Editorial
`
`Oliver Sartor, MD
`Dana-Farber Cancer Institute
`Harvard Medical School
`Boston, MA
`
`The Continuing Challenge of Hormone-Refractory Prostate Cancer
`
`Data from 2 prospective randomized trials (TAX 327 and
`Southwest Oncology Group 9916) using docetaxel-based
`chemotherapy have demonstrated prolongation of survival in
`patients with hormone-refractory prostate cancer (HRPC). Nearly
`2 years have passed since these data were first presented at the
`American Society of Clinical Oncology Annual Meeting, and it is
`time to reexamine the progress and lack thereof since that time.
`First, how do we define hormone-refractory disease? This
`issue has been addressed in a consensus statement,1 but the sim-
`plest and most pragmatic definition of this disease state is “pro-
`gressive” prostate cancer despite “castrate” levels of testosterone.
`Castrate testosterone levels have typically been defined as being
`< 50 ng/dL; progression can occur under a variety of different
`guises; however, for patients who are sequentially monitored by
`prostate-specific antigen (PSA) levels, scans, histories, and phys-
`ical examinations, an increasing PSA level is the first evidence of
`progression in the vast majority of cases. Most patients today are
`serially and closely monitored with PSA measurements; conse-
`quently, some threshold for PSA change is required to declare
`progression. This number is not consensus driven at this
`time; however, a number of clinical trials in HRPC have eli-
`gibility criteria that include a PSA increase of ≥ 1-5 ng/mL
`to ensure that patients with minor PSA fluctuations (for
`instance 0.11-0.12 ng/mL) are not inappropriately categorized
`as having progressive disease. Most studies also require that a PSA
`increase be confirmed with ≥ 1 repeated measurement. Because of
`the importance of PSA kinetics in determining prognosis (vide
`infra), it is not unreasonable to attempt to establish the rate of PSA
`increase using several PSA values before secondary intervention.
`Secondly, what do we know about the natural history of
`HRPC? We now know that individuals with radiographic evi-
`dence of metastases are distinct from those without. For those
`with metastatic disease, well-conducted studies from the Cancer
`and Leukemia Group B have examined prognostic factors and
`survival: PSA, lactate dehydrogenase, alkaline phosphatase,
`Gleason score, performance status, hemoglobin level, and the
`presence of visceral disease have been incorporated into a com-
`prehensive prognostic model predictive of overall survival.2
`However, potential prognostic factors such as vascular endothe-
`lial growth factor, chromogranin A, interleukin-6, body mass,
`cigarette smoking, previous radical prostatectomy, and reverse
`transcriptase-polymerase chain reaction for circulating PSA
`messenger RNA have also been implicated by various multivari-
`ate analyses.3-8 For patients with asymptomatic metastatic dis-
`ease (Abbott-sponsored study M00-211), using a composite
`endpoint with radiographic and clinical parameters demonstrat-
`
`ed that non-PSA progression is driven primarily by bone scan
`frequency; approximately 50% of placebo-treated patients will
`have disease progression 90 days after study enrollment when
`bone scans are done at 90-day intervals.9
`For patients with PSA progression after castration but with-
`out evidence of metastatic disease, fewer data are available, and
`those data that are available are not necessarily consistent
`with one another. Retrospective studies from Memorial
`Sloan-Kettering Cancer Center indicate that the median time
`to metastases after PSA increase is 9 months and that death fol-
`lows after a median of 26.5 months.10 In a second retrospective
`analysis of HRPC without bone metastases, median survival was
`68 months after the initial postcastration PSA increase.11
`Prospective studies of patients enrolled into the placebo arm of
`a Novartis-sponsored study indicate that the median time to
`bone metastases after study entry is 30 months.12 Median time
`to survival was not reached in this study, but data emphasized
`the importance of PSA kinetics (velocity) in determining the
`prognosis of patients with HRPC.
`Because a standard treatment for HRPC is now established
`(docetaxel), one can now ask how this treatment stands in rela-
`tionship to other (nonstandard) treatments. Secondary hormon-
`al manipulations (ie, ketoconazole, estrogens, glucocorticoids,
`antiandrogens, and antiandrogen withdrawal) have long been
`used in HRPC, but because no study with these agents has
`demonstrated a survival advantage, their potential role is not
`agreed upon by all. Of note, a study comparing a secondary hor-
`monal manipulation with docetaxel for patients with HRPC
`failed to accrue, and consequently, the trial was closed prema-
`turely (Eastern Cooperative Oncology Group trial 1899).
`Is it possible to enhance docetaxel activity with the addition of
`another active agent? This is currently an area of considerable dis-
`cussion and exploration. Large, prospective, phase III trials are
`now under way using docetaxel with atrasentan, bevacizumab,
`GVAX®, or calcitriol. Results of these trials are eagerly anticipat-
`ed. Smaller exploratory trials are now being conducted with a
`variety of active agents, including docetaxel/samarium-153 lex-
`idronam, docetaxael/ketoconazole, docetaxel/thalidomide/
`bevacizumab, docetaxel/diethylstilbestrol, docetaxel/satraplatin,
`and docetaxel/mitoxantrone.
`What about patients whose disease has failed to respond to
`docetaxel therapy? Data in this setting are preliminary but
`changing rapidly. Combinations of docetaxel/carboplatin have
`some activity, but the extent of activity is not yet clear.13 A large
`registrational trial examining satraplatin/prednisone versus
`prednisone alone for second-line chemotherapy in HRPC has
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`238 • Clinical Genitourinary Cancer March 2006
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`JANSSEN EXHIBIT 2156
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`now completed accrual (> 900 patients), and the results from
`this trial are critical for determining the next appropriate step in
`this setting.
`A variety of novel agents are also under investigation.
`Vaccines such as antigen-presenting cells 8015 and GVAX®,
`immunostimulants such as granulocyte-macrophage colony-
`stimulating factor and anti–cytotoxic T-lymphocyte–associated
`antigen 4, novel chemotherapies such as the epothilones and
`histone deacetylase inhibitors, monoclonal antibodies to anti-
`gens such as prostate-specific membrane antigen and prostate
`stem cell antigen, as well as variety of signal transduction
`inhibitors
`(targeting hedgehog, mammalian
`target of
`rapamycin, etc) are currently in clinical trials.
`Taken together, many challenges remain in HRPC. Despite
`the promise of docetaxel-based chemotherapy, optimal sequenc-
`ing of agents and optimal agents to combine with docetaxel are
`still undefined. Additionally, the prognosis of patients with
`HRPC and no radiographically demonstrable metastases
`remains incompletely understood. Much work remains to be
`done for this disease state, which represents the final common
`pathway for the vast majority of patients dying from prostate
`cancer.
`
`Oliver Sartor, MD
`Editor-in-Chief
`
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`
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