Clinical endpoints for drug development in prostate cancer
`Veshana Ramiaha,b, Daniel J. Georgea,b,c and Andrew J. Armstronga,b,c
`
`aDuke Prostate Center, Durham, bDivision of Medical
`Oncology, Department of Medicine and the Duke
`Comprehensive Cancer Center, Durham and cDivision
`of Urologic Surgery, Department of Surgery, Duke
`University Medical Center, Durham, North Carolina,
`USA
`
`Correspondence to Veshana Ramiah, Box 3850,
`DUMC, Durham, NC 27710, USA
`Tel: +1 919 668 8108; fax: +1 919 668 7117;
`e-mail: veshana.ramiah@duke.edu
`
`Current Opinion in Urology 2008, 18:303–308
`
`Purpose of review
`Overall survival remains the benchmark in phase III settings of novel agents in castration-
`resistant metastatic prostate cancer. This review highlights many of the current potential
`early measures of response and clinical benefit that are worthy of future study and
`validation in this disease.
`Recent findings
`The clinical evaluation of novel agents in advanced prostate cancer remains challenging
`for several reasons. Men with metastatic prostate cancer often have bone-only disease
`in which formal radiologic response and progression criteria may not apply. Declines in
`serum prostate-specific antigen levels may be modest surrogates of response to
`cytotoxic agents such as docetaxel, but have not been validated for agents with novel
`mechanisms of action, such as antiangiogenic, immunologic, or cytostatic drugs. Novel
`radiologic imaging techniques such as PET scans are not yet validated for use in
`monitoring or staging advanced prostate cancer. Measures of delay, control, and
`palliation of metastatic disease such as pain response, time to progression and
`progression-free survival, while appealing endpoints that may highlight the clinical
`benefit of novel agents, have been difficult to define rigorously and have not yet
`demonstrated adequate surrogacy for overall survival.
`Summary
`The measures of response highlighted in this review, if validated, may improve the
`current evaluation of novel agents in phase II settings and the potential accelerated
`approval of these agents.
`
`Keywords
`castration-resistant prostate cancer, chemotherapy, hormone-refractory metastatic
`prostate cancer, novel therapies, prostate-specific antigen, surrogate endpoints
`
`Curr Opin Urol 18:303–308
`ß 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins
`0963-0643
`
`Introduction
`In 2008 there are as yet no validated surrogate endpoints
`for the assessment of early clinical benefit from systemic
`therapy in metastatic castration-resistant prostate cancer
`(CRPC). The reasons for this include difficulty in objec-
`tively quantifying changes in bone scans and prostate-
`specific antigen (PSA) levels that are not always associated
`with clinically important or approvable endpoints such as
`overall survival or pain palliation. Response Evaluation
`Criteria in Solid Tumors (RECIST) criteria, which are
`used to determine radiographic response in most solid
`tumors, are not easily applicable to the most common
`radiographic site of metastasis in prostate cancer (bone).
`For rapid and successful development of novel agents, we
`need early measures of efficacy in phase II trials in CRPC
`that will provide an improvement in overall survival in
`phase III testing. The following is an overview of many
`of the standard and investigational clinical choices for
`monitoring response.
`
`Endpoints in phase II and III trials in
`castration-resistant metastatic prostate
`cancer
`The following is an outline of the different endpoints
`studied to evaluate response in phase II and III studies in
`metastatic CRPC (Table 1) [1,2,3–8].
`
`Prostate-specific antigen declines
`The widespread use of PSA as a screening measure led to
`its incorporation as a biomarker of response to hormonal
`and cytotoxic agents in advanced or recurrent prostate
`cancer [9]. Initial studies were based on a collection of
`trials of marginally effective agents that did not demon-
`strate an overall survival advantage, and were essentially
`based on the prognostic value of PSA changes [3]. Using
`these data, the first PSA Working Group [3,4] published
`widely accepted criteria for a PSA partial response: a 50%
`decline in PSA from baseline, confirmed 4 weeks later, in
`those patients with sufficient levels of PSA (usually
`
`0963-0643 ß 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins
`
`Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
`
`002009
`
`AVENTIS EXHIBIT 2030
`Mylan v. Aventis, IPR2016-00712
`
`

`
`304 Prostate cancer
`
`Table 1 Summary of standard and investigational endpoints for clinical trials in castration-resistant prostate cancer (CRPC)
`
`Pros
`
`Cons
`
`Endpoint
`
`PSA decline
`
`OS
`
`PFS
`
`Trial/author
`Petrylak [1,2]
`Scher [3,4]
`Armstrong [5]
`
`TAX 327 [6]
`
`Scher [3,4]
`
`Armstrong [5]
`
`Easily measurable
`Widely available
`Time < 3 months
`Evidence to support use
`with cytotoxic therapy
`Accepted endpoint
`Could enrich studies for short
`expected survival (risk-adapted studies)
`May capture clinical benefit as a
`delay in pain/tumor growth
`Improved measure of effect of cytostatic
`or antiangiogenic agents
`Flexible definitions
`
`Not validated with novel agents
`PSA can rise after start therapy in minority
`Threshold unclear
`Does not allow for unique mechanism of novel agents
`
`Length of time for treatment by novel agent
`Secondary treatments may modify overall
`survival hypothetically
`Exact definition is critical
`
`Composites likely necessary
`
`Lack of validation
`Censorship prevents current surrogate analyses
`Qualitative thus requires validated scales
`Many men with CRPC are painfree
`Not validated
`Cannot be used as a marker by itself – many causes
`of pain independent of tumor progression
`Qualitative thus requires validated scales/measure
`Defining clinically significant changes
`Bias is inherent in nonplacebo-controlled trials
`No target lesions in patients with increasing PSA and
`localized disease, or bone-only disease
`Not always measurable soft tissue disease in prostate cancer
`No correlation with clinical or PSA progression
`Important treatment effects are missed
`Only approximately 50% of men have detectable levels even
`with widespread metastases
`Not validated as surrogate yet
`Expensive, performed in specialized labs only
`Quick turnaround necessary
`
`Pain
`
`TAX 327 [5,6]
`
`Direct patient measure
`
`QOL
`
`Tannock [6]
`
`Direct patient measure
`
`RECIST
`
`Scher [8]
`
`Well defined criteria if measurable
`disease present
`
`CTCs
`
`Moreno [7]
`
`Early detection before PSA rise
`
`PFS, progression free survival; OS, overall survival; QOL, quality of life; RECIST, Response Evaluation Criteria in Solid Tumors; CTC, circulating tumor
`cell; PSA, prostate-specific antigen.
`
`>20 ng/ml). This level of decline was strongly prognostic
`in studies of cytotoxic agents; however, surrogacy was
`not demonstrated.
`
`The initial analysis of PSA declines as surrogates for
`overall survival was performed by Petrylak et al. [1,10]
`using data from the Southwest Oncology Group Protocol
`99-16 (SWOG 99-16). In this study, men with metastatic
`CRPC were randomly assigned to either docetaxel/estra-
`mustine or mitoxantrone/prednisone treatment, with
`docetaxel/estramustine providing a 2–3 month overall
`survival benefit. PSA declines of 5–90% and PSA
`velocity at 1, 2 and 3 months were tested for surrogacy.
`The Group concluded that a 30% or greater PSA decline
`with cytotoxic chemotherapy fully captured the overall
`survival benefit seen in this trial (100% surrogacy) and
`thus this level of decline would be a reasonable surrogate
`for a phase II endpoint. This study, however, was retro-
`spective and required prospective validation.
`Armstrong and colleagues [2] from the TAX 327 study
`group examined various degrees of PSA decline and pain
`response as surrogates for the survival benefit observed
`for docetaxel and prednisone. They showed that a 30% or
`greater PSA decline within 3 months of starting treatment
`also showed the greatest degree of surrogacy, but in this
`
`study accounted for about two-thirds of the overall sur-
`vival benefit seen.
`
`In summary, PSA declines are highly prognostic and an
`easy measure to evaluate response within a few months of
`initiation of chemotherapy, but no one cutpoint fully
`predicts for benefit in a population or individual patient.
`Since no therapy, other than docetaxel chemotherapy,
`has demonstrated a survival advantage in CRPC, PSA
`declines have an uncertain role in the evaluation of these
`agents with novel mechanisms of action. With advanced
`metastatic CRPC, PSA production may not be consistent
`in all cancer cells. Since targeted therapies may impact
`specific subsets of cancer cells, PSA changes may or may
`not
`reflect
`this biology. Therefore, we recommend
`recording changes in PSA levels in patients on phase
`II and III trials of novel agents, but caution using this
`endpoint as a sole means of determining efficacy.
`
`Radiologic response
`Using the RECIST criteria in trials of men with CRPC
`has several problems which were well illustrated in a
`study done by Scher and colleagues [3,5]. When RECIST
`criteria are applied to men with CRPC, less than half of
`patients have measurable target lesions greater than 2 cm
`in size. These lesions were mainly lymph nodes that are
`
`Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
`
`

`
`not always present in recurrent or advanced prostate
`cancer. RECIST does not apply to localized or PSA-only
`recurrent prostate cancer. There are no criteria in
`RECIST for patients with ‘flare’ phenomena, when heal-
`ing bone lesions after starting therapy may appear as
`worsening existing or even as new lesions [3,11]. To
`address this deficiency, current guidelines have been
`established to require confirmatory bone scans for new
`lesions seen on initial bone scans before stopping therapy
`that is otherwise continuing to benefit a patient [3].
`
`Pain and quality of life improvements
`Pain and other cancer-related symptoms can serve as
`useful markers of clinical benefit in patients with meta-
`static CRPC. Improvement
`in pain responses and
`duration led to the approval of mitoxantrone for men
`with CRPC. Two randomized controlled studies com-
`pared mitoxantrone/prednisone with prednisone therapy
`alone in patients with metastatic CRPC and demon-
`strated improved pain control and duration as well as
`better quality of life in favor of mitoxantrone [6]. One
`limiting feature with a pain control endpoint is that many
`patients with CRPC do not have pain yet have a relatively
`short expected survival, on the order of 1.5–2 years.
`Restricting the study of novel agents to men with CRPC
`and significant pain would limit accrual to clinical trials
`for this lethal disease, unless the agent was intended as a
`purely palliative therapy. Regarding quality of life, out-
`comes remain problematic given their subjectivity, lack
`of standardization, inherent biases in comparison with
`control arms, and the need to balance quantity of life
`improvements with quality of life improvements [12].
`
`Skeletal-related events
`In certain circumstances, a novel clinical endpoint may be
`utilized that directly reflects the mechanism of action of
`the agent being tested. A good example of this is the
`approval of zoledronic acid for the prevention of skeletal
`related events despite no difference in overall survival
`[13]. In a multicenter randomized controlled trial, Saad
`et al. showed that the bisphosphonate zoledronic acid
`significantly decreased incidence of bone-related com-
`plications in patients with prostate cancer with osteo-
`blastic bone lesions. Zoledronic acid also increased the
`time to first skeletal event and decreased bone pain
`compared with placebo. This endpoint thus represents
`a potential mechanism for approval of agents that target
`bone health rather than the tumor directly, but will likely
`need to improve on zoledronic acid as the standard
`comparator.
`
`Progression-free survival and time to progression (time
`to event endpoints)
`Scher et al. [14] retrospectively explored the association
`between progression-free survival (PFS) and overall sur-
`vival time in patients with CRPC treated with micro-
`
`Clinical endpoints for drug development Ramiah et al. 305
`
`tubule-targeted therapies. They looked at the association
`between radiographic PFS and PSA PFS with overall
`survival and these were adjusted for censoring. They
`found that the overall association between PFS and
`overall survival time was weak to moderate: 0.4 for
`radiographic PFS and 0.33 for PSA PFS (on a 0–1 scale
`with 1 indicating perfect surrogacy). The association
`between radiographic PFS and overall survival was weak-
`est early in the follow-up process, whereas the PSA
`association was weakest when the PFS-related event
`(PSA progression, death, or censoring) occurred after
`6 months from the start of treatment. They concluded
`that current measures of PFS for men with CRPC are not
`strong surrogates for overall survival. Factors that reduce
`this association include interval censoring of progression
`data and the discontinuation of therapy early in the follow
`up due to imaging changes that may not reflect true
`failure of the treatment. For radiographic PFS, a second
`confirmatory bone scan may increase the surrogate value
`of this endpoint.
`Armstrong et al. [2] evaluated various definitions of
`progression in the TAX 327 trial for postprogression
`survival and the benefit associated with continuing or
`stopping chemotherapy. They found that the more
`criteria that were met for progression, the lower the
`postprogression survival. For example, men who had
`progression by only one criterion (PSA, pain or tumor)
`lived a median of 15–17 months after progression on
`docetaxel. Men who progressed by two criteria lived a
`median of 10–14 months after progression, while those
`who met all three criteria had a median postprogression
`survival of only 7.8 months. A survival advantage to
`continuing chemotherapy was suggested for those men
`who had pain progression only. These data indicate that
`composite PFS definitions may be more clinically useful,
`and that if pain is included in the PFS definition, it
`should be combined with other measures of clinical
`progression, such as PSA or tumor progression.
`
`Recent studies have used a composite endpoint of PFS
`which included tumor progression, skeletal events and
`symptomatic progression (i.e. pain), but not PSA changes
`as in the Satraplatin and Prednisone Against Refractory
`Cancer (SPARC) trial by Sternberg et al. [15]. Satraplatin,
`a novel oral platinum compound, was evaluated in this
`multinational randomized double-blind study comparing
`satraplatin and prednisone to prednisone and placebo in
`CRPC patients who failed prior chemotherapy. In this
`analysis, PFS was the primary endpoint, defined as a
`composite endpoint of radiologic progression, sympto-
`matic progression, skeletal events or death. Satraplatin
`was associated with reduction in risk of PFS and
`decreased pain progression. Also noted was significant
`improvement in pain, tumor and PSA response rates [16].
`Median survival, however, was not statistically different
`
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`
`

`
`306 Prostate cancer
`
`and consequently the differences in median PFS and
`pain have not yet been validated as surrogates for overall
`survival in this setting.
`
`Overall survival: TAX 327 data
`Currently, overall survival remains the benchmark for
`the evaluation of novel agents in trials of men with
`CRPC. Given the problems associated with PSA
`declines, tumor responses, pain improvements, and lack
`of data on other radiologic or blood-based biomarkers,
`these endpoints cannot currently be recommended as
`approvable endpoints for agents whose intent is not
`purely palliative. The TAX 327 primary endpoint was
`overall survival, with secondary endpoints including
`pain, PSA levels, and quality of life [6]. Median overall
`survival in TAX 327 was improved by 2–3 months in the
`every 3-week docetaxel arm versus the every 3-week
`mitoxantrone arm (18.9 versus 16.5 months, hazard ratio
`0.76, P¼ 0.009). The every 3-week regimen also showed
`statistically significant improvements in pain control,
`quality of life, and PSA level. Currently there are a
`number of ongoing phase III trials with docetaxel and
`prednisone backbone as a comparator; overall survival is
`the primary endpoint for these studies. Until a reason-
`able surrogate can be identified in these trials, overall
`survival will continue to be used. Given the difficulty in
`validating a surrogate and the dependence of a surrogate
`on the mechanism of action of the therapy, it is unlikely
`that a novel surrogate will replace overall survival in the
`near future.
`
`Novel biomarkers
`New biomarkers for disease response in CRPC could be
`valuable for several reasons. As a complement to PSA,
`additional biomarkers may identify other functional path-
`ways for CRPC. Like PSA, other biomarkers could be
`monitored serially and frequently in patients, allowing for
`trends over time to be used as well as baseline values.
`One novel surrogate being investigated in patients with
`CRPC is circulating tumor cells (CTCs). CTCs have
`demonstrated strong prognostic significance and predic-
`tive value for response to therapy [17]. A recent study by
`Moreno et al. [7] used CTCs in CRPC patients under-
`going cytotoxic chemotherapy to predict outcome and
`monitor ongoing treatment response. This study found
`that patients with decreasing levels of CTCs after starting
`therapy had increased overall survival compared with
`those who did not have reduction in CTCs: 20 versus
`9.3 months. CTCs were not detectable in about half the
`study patients even though they had widespread metas-
`tases. Given that many patients with CRPC do not have
`detectable levels of CTCs, it remains to be seen how
`reliable a surrogate this test will be and prospective
`validation in a trial with a survival advantage to therapy
`is needed. There are current plans for exactly this type of
`analysis in a second-line study of the novel adrenal
`
`androgen lowering agent abiraterone acetate and predni-
`sone versus prednisone alone.
`
`Assessment using imaging modalities
`Bone scans are generally used in patients with PSA
`greater than 10 ng/ml to assess risk of distant spread.
`Lesions may not be visible in early disease, however,
`if no osteoblastic response is present. There may also be
`false positive findings associated with degenerative dis-
`ease or previous trauma. Also there may be ‘flare’
`phenomena when uptake increases after chemotherapy
`during bone remodeling [14].
`
`F-18 fluorodeoxyglucose (FDG) PET scan has been
`shown to be better than both bone scan and computed
`tomography scan for discerning between actual metasta-
`sis and healing bone [18]. FDG does not do as well in
`distinguishing tumors from inflammation [19] and newer
`tracers are being investigated to this end. Some of these
`include methionine as well as 11C acetate and 11C cho-
`line. 18F fluorodihydrotestosterone has also recently been
`studied to assess androgen receptors [18].
`
`MRI and magnetic resonance spectroscopic imaging
`(MRSI) data have shown that tumor detection is depen-
`dent on tumor grade, with tumor detection at 90% for
`Gleason score 8–9 [20]. There was a suggestion in this
`study of correlation between metabolic abnormality
`detected on MRSI and the aggressiveness of the cancer.
`Studies are underway to look at findings on MRI and
`MRSI and their correlation with tumor pathology and a
`variety of molecular markers including Ki-67, PTEN,
`phosphorylated AKT and Bcl-2 [18].
`
`Tissue and pathologic endpoints
`The spectrum of prostate cancer progression together
`with our increasing understanding of tumor biology and
`of novel agents directs us to study tissue endpoints that
`address mechanism of action and pathologic effects.
`A number of studies are being done with novel agents
`in the preprostatectomy setting. For example,
`in a
`preprostatectomy rapamycin study (Table 2 [21–33]),
`the primary endpoint is inhibition of the downstream
`mammalian target of rapamycin (mTOR) targets S6
`kinase phosphorylation and 4EBP1 activation, with
`secondary endpoints being changes in proliferation
`and apoptosis. For our ongoing RAD001 phase II study
`in CRPC,
`induction of apoptosis
`(TUNEL) and
`reduction in proliferation in bone biopsies are patho-
`logic endpoints, with the intent to correlate these with
`PTEN loss or Akt activation and clinical TTP. Each
`trial is uniquely geared to the mechanism of action of
`the drug (mTOR inhibition) and the clinical state.
`Preprostatectomy models may not, however, reflect
`the biology of progressive CRPC. Also these tissue
`biomarkers are not yet validated surrogates of clinical
`
`Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
`
`

`
`Clinical endpoints for drug development Ramiah et al. 307
`
`Table 2 Studies using novel agents in the preprostatectomy setting
`
`Trial/PI
`
`Prostate cancer setting
`
`Local treatment
`
`Number
`
`Phase
`
`Regimen
`
`Locations
`
`Thomas [21]
`
`High risk localized
`
`Amato [22]
`
`Intermediate to high risk
`
`Chi [23]
`Trump [24]
`Febbo [25]
`Carducci/
`Armstrong [26]
`Lerut [27]
`George
`
`Lerut/Carducci [27,28]
`Fong [29]
`Bergan [30]
`Kadmon [31]
`Oh [32]
`Eastham [33]
`CALGB 90203
`
`Localized
`Localized
`Localized
`Intermediate risk
`
`Localized
`Intermediate to
`high risk localized
`Localized
`Any localized
`Localized
`Localized
`High risk
`High risk, localized
`
`RP
`
`RP
`
`RP
`RP
`RP
`RP
`
`RP
`RP
`
`RP
`RP
`RP
`RP
`RP
`RP
`
`40
`
`40
`
`45
`80
`
`42
`
`15
`30
`
`64
`28
`88
`36
`42
`700
`
`I/II
`
`II
`
`II
`II
`PD
`PD
`
`PD
`Pilot
`
`PD
`Pilot
`I/II
`I
`II
`III
`
`Temsirolimus
`Cetuximabþ docetaxel
`versus cetuximab
`OGX-011
`Calcitriolþ dexamethasone
`Imatinib
`Rapamycin (sirolimus)
`
`RAD001
`Sunitinib
`
`MD Anderson/
`UCLA/Fox Chase
`MHS
`
`UBC
`RPCI
`DFCI
`JHM/UM/Duke
`
`Leuven, Belgium
`Duke
`
`Celecoxib
`GM-CSF
`Genistein
`RTVP-1 gene therapy
`Docetaxelþ bevacizumab
`Docetaxelþ estramustine
`
`Johns Hopkins
`UCSF
`RLCC
`Baylor
`DFCI/BIDMC/Duke
`MSKCC
`
`PI, principal investigator; RP, radical prostatectomy; UCLA, University of California Los Angeles; MHS, Methodist Hospital System, Texas; OGX-011,
`Oncogenex-011; UBC, University of British Columbia; RPCI, Roswell Park Cancer Institute; PD, pharmodynamic; DFCI, Dana Farber Cancer Institute;
`JHM, Johns Hopkins Medicine; UM, University of Michigan; RAD001, everolimus; GM-CSF, granulocyte macrophage colony stimulating factor; UCSF,
`University of California, San Francisco; RLCC, Robert H. Lurie Cancer Center; RTVP, related to testes-specific, vespid, and pathogenesis protein 1;
`BIDMC, Beth Israel Deaconess Medical Center; CALGB, Cancer and Leukemia Group B; MSKCC, Memorial Sloan Kettering Cancer Center.
`
`References and recommended reading
`Papers of particular interest, published within the annual period of review, have
`been highlighted as:
`
`of special interest
` of outstanding interest
`Additional references related to this topic can also be found in the Current
`World Literature section in this issue (pp. 341–342).
`
`1
`
`Petrylak DP, Ankerst DP, Jiang CS, et al. Evaluation of prostate-specific
`antigen declines for surrogacy in patients treated on SWOG 99-16. J Natl
`Cancer Inst 2006; 98:516–521.
`
`2
`
`Armstrong AJ, Garrett-Mayer E, Ou Yang YC, et al. Prostate-specific antigen
`and pain surrogacy analysis in metastatic hormone-refractory prostate cancer.
`J Clin Oncol 2007; 25:3965–3970.
`This study identified 30% decline in PSA and pain responses as having a
`moderately high degree of surrogacy for the overall survival benefit seen in this
`study.
`
`3
`
`4
`
`5
`
`6
`
`Scher HI, Halabi S, Tannock I, et al. The Prostate Cancer Clinical Trials
`Working Group (PCCTWG) consensus criteria for phase II clinical trials for
`castration-resistant prostate cancer. ASCO Meeting Abstracts 2007; 25:
`5057.
`
`Bubley GJ, Carducci M, Dahut W, et al. Eligibility and response guidelines for
`phase II clinical trials in androgen-independent prostate cancer: recommen-
`dations from the Prostate-Specific Antigen Working Group. J Clin Oncol
`1999; 17:3461–3467.
`
`Scher HI, Morris MJ, Kelly WK, et al. Prostate cancer clinical trial end
`points: ‘RECIST’ing a step backwards. Clin Cancer Res 2005; 11:5223–
`5232.
`
`Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or
`mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med
`2004; 351:1502–1512.
`
`7 Moreno J, DeBono JS, Shaffer D, et al. Multicenter study evaluating circulating
`tumor cells (CTCs) as a surrogate for survival in men treated for castration
`refractory prostate cancer (CRPC). ASCO Meeting Abstracts 2007; 25:
`5016.
`
`8
`
`Scher HI, Sawyers CL. Biology of progressive, castration-resistant prostate
`cancer: directed therapies targeting the androgen-receptor signaling axis.
`J Clin Oncol 2005; 23:8253–8261.
`
`9 Collette L, Burzykowski T, Carroll KJ, et al. Is prostate-specific antigen a valid
`surrogate end point for survival in hormonally treated patients with metastatic
`prostate cancer? Joint research of the European Organisation for Research
`and Treatment of Cancer, the Limburgs Universitair Centrum, and Astra-
`Zeneca Pharmaceuticals. J Clin Oncol 2005; 23:6139–6148.
`
`benefit. Many of these biomarkers are sensitive to
`collection conditions (ischemic time, processing, freez-
`ing, manipulation, etc.) that make them difficult to
`evaluate, and the yield on bone biopsies in CRPC
`has been fairly low in the past. At Duke, we are trying
`to improve on this yield using computed tomography-
`guided pelvic bone biopsies and a dedicated radiology
`team that can improve on these techniques and number
`of core biopsies over time that can be used for genomic
`and proteomic measures.
`
`Conclusion
`In summary, the only validated phase III endpoint in
`advanced prostate cancer, particularly CRPC, is overall
`survival. Other measures of palliation and or clinical
`benefit, such as prevention of fracture, may be approvable
`in select scenarios depending on the trial design and drug
`mechanism of action. In phase II trials, however,
`it
`remains a challenge to select the ideal
`intermediate
`endpoint to gauge the efficacy of novel agents. The lack
`of proven surrogates, the heterogeneity of PFS defi-
`nitions, the unknown effects of novel agents on PSA
`production, and the variability in patient-reported out-
`comes make many of these endpoints problematic. Cur-
`rent efforts to standardize case-report forms, reporting of
`trial results, and measures of response and progression
`will improve our ability to identify an ideal surrogate that
`may be used in phase II studies. Until that time, end-
`points such as composite PFS definitions and rates of 3-
`month PSA declines (>30 or >50%) are reasonable but
`fallible measures of early activity and their use should
`intrinsically be linked to drug mechanism of action.
`
`Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
`
`

`
`308 Prostate cancer
`
`10 Petrylak DP, Tangen CM, Hussain MH, et al. Docetaxel and estramustine
`compared with mitoxantrone and prednisone for advanced refractory prostate
`cancer. N Engl J Med 2004; 351:1513–1520.
`
`22 Amato RJ. Efficacy and safety study of cetuximab or cetuximab plus docetaxel
`to treat prostate cancer before prostatectomy. http://clinicaltrials.gov/ct2/
`show/NCT00448097. [Accessed 18 February 2008]
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