, but does not
`recommend delaying either treatment or enrollment onto a trial simply to estimate PSA-
`DT.11a
`
`Target (nodal and visceral) lesions or measurable disease—A requirement of
`
`measurable lesions (target lesions as defined by RECIST) for trial entry is not recommended
`
`by PCWG2 because it shifts the emphasis from bone metastases, which develop in upwards
`
`of 90% of patients, to lymph nodes, which occur in only 20% to 25% of patients with
`prostate cancer and contribute less to morbidity than do other sites of metastases.3 The result
`is that much energy might be wasted on an end point of lesser clinical significance. That
`
`said, however, trials that are collecting data on measurable lesions should follow RECIST,
`
`and progression in a nodal or visceral site is sufficient to document disease progression.
`
`PCWG2 advises recording the presence or absence of nodal and visceral disease (ie, liver
`
`and lung) pretreatment and outcomes post-treatment separately. Up to 10 visceral and nodal
`lesions in total should be recorded (with a maximum of five in any one organ),2 although, in
`one series, the median number of target lesions was three.3 Because small lymph nodes are
`difficult to measure accurately and may not be malignant, PCWG2 recommends that the
`
`greatest diameter of a lymph node must measure at least 2 cm by spiral CT to be considered
`a target lesion.3
`
`The prostate (primary site)—PCWG2 recommends both recording the treatments that
`
`targeted the primary tumor and performing directed pelvic imaging to determine whether
`
`disease is present in this area at the time of enrollment. This should include a CT scan or
`
`MRI at a minimum, and, in centers with the relevant expertise, endorectal MRI or transrectal
`
`ultrasound. A prostate mass or recurrence in the prostate bed is not considered metastatic
`
`disease; many develop in cases where the surgical margins were positive or there was
`
`extracapsular extension.
`
`Bone—Even with the improved imaging modalities that have developed since the
`
`publication of PCWG1, it is difficult to interpret the clinical significance of changes in size
`
`or intensity of bone metastases on bone scan. When the bone scan is the sole indicator of
`
`progression, PCWG2 defines progression in bone when at least two or more new lesions are
`
`seen on bone scan compared with a prior scan for trial entry. In situations where the scan
`
`findings are suggestive of a flare reaction, or apparent new lesion(s) may represent trauma, it
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`may prove useful to confirm these results with other imaging modalities such as MRI or
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`fine-cut CT. Confirmation is generally not necessary if multiple new areas of uptake are
`
`observed. Consistent criteria for progression of disease in bone using PET and MRI are still
`
`under investigation.
`
`Other sites of disease—PCWG2 recommends that patients who meet other trial criteria
`
`may be enrolled if they have epidural disease that has been treated and there is no
`
`progression in the treated area. Aside from epidural lesions, other nontarget lesions
`
`considered by RECIST (including leptomeningeal spread, ascites, pleural/pericardial
`
`effusions, and abdominal masses not confirmed) are rare in prostate cancer.
`
`Evaluating hormonal status and prior systemic therapies—Equally important as
`
`pretreatment assessments and in defining disease progression is to evaluate and record
`
`historical factors that may affect sensitivity to treatment.
`
`Prior hormonal interventions—PCWG2 considers a “hormonal intervention” the
`
`addition or discontinuation of a hormonal therapy with therapeutic intent because of disease
`
`progression. Androgen depletion that is discontinued and restarted as part of a planned
`
`intermittent or cycling approach is considered a single intervention independent of the
`
`number of cycles. PCWG2 recommends that investigators record the prior hormonal
`
`interventions received by a patient by documenting the number, type, and duration of
`
`administration when available. Although most patients treated with gonadotropin-releasing
`
`hormone (GnRH) analog therapy initially or subsequently receive an antiandrogen, many do
`
`not. The duration of administration may be as short as 1 month in some and continuous in
`
`others. Because a range of outcomes have been reported for secondary hormonal
`
`manipulations. PCWG2 advises classifying tumors that are progressing with castrate levels
`of testosterone as “castration resistant”12; and not “hormone refractory” because many
`patients respond to second- and third-line hormonal therapies. Patients who are receiving
`
`antiandrogens as monotherapy and have noncastrate testosterone levels should receive
`
`testosterone-lowering therapy before being considered for trial.
`
`Serum testosterone levels—PCWG1 defined castrate status as a serum testosterone
`
`level of less than 50 ng/dL (< 1.7 nmol/L). It is now recognized that the measured level of
`testosterone in the blood may not accurately reflect intratumoral androgen levels,13,14,14a
`which are often sufficient to stimulate tumor growth. Sources include the adrenal glands or
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`the tumor itself as a result of the upregulation of the genes involved in androgen
`synthesis.15,16 Recognizing that some patients have higher testosterone levels despite
`continued androgen depletion with GnRH analog therapy, and that total testosterone levels
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`do not reflect bioavailable testosterone because of the variation in the levels of sex hormone-
`
`binding globulin and the laboratory-to-laboratory variation in the measurement of hormone
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`levels, PCWG2 retains the maximal serum testosterone level of 50 ng/dL (1.7 nmol/L) for
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`entry. PCWG2 also reaffirms that castrate status be maintained for any patient who has not
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`undergone surgical orchiectomy by continued GnRH analog administration, recognizing
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`that, in some patients, testosterone levels might remain suppressed if GnRH analog therapy
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`were discontinued.
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`J Clin Oncol. Author manuscript; available in PMC 2014 May 05.
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`NIH-PA Author Manuscript
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`NIH-PA Author Manuscript
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`NIH-PA Author Manuscript
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`MYLAN PHARMS. INC. EXHIBIT 1124 PAGE 8
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`Scher et al.
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`Page 9
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`Antiandrogen discontinuation responses—To avoid misattributing benefit to a study
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`agent, PCWG1 required documenting progressive disease after discontinuing antiandrogen
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`treatment. However, because the time to completely withdraw from the treatment can range
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`from 4 to 8 weeks, depending on the half-life of the antiandrogen, many otherwise eligible
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`patients were not included in clinical trials. Withdrawal responses typically occur in patients
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`who are treated with combined androgen blockade (a GnRH analog or orchiectomy in
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`combination with continuous antiandrogen) as initial therapy for a prolonged period of time,
`or who have responded to adding a peripheral antiandrogen as second-line therapy.17 For
`these situations, PCWG2 recommends evaluating patients for withdrawal responses.
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`PCWG2 advises investigators not to wait to assess for a withdrawal response in patients who
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`did not respond or who showed a decline in PSA for 3 months or less after an antiandrogen
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`was administered as a second-line or later intervention.
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`Prior nonhormonal therapies—All of the treatments for local disease (surgery,
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`radiation therapy, and so on) should be recorded. Other systemic therapies (eg, first-line
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`docetaxel and/or biologic agents) should also be described in detail, including the response,
`the reason for discontinuation, and the interval off treatment.18
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`Clinical Subtypes Based on Patterns of Spread
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`Investigators can enhance eligibility guidelines by defining clinical subtypes based on the
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`patterns of spread. PCWG1 defined four patient cohorts: (1) progressive measurable disease;
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`(2) progressive bone metastases; (3) increasing PSA and stable metastases; and (4)
`increasing PSA and no metastatic disease.1 This classification does not reflect the pattern of
`spread of disease, nor does it separate patients on the basis of prognosis, more favorable for
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`patients in the rising-PSA–castrate state with no documented metastatic disease at present or
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`in the past, and worse for patients with visceral disease. In response, PCWG2 defines five
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`patient cohorts (Table 3) that include a poor prognostic group with visceral disease, a group
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`with bone metastases with or without nodal metastases but no visceral organ disease, a
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`group with nodal disease and no visceral or bone disease, an