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1.  Phase I Study of ARN-509, a Novel Antiandrogen, in the Treatment of Castration-Resistant Prostate Cancer 
Journal of Clinical Oncology  2013;31(28):3525-3530.
Purpose
ARN-509 is a novel androgen receptor (AR) antagonist for the treatment of castration-resistant prostate cancer (CRPC). ARN-509 inhibits AR nuclear translocation and AR binding to androgen response elements and, unlike bicalutamide, does not exhibit agonist properties in the context of AR overexpression. This first-in-human phase I study assessed safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity of ARN-509 in men with metastatic CRPC.
Patients and Methods
Thirty patients with progressive CRPC received continuous daily oral ARN-509 at doses between 30 and 480 mg, preceded by administration of a single dose followed by a 1-week observation period with pharmacokinetic sampling. Positron emission tomography/computed tomography imaging was conducted to monitor [18F]fluoro-α-dihydrotestosterone (FDHT) binding to AR in tumors before and during treatment. Primary objective was to determine pharmacokinetics, safety, and recommended phase II dose.
Results
Pharmacokinetics were linear and dose proportional. Prostate-specific antigen declines at 12 weeks (≥ 50% reduction from baseline) were observed in 46.7% of patients. Reduction in FDHT uptake was observed at all doses, with a plateau in response at ≥ 120-mg dose, consistent with saturation of AR binding. The most frequently reported adverse event was grade 1/2 fatigue (47%). One dose-limiting toxicity event (grade 3 abdominal pain) occurred at the 300-mg dose. Dose escalation to 480 mg did not identify a maximum-tolerated dose.
Conclusion
ARN-509 was safe and well tolerated, displayed dose-proportional pharmacokinetics, and demonstrated pharmacodynamic and antitumor activity across all dose levels tested. A maximum efficacious dose of 240 mg daily was selected for phase II exploration based on integration of preclinical and clinical data.
doi:10.1200/JCO.2013.50.1684
PMCID: PMC3782148  PMID: 24002508
2.  Analytical and Clinical Validation of a Prostate Cancer-Enhanced messenger RNA Detection Assay in Whole Blood as a Prognostic Biomarker for Survival 
European urology  2013;65(6):1191-1197.
Background
Biomarkers based on detecting prostate cancer-specific transcripts are associated with inferior outcomes, but their validation in a clinical context is lacking.
Objective
To determine whether detecting prostate cancer enhanced transcripts in whole blood using an analytically valid assay has prognostic significance relative to circulating tumor cell (CTC) enumeration.
Design, Setting, and Participants
The predictive value for overall survival of the detection in whole blood by reverse transcription real-time polymerase chain reaction (RT-PCR) of KLK3, KLK2, HOXB13, GRHL2, and FOXA1 was studied in 97 men with metastatic castration-resistant prostate cancer (mCRPC).
Intervention
2.5ml of blood was collected in PAXgene tubes for total RNA extraction and 7.5 ml for CTC enumeration from patients with progressive mCRPC.
Outcome Measurements and Statistical Analysis
Prostate cancer enriched genes were detected using a sensitive RT-PCR assay in whole blood from patients with mCRPC. Analytical validity of the assay was established in a clinical laboratory environment. The frequency of detecting transcripts was compared to CTC enumeration using CellSearch® in an independent data set and survival associations were explored by concordance probability estimate (CPE).
Results and Limitations
Two or more genes were detected by PCR in 53% (51 of 97, 95% CI 43–63%) of patients, and unfavorable CTC counts (≥5cells) were seen in 46% (45 of 97, 95% CI 36–56%). Importantly, transcripts were detectable in 11 of 52 patients with favorable CTC counts (21%, 95% CI 8–35%). Transcript detection predicted overall survival in a proportional hazards model. Significantly, the predictive accuracy of RT-PCR detection in combination with CTC enumeration had a CPE of 0.752 (SE=0.038), although limited by the number of patients.
Conclusions
This validated RT-PCR assay detecting prostate-specific RNA in whole blood is prognostic for survival, and may assess patient risk complimentary with CellSearch CTC enumeration. Its clinical utility is being prospectively explored.
doi:10.1016/j.eururo.2013.07.006
PMCID: PMC4113474  PMID: 23954088
biomarker; circulating tumor cells; prostate cancer; prostate-specific markers
3.  Feasibility of Long-Term Patient Self-Reporting of Toxicities From Home via the Internet During Routine Chemotherapy 
Journal of Clinical Oncology  2013;31(20):2580-2585.
Purpose
Patient-reported outcomes are increasingly used in routine outpatient cancer care to guide clinical decisions and enhance communication. Prior evidence suggests good patient compliance with reporting at scheduled clinic visits, but there is limited evidence about compliance with long-term longitudinal reporting between visits.
Patients and Methods
Patients receiving chemotherapy for lung, gynecologic, genitourinary, or breast cancer at a tertiary cancer center, with access to a home computer and prior e-mail experience, were asked to self-report seven symptomatic toxicities via the Web between visits. E-mail reminders were sent to participants weekly; patient-reported high-grade toxicities triggered e-mail alerts to nurses; printed reports were provided to oncologists at visits. A priori threshold criteria were set to determine if this data collection approach merited further development based on monthly (≥ 75% participants reporting at least once per month on average) and weekly compliance rates (60% at least once per week).
Results
Between September 2006 and November 2010, 286 patients were enrolled (64% were women; 88% were white; median age, 58 years). Mean follow-up was 34 weeks (range, 2 to 214). On average, monthly compliance was 83%, and weekly compliance was 62%, without attrition until the month before death. Greater compliance was associated with older age and higher education but not with performance status. Compliance was greatest during the initial 12 weeks. Symptomatic illness and technical problems were rarely barriers to compliance.
Conclusion
Monthly compliance with home Web reporting was high, but weekly compliance was lower, warranting strategies to enhance compliance in routine care settings.
doi:10.1200/JCO.2012.47.6804
PMCID: PMC3699724  PMID: 23733753
4.  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 
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 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.
doi:10.1200/JCO.2007.12.4487
PMCID: PMC4010133  PMID: 18309951
5.  Circulating Tumors Cells as Biomarkers 
Cancer journal (Sudbury, Mass.)  2011;17(6):438-450.
Personalized cancer medicine requires the development of tumor-specific biomarkers to optimize selection of targeted therapies and to better assess response to therapy. Current efforts in several tumor types have shown that patients in whom circulating tumor cells (CTCs) are detected have an inferior prognosis relative to those in whom CTCs are not detected and that the elimination or decrease of CTCs following treatment is associated with improved clinical outcomes. Technological advances in the detection, isolation, capture, and characterization of CTCs from phlebotomy samples obtained in a routine clinical practice setting have enabled the evaluation of different CTC biomarkers. Unmet needs in cancer diagnosis and treatment where CTC biomarkers have been studied include determining prognosis, assessing the effects of treatment, and as a source of tumor for the biologic identification and characterization of determinants to predict sensitivity to one form of treatment versus another and to understand mechanisms of treatment resistance.
At present, there is no single definition of a CTC and no single CTC “biomarker.” Rather, multiple assays (tests) are in development for CTC biomarkers. However, before the role of any biomarker in medical decision making can be determined, it is essential that the assays used to measure the biomarker are analytically validated in a sequence of trials to generate the evidence to support the biomarker’s use in the given context of use. It is against this background that this review focuses on the process of developing CTC biomarker assays, with the objective of outlining the necessary steps to qualify specific CTC tests for medical decision making in clinical practice or drug development. The potential for point-of-care tests is clear.
doi:10.1097/PPO.0b013e31823e69ac
PMCID: PMC3985131  PMID: 22157288
Circulating tumor cells; biomarker; regulatory qualification; personalized medicine
6.  Bone Scan Index: A Quantitative Treatment Response Biomarker for Castration-Resistant Metastatic Prostate Cancer 
Journal of Clinical Oncology  2012;30(5):519-524.
Purpose
There is currently no imaging biomarker for metastatic prostate cancer. The bone scan index (BSI) is a promising candidate, being a reproducible, quantitative expression of tumor burden seen on bone scintigraphy. Prior studies have shown the prognostic value of a baseline BSI. This study tested whether treatment-related changes in BSI are prognostic for survival and compared BSI to prostate-specific antigen (PSA) as an outcome measure.
Patients and Methods
We retrospectively examined serial bone scans from patients with castration-resistant metastatic prostate cancer (CRMPC) enrolled in four clinical trials. We calculated BSI at baseline and at 3 and 6 months on treatment and performed univariate and bivariate analyses of PSA, BSI, and survival.
Results
Eighty-eight patients were scanned, 81 of whom have died. In the univariate analysis, the log percent change in BSI from baseline to 3 and 6 months on treatment prognosticated for survival (hazard ratio [HR], 2.44; P = .0089 and HR, 2.54; P < .001, respectively). A doubling in BSI resulted in a 1.9-fold increase in risk of death. Log percent change in PSA at 6 months on treatment was also associated with survival (HR, 1.298; P = .013). In the bivariate analysis, change in BSI while adjusting for PSA was prognostic at 3 and 6 months on treatment (HR, 2.368; P = .012 and HR, 2.226; P = .002, respectively), but while adjusting for BSI, PSA was not prognostic.
Conclusion
These data furnish early evidence that on-treatment changes in BSI are a response indicator and support further exploration of bone scintigraphy as an imaging biomarker in CRMPC.
doi:10.1200/JCO.2011.36.5791
PMCID: PMC3295554  PMID: 22231045
7.  Adaptive Clinical Trial Designs for Simultaneous Testing of Matched Diagnostics and Therapeutics 
A critical challenge in the development of new molecularly targeted anticancer drugs is the identification of predictive biomarkers and the concurrent development of diagnostics for these biomarkers. Developing matched diagnostics and therapeutics will require new clinical trial designs and methods of data analysis. The use of adaptive design in phase III trials may offer new opportunities for matched diagnosis and treatment because the size of the trial can allow for subpopulation analysis. We present an adaptive phase III trial design that can identify a suitable target population during the early course of the trial, enabling the efficacy of an experimental therapeutic to be evaluated within the target population as a later part of the same trial. The use of such an adaptive approach to clinical trial design has the potential to greatly improve the field of oncology and facilitate the development of personalized medicine.
doi:10.1158/1078-0432.CCR-11-1105
PMCID: PMC3853353  PMID: 22046024
8.  Phase II study of lutetium-177 labeled anti-prostate-specific membrane antigen (PSMA) monoclonal antibody J591 for metastatic castration-resistant prostate cancer 
Purpose
To assess the efficacy of a single infusion of radiolabeled anti-prostate specific membrane antigen monoclonal antibody J591 (177Lu-J591) by PSA decline, measurable disease response, and survival.
Experimental Design
In this dual-center phase II study, 2 cohorts with progressive metastatic castration-resistant prostate cancer received one dose of 177Lu-J591 (15 patients at 65 mCi/m2, 17 at 70 mCi/m2) with radionuclide imaging. Expansion cohort (n=15) received 70 mCi/m2 to verify response rate and examine biomarkers.
Results
47 patients who progressed after hormonal therapies (55.3% also received prior chemotherapy) received 177Lu-J591. 10.6% experienced ≥ 50% decline in PSA, 36.2% experienced ≥ 30% decline, and 59.6% experienced any PSA decline following their single treatment. One of 12 with measurable disease experienced a partial radiographic response (8 with stable disease). Sites of prostate cancer metastases were targeted in 44 of 47 (93.6%) as determined by planar imaging. All experienced reversible hematologic toxicity with grade 4 thrombocytopenia occurring in 46.8% (29.8% received platelet transfusions) without significant hemorrhage. 25.5% experienced grade 4 neutropenia with 1 episode of febrile neutropenia. The phase I maximum tolerated dose (70 mCi/m2) resulted in more 30% PSA declines (46.9% vs 13.3%, p=0.048) and longer survival (21.8 vs 11.9 months, p=0.03), but also more grade 4 hematologic toxicity and platelet transfusions. No serious non-hematologic toxicity occurred. Those with poor PSMA imaging were less likely to respond.
Conclusion
A single dose of 177Lu-J591 was well-tolerated with reversible myelosuppression. Accurate tumor targeting and PSA responses were seen with evidence of dose-response. Imaging biomarkers appear promising.
doi:10.1158/1078-0432.CCR-13-0231
PMCID: PMC3778101  PMID: 23714732
Prostate Cancer; Prostate-specific Membrane Antigen; Radioimmunotherapy; Monoclonal Antibody
9.  Prevalence of Pain and Analgesic Use in Men With Metastatic Prostate Cancer Using a Patient-Reported Outcome Measure 
Journal of Oncology Practice  2013;9(5):223-229.
The authors' results provide a method for estimating accruals along the disease continuum, and for enabling design of trials appropriately powered to assess pain.
Purpose:
Contemporary tumor-directed therapies for metastatic castration-resistant prostate cancer (mCRPC) are approved to prolong life, but their effects on symptoms such as pain are less well understood as a result of the lack of analytically valid assessments of pain prevalence and severity, clinically meaningful definitions of therapeutic benefit, and methodologic standards of trial conduct. This study establishes pain characteristics in the mCRPC population using a PRO measure.
Materials and Methods:
Patients with prostate cancer participated in an anonymous survey at five US comprehensive cancer centers in the Prostate Cancer Clinical Trials Consortium that incorporated the Brief Pain Inventory (BPI), analgesic use, and interference with daily activities. Prevalence and severity of cancer-related pain and analgesic use were tabulated according to castration-resistant status and exposure to docetaxel chemotherapy.
Results:
Four hundred sixty-one patients with prostate cancer participated, of whom 147 had mCRPC involving bone (61% [89 of 147] docetaxel exposed, 39% [58 of 147] docetaxel naive). Pain of any level was more common among docetaxel-exposed versus docetaxel-naive patients with mCRPC (70% [62 of 89] v 38% [22 of 58], respectively; P < .001). BPI score ≥ 4 was reported by 38% (34 of 89) of docetaxel-pretreated and 24% (14 of 58) of docetaxel-naive patients with mCRPC; 40% of these patients with pain intensity ≥ 4 reported no current narcotic analgesic.
Conclusion:
Pain prevalence and severity were higher in patients with prior docetaxel exposure. Analgesics were underutilized. These results provide a method for estimating accruals along the disease continuum, and for enabling design of trials appropriately powered to assess pain.
doi:10.1200/JOP.2013.000876
PMCID: PMC3994234  PMID: 23943897
10.  Repetitively Dosed Docetaxel and 153Samarium-EDTMP as an Anti-Tumor Strategy for Metastatic Castration-Resistant Prostate Cancer 
Cancer  2013;119(17):3186-3194.
Background
Beta-emitting bone-seeking radiopharmaceuticals have historically been administered for pain palliation while docetaxel prolongs life in metastatic castration-resistant prostate cancer (mCRPC). In combination, these agents simultaneously target the bone stroma and cancer cell to optimize anti-tumor effects. The toxicity and efficacy when each agent is combined at full, recommended doses, in a repetitive fashion is not well established.
Methods
Patients with progressive mCRPC and ≥3 bone lesions received 153Sm-EDTMP 1.0 mCi/kg every 9 weeks and docetaxel 75mg/m2 every 3 weeks. In the absence of unacceptable toxicity, patients were allowed to continue additional cycles, defined by 9 weeks of treatment, until intolerance or biochemical/radiographic progression.
Results
Of 30 patients treated, 50% were taxane-naïve, 36.7% taxane-refractory, and 13.3% previously exposed to taxanes but not considered refractory. Patients received on average 2.5 cycles: 6.5 doses of docetaxel and 2.5 doses of 153Sm-EDTMP. Twelve (40%) demonstrated decline in prostate-specific antigen of ≥50%. Median progression-free survival (biochemical or radiographic) was 7.0 months and overall survival was 14.3 months. Nine patients (30%) did not recover platelet counts above 100 K/mm3 after a median of 3 cycles to allow for additional treatment, with four experiencing prolonged thrombocytopenia. The most common reasons for trial discontinuation were progressive disease and hematologic toxicity.
Discussion
153Sm-EDTMP can be safely combined with docetaxel at full doses on an ongoing basis. Thrombocytopenia limited therapy for some patients; preliminary efficacy supports the strategy of combining a radiopharmaceutical with chemotherapy, an appealing strategy given the anticipated availability of alpha emitters that can prolong survival.
doi:10.1002/cncr.28103
PMCID: PMC3775970  PMID: 23765638
prostate cancer; 153Sm-EDTMP; docetaxel; chemotherapy; radiopharmaceutical
11.  Circulating tumor cells as biomarkers in prostate cancer 
Unmet needs in prostate cancer drug development and patient management are the ability to monitor treatment benefit and to identify the target of interest in a tumor at the time treatment is being considered. This review focuses on establishing analytical valid biomarkers for specific contexts of use in patients with castration-resistant prostate cancer (CRPC), emphasizing a biomarker currently in clinical use, circulating tumor cells (CTC). The Oncology Biomarker Qualification Initiative provides a road map for these investigations, which, if followed, will facilitate the incorporation of these types of assays into clinical decision-making.
CTC enumeration at baseline and post-treatment is prognostic of survival, with no threshold effect, and the shedding of cells into the circulation represents an intrinsic property of the tumor, distinct from extent of disease. The clinical utility of monitoring CTC changes with treatment as an efficacy-response surrogate biomarker of survival is currently being tested in large phase III trials with the novel antiandrogen therapies abiraterone acetate and MDV3100.
Molecular biomarkers can be characterized in CTC as potential predictive biomarkers of tumor sensitivity to a therapeutic modality. Additionally, we discuss novel technologies to enrich and characterize CTC from more patients, and the potential clinical uses of CTC's in determining prognosis and monitoring treatment effects, and as a source of tissue to identify predictive markers of drug sensitivity to guide treatment selection. Prospective studies, designed around the biomarker itself and the specific clinical context for which it is applied, are needed to further assess the role of these and novel markers in clinical practice.
doi:10.1158/1078-0432.CCR-10-2650
PMCID: PMC3743247  PMID: 21680546
12.  A Phase 2 Study of Intravenous Panobinostat in Patients With Castration-Resistant Prostate Cancer 
Purpose
Panobinostat, a pan-deacetylase inhibitor, increases acetylation of proteins associated with growth and survival of malignant cells. This phase 2 study evaluated the efficacy of intravenous (IV) panobinostat in patients with castration-resistant prostate cancer (CRPC) who had previously received chemotherapy. The primary end point was 24-week progression-free survival. Secondary end points included safety, tolerability, and the proportion of patients with a prostate-specific antigen (PSA) decline.
Methods
IV panobinostat (20 mg/m2) was administered to patients on days 1 and 8 of a 21-day cycle. Tumor response was assessed by imaging every 12 weeks (4 cycles) according to modified Response Evaluation Criteria In Solid Tumors (Scher HI et al, 2005), and PSA response was defined as a 50% decrease from baseline maintained for ≥ 4 weeks. Safety monitoring was routinely performed and included electrocardiogram monitoring.
Results
Of 35 enrolled patients, 4 (11.4%) were alive without progression of disease at 24 weeks. PSA was evaluated in 34 (97.1%) patients: 5 (14.3%) patients demonstrated a decrease in PSA but none ≥ 50%; 1 patient (2.9%) had carcinoembryonic antigen as a marker of his prostate cancer, which declined by 43%. Toxicities regardless of relationship to panobinostat included fatigue (62.9%), thrombocytopenia (45.7%), nausea (51.4%), and decreased appetite (37.1%).
Conclusions
Despite promising preclinical data and scientific rationale, treatment with IV panobinostat did not show a sufficient level of clinical activity to pursue further investigation as a single agent in CRPC.
doi:10.1007/s00280-013-2224-8
PMCID: PMC3970811  PMID: 23820963
Prostate cancer; Deacetylase inhibitor; Panobinostat; Prostate-specific antigen
13.  End Points and Outcomes in Castration-Resistant Prostate Cancer: From Clinical Trials to Clinical Practice 
Journal of Clinical Oncology  2011;29(27):3695-3704.
New therapeutic approaches for castration-resistant prostate cancer (CRPC) introduce new treatment dilemmas: how best to sequence these options to maximally benefit patients, what tests to perform before and after treatment to assess disease status, and how to interpret the test results and use them to guide treatment. New and specific end points for different classes of drugs are needed to provide the information to guide these treatment decisions. In 2008, the Prostate Cancer Working Group 2 consensus criteria for early-phase clinical trials redefined clinical trial end points as first, to control, relieve, or eliminate disease manifestations present when treatment is started and second, to prevent or delay future disease manifestations. Disease manifestations include prostate-specific antigen (PSA), soft-tissue disease (nodes and/or viscera), bone disease (most common site of spread), and symptoms. Recent US Food and Drug Administration (FDA) approvals for CRPC therapies have been based on the prevent/delay end points that reflect unequivocal benefit to a patient: prolongation of life or reduction in skeletal-related events (SREs). For the practicing oncologist, the control/relieve/eliminate outcomes should serve primarily to inform the decision of whether to continue therapy. In this review, we consider individual end points such as PSA, imaging, and patient-reported outcomes in the context of the control/relieve/eliminate and prevent/delay framework. We address the time-to-event end points of metastasis prevention, SRE, time to progression, and overall survival in the context of regulatory approvals. We also discuss circulating tumor cells measured with the CellSearch assay, recently cleared by the FDA for monitoring CRPC.
doi:10.1200/JCO.2011.35.8648
PMCID: PMC3675708  PMID: 21859988
14.  A Novel Automated Platform for Quantifying the Extent of Skeletal Tumour Involvement in Prostate Cancer Patients Using the Bone Scan Index 
European Urology  2012;62(1):78-84.
Background
There is little consensus on a standard approach to analysing bone scan images. The Bone Scan Index (BSI) is predictive of survival in patients with progressive prostate cancer (PCa), but the popularity of this metric is hampered by the tedium of the manual calculation.
Objective
Develop a fully automated method of quantifying the BSI and determining the clinical value of automated BSI measurements beyond conventional clinical and pathologic features.
Design, setting, and participants
We conditioned a computer-assisted diagnosis system identifying metastatic lesions on a bone scan to automatically compute BSI measurements. A training group of 795 bone scans was used in the conditioning process. Independent validation of the method used bone scans obtained ≤3 mo from diagnosis of 384 PCa cases in two large population-based cohorts. An experienced analyser (blinded to case identity, prior BSI, and outcome) scored the BSI measurements twice. We measured prediction of outcome using pretreatment Gleason score, clinical stage, and prostate-specific antigen with models that also incorporated either manual or automated BSI measurements.
Measurements
The agreement between methods was evaluated using Pearson’s correlation coefficient. Discrimination between prognostic models was assessed using the concordance index (C-index).
Results and limitations
Manual and automated BSI measurements were strongly correlated (ρ = 0.80), correlated more closely (ρ = 0.93) when excluding cases with BSI scores ≥10 (1.8%), and were independently associated with PCa death (p < 0.0001 for each) when added to the prediction model. Predictive accuracy of the base model (C-index: 0.768; 95% confidence interval [CI], 0.702–0.837) increased to 0.794 (95% CI, 0.727–0.860) by adding manual BSI scoring, and increased to 0.825 (95% CI, 0.754–0.881) by adding automated BSI scoring to the base model.
Conclusions
Automated BSI scoring, with its 100% reproducibility, reduces turnaround time, eliminates operator-dependent subjectivity, and provides important clinical information comparable to that of manual BSI scoring.
doi:10.1016/j.eururo.2012.01.037
PMCID: PMC3402084  PMID: 22306323
15.  Department of Defense Prostate Cancer Clinical Trials Consortium: A New Instrument for Prostate Cancer Clinical Research 
Clinical Genitourinary Cancer  2009;7(1):51-57.
Background
In 2005, the US Department of Defense, through the US Army Medical Research and Materiel Command, Office of the Congressionally Directed Medical Research Programs, created a funding mechanism to form a clinical trials consortium to conduct phase I and II studies in prostate cancer. This is the first report of the Prostate Cancer Clinical Trials Consortium (PCCTC).
Patients and Methods
The Department of Defense award supports a consortium of 10 prostate cancer research centers. Memorial Sloan-Kettering Cancer Center was awarded the Coordinating Center grant for the consortium and charged with creating an infrastructure to conduct early-phase multicenter clinical trials. Each participating center was required to introduce ≥ 1 clinical trial per year and maintain accrual of a minimum of 35 patients per year.
Results
The PCCTC was launched in 2006 and now encompasses 10 leading prostate cancer research centers. Fifty-one trials have been opened, and 1386 patients have been accrued at member sites. Members share an online clinical trial management system for protocol tracking, electronic data capture, and data storage. A legal framework has been instituted, and standard operating procedures, an administrative structure, editorial support, centralized budgeting, and mechanisms for scientific review are established.
Conclusion
The PCCTC fulfills a congressional directive to create a clinical trials instrument dedicated to early-phase prostate cancer studies. The member institutions have built an administrative, informatics, legal, financial, statistical, and scientific infrastructure to support this endeavor. Clinical trials are open and accruing in excess of federally mandated goals.
doi:10.3816/CGC.2009.n.009
PMCID: PMC3394090  PMID: 19213669
Clinical consortium; Collaborative; Infrastructure; Phase I/II trial
16.  ETS factors reprogram the androgen receptor cistrome and prime prostate tumorigenesis in response to PTEN loss 
Nature medicine  2013;19(8):1023-1029.
Studies of ETS-mediated prostate oncogenesis have been hampered by the lack of suitable experimental systems. Here we describe a new conditional mouse model which gives robust, homogenous ERG expression throughout the prostate. When combined with homozygous Pten loss, mice developed accelerated, highly penetrant invasive prostate cancer. In mouse prostate tissue, ERG significantly increased androgen receptor (AR) binding. Robust ERG-mediated transcriptional changes, observed only in the setting of Pten loss, included restoration of AR transcriptional outut and genes involved in cell death, migration, inflammation and angiogenesis. Similarly, ETV1 positively regulated AR cistrome and transcriptional output in ETV1-translocated, PTEN-deficient human prostate cancer cells. In two large clinical cohorts, ERG and ETV1 expression correlated with higher AR transcriptional output in PTEN-negative prostate cancer specimens. We propose that ETS factors cause prostate-specific transformation by altering the AR cistrome, priming the prostate epithelium to respond to aberrant upstream signals such as PTEN loss.
doi:10.1038/nm.3216
PMCID: PMC3737318  PMID: 23817021
17.  Randomized Phase 3 Trial of Abiraterone Acetate in Men with Metastatic Castration-Resistant Prostate Cancer and No Prior Chemotherapy 
The New England journal of medicine  2012;368(2):138-148.
Background
Abiraterone acetate, an androgen biosynthesis inhibitor, improves overall survival (OS) in metastatic castration-resistant prostate cancer (mCRPC) post-chemotherapy. Many mCRPC patients never receive chemotherapy and thus cannot benefit from abiraterone acetate; we evaluated this agent in mCRPC patients who had not received chemotherapy.
Methods
In this double-blind study, 1088 patients were randomized 1:1 to abiraterone acetate (1000 mg) plus prednisone (5 mg twice daily) or placebo plus prednisone. Co-primary end points were radiographic progression-free survival (rPFS) and OS. Secondary end points measured clinically relevant landmarks of mCRPC progression. Patient-reported outcomes included pain progression and quality of life.
Results
The study was unblinded after a planned interim analysis (IA) at 43% of OS events. Treatment with abiraterone acetate-prednisone resulted in a 57% reduction in the risk of radiographic progression or death (hazard ratio [HR], 0.43; 95% confidence interval [CI]: 0.35 to 0.52; P<0.001; 13% OS events IA) and an estimated 25% decrease in the risk of death (HR, 0.75; 95% CI: 0.61 to 0.93; P=0.009; 43% OS events IA). Secondary end points supported superiority of abiraterone acetate-prednisone: time to cytotoxic chemotherapy initiation, opiate use for cancer-related pain, prostate-specific antigen progression (all P<0.001) and performance status deterioration (P=0.005). Self-reported time to pain progression and patient functional status degradation favored abiraterone acetate-prednisone (P=0.05 and P=0.003). Grade 3/4 mineralocorticoid-related adverse events and liver function test abnormalities were more common with abiraterone acetate-prednisone.
Conclusions
Abiraterone acetate produces OS and rPFS benefits, as well as significant delays in clinical deterioration and initiation of chemotherapy, in mCRPC.
doi:10.1056/NEJMoa1209096
PMCID: PMC3683570  PMID: 23228172
Abiraterone acetate; prednisone; metastatic castration-resistant prostate cancer; androgen; CYP17
18.  Phase I Dose-Escalation Study of the Novel Anti-androgen BMS-641988 in Patients with Castration-Resistant Prostate Cancer 
Purpose
BMS-641988 is an androgen receptor antagonist with increased potency relative to bicalutamide in both in vitro and in vivo prostate cancer models. A first-in-man phase I study was conducted to define the safety and tolerability of oral BMS-641988 in patients with castration-resistant prostate cancer (CRPC).
Experimental Design
Doses were escalated from 5 to 150 mg based on discrete pharmacokinetic parameters in cohorts of 3 to 6 subjects. After establishing safety with 20 mg of BMS-641988 in the United States, a companion study was opened in Japan to assess differences in drug metabolism between populations.
Results
Sixty-one men with CRPC were treated with daily BMS-641988. The pharmacokinetics of BMS-641988 and its active metabolites were proportional to dose. One patient experienced an epileptic seizure at a dose of 60 mg administered twice. Despite achieving target drug exposures, anti-tumor activity was limited to 1 partial response. Seventeen of 23 evaluable patients (74%) exhibited stable disease on imaging (median 15 weeks; range 8–32), and 10 of 61 patients (16%) achieved a ≥30%. decline in levels of prostate-specific antigen (PSA). Partial agonism was seen within the context of this study upon removal of the drug as evidenced by a decrease in PSA.
Conclusions
Although the clinical outcomes of predominantly stable disease and partial agonism were similar to what was observed in the preclinical evaluation of the compound, the limited anti-tumor activity of BMS-641988 at therapeutic dose levels coupled with an episode of seizure activity led to study closure.
doi:10.1158/1078-0432.CCR-10-2955
PMCID: PMC3070382  PMID: 21131556
19.  Androgen Receptor Antagonists in Castration-Resistant Prostate Cancer 
Persistent androgen receptor signaling despite low levels of serum androgens has been identified as a critical target for drug discovery in castration-resistant prostate cancer. As proof of principle that the androgen receptor remains relevant in castration-resistant prostate cancer, two recently FDA-approved androgen receptor–targeted agents—abiraterone and enzalutamide—have increased overall survival for patients with castration-resistant prostate cancer in the setting of prior chemotherapy. This review focuses on the androgen receptor and two direct antagonists, enzalutamide and ARN-509. These next-generation androgen receptor antagonists offer great promise for patients with advanced disease. Relative to conventional antiandrogens such as bicalutamide, they bind to the receptor with higher affinity, prevent nuclear translocation and DNA binding, and induce apoptosis without agonist activity in preclinical models. The success of these androgen receptor–targeted agents in the clinic has changed the landscape of therapy for patients with castration-resistant prostate cancer, and further therapeutic options building on this platform are currently in development.
doi:10.1097/PPO.0b013e318282635a
PMCID: PMC3788593  PMID: 23337756
prostate cancer; androgen receptor; androgen receptor antagonists; antiandrogens; enzalutamide; ARN-509
20.  Phase I Trial of 17-Allylamino-17-Demethoxygeldanamycin in Patients with Advanced Cancer 
Purpose
To define the maximum tolerated dose (MTD), toxicities, and pharmacokinetics of 17-allylamino-17-demethoxygeldanamycin (17-AAG) when administered using continuous and intermittent dosing schedules.
Experimental Design
Patients with progressive solid tumor malignancies were treated with 17-AAG using an accelerated titration dose escalation schema. The starting dose and schedule were 5 mg/m2 daily for 5 days with cycles repeated every 21 days. Dosing modifications based on safety, pharmacodynamic modeling, and clinical outcomes led to the evaluation of the following schedules: daily × 3 repeated every 14 days; twice weekly (days 1, 4, 8, and 11) for 2 weeks every 3 weeks; and twice weekly (days 1 and 4) without interruption. During cycle 1, blood was collected for pharmacokinetic and pharmacodynamic studies.
Results
Fifty-four eligible patients were treated. The MTD was schedule dependent: 56 mg/m2 on the daily × 5 schedule; 112 mg/m2 on the daily × 3 schedule; and 220 mg/m2 on the days 1, 4, 8, and 11 every-21-day schedule. Continuous twice-weekly dosing was deemed too toxic because of delayed hepatotoxicity. Hepatic toxicity was also dose limiting with the daily × 5 schedule. Other common toxicities encountered were fatigue, myalgias, and nausea. This latter adverse effect may have been attributable, in part, to the DMSO-based formulation. Concentrations of 17-AAG above those required for activity in preclinical models could be safely achieved in plasma. Induction of a heat shock response and down-regulation of Akt and Raf-1 were observed in biomarker studies.
Conclusion
The MTD and toxicity profile of 17-AAG were schedule dependent. Intermittent dosing schedules were less toxic and are recommended for future phase II studies.
doi:10.1158/1078-0432.CCR-06-1863
PMCID: PMC3203693  PMID: 17363532
21.  Distinct patterns of dysregulated expression of enzymes involved in androgen synthesis and metabolism in metastatic prostate cancer tumors 
Cancer research  2012;72(23):6142-6152.
Androgen receptor (AR) signaling persists in castration-resistant prostate carcinomas (CRPCs), due to several mechanisms that include increased AR expression and intratumoral androgen metabolism. We investigated the mechanisms underlying aberrant expression of transcripts involved in androgen metabolism in CRPC. We compared gene expression profiles and DNA copy number alteration (CNA) data from 29 normal prostate tissue samples, 127 primary prostate carcinomas (PCas) and 19 metastatic PCas. Steroidogenic enzyme transcripts were evaluated by qRT-PCR in PCa cell lines and circulating tumor cells (CTCs) from CRPC patients. Metastatic PCas expressed higher transcript levels for AR and several steroidogenic enzymes, including SRD5A1, SRD5A3, and AKR1C3, while expression of SRD5A2, CYP3A4, CYP3A5 and CYP3A7 was decreased. This aberrant expression was rarely associated with CNAs. Instead, our data suggest distinct patterns of coordinated aberrant enzyme expression. Inhibition of AR activity by itself stimulated AKR1C3 expression. The aberrant expression of the steroidogenic enzyme transcripts were detected in CTCs from CRPC patients. In conclusion, our findings identify substantial interpatient heterogeneity and distinct patterns of dysregulated expression of enzymes involved in intratumoral androgen metabolism in PCa. These steroidogenic enzymes represent targets for complete suppression of systemic and intratumoral androgen levels, an objective that is supported by the clinical efficacy of the CYP17 inhibitor abiraterone. A comprehensive AR axis targeting approach via simultaneous, frontline enzymatic blockade and/or transcriptional repression of several steroidogenic enzymes, in combination with GnRH analogs and potent anti-androgens, would represent a powerful future strategy for PCa management.
doi:10.1158/0008-5472.CAN-12-1335
PMCID: PMC3685485  PMID: 22971343
Prostate cancer; androgen synthesis; testosterone; dihydrotestosterone; CYP17; AKR1C3; abiraterone; MDV3100 (enzalutamide)
22.  Rapid elimination kinetics of free PSA or human kallikrein-related peptidase 2 after initiation of gonadotropin-releasing hormone-antagonist treatment of prostate cancer: potential for rapid monitoring of treatment responses 
Background
The utility of conventional prostate-specific antigen (PSA) measurements in blood for monitoring rapid responses to treatment for prostate cancer is limited because of its slow elimination rate. Prior studies have shown that free PSA (fPSA), intact PSA (iPSA) and human kallikrein-related peptidase 2 (hK2) are eliminated more rapidly after radical prostatectomy. In contrast, all three markers have similarly slow elimination rates after castration induced by GnRH agonists, possibly due to the slow onset of castration. Therefore, we assessed elimination rates of tPSA, fPSA, iPSA and hK2 after rapid induction of castration with degarelix (Firmagon®), a novel GnRH antagonist.
Methods
This study included 24 patients treated with degarelix. Blood was taken at 1, 3, 7, 14, 21, and 28 days after injection of degarelix. Free and total PSA were measured with a commercial dual-label assay, and with in-house research assays of intact PSA and hK2.
Results
Median (interquartile range, IQR) tPSA at baseline was 23.4 (15.8, 59.8). Twenty-two patients (92%) reached castrate levels of testosterone within 24 hours of degarelix initiation, and all patients did so within 72 hours. All kallikrein forms declined in an exponential fashion after degarelix administration. The median time to 50% reduction in biomarker level was 8–9 days for tPSA or complexed PSA versus 2–4 days for hK2, iPSA and fPSA. The percentage eliminated at day 3 and day 7 was significantly higher for hK2, iPSA and fPSA than for tPSA (all p<0.02), while tPSA and complexed PSA were similar.
Conclusions
The rapid decline of fPSA, iPSA and hK2 after fast induction of castration with degarelix is similar to that reported after prostatectomy and offers a novel, informative method to monitor rapid onset of therapeutic action targeting signaling of the androgen receptor,
doi:10.1515/cclm-2011-0967
PMCID: PMC3474140  PMID: 22718641
androgen deprivation therapy; human kallikrein-related peptidase 2; prostate cancer; prostate-specific antigen; tumor markers
23.  The Brief Pain Inventory and its “Pain at its Worst in the last 24 Hours” Item: Clinical Trial Endpoint Considerations* 
Pain medicine (Malden, Mass.)  2010;11(3):337-346.
Context
In 2006, the United States Food and Drug Administration (FDA) released a draft Guidance for Industry on the use of Patient-Reported Outcomes (PRO) Measures in Medical Product Development to Support Labeling Claims. This draft guidance outlines psychometric aspects that should be considered when designing a PRO measure, including conceptual framework, content validity, construct validity, reliability, and the ability to detect clinically meaningful score changes. When finalized, it may provide a blueprint for evaluations of PRO measures which can be considered by sponsors and investigators involved in PRO research and drug registration trials.
Objective
In this review we examine the short form of the Brief Pain Inventory (BPI) and particularly the “pain at its worst in the last 24 hours” item in the context of the FDA draft guidance, to assess its utility in clinical trials that include pain as a PRO endpoint.
Results and Conclusions
After a systematic evaluation of the psychometric aspects of the BPI, we conclude that the BPI and its “pain at its worst in the last 24 hours” item generically satisfy most key recommendations outlined in the draft guidance for assessing a pain-reduction treatment effect. Nonetheless, when the BPI is being considered for assessment of pain endpoints in a registration trial, sponsors and investigators should consult with the appropriate FDA division early during research design to discuss whether there is sufficient precedent to use the instrument in the population of interest or whether additional evaluations of measurement properties are advisable.
doi:10.1111/j.1526-4637.2009.00774.x
PMCID: PMC3806650  PMID: 20030743
Pain Measurement; Patient Outcome Assessment; United States Food and Drug Administration; Drug Labeling
24.  Validation and clinical utility of prostate cancer biomarkers 
Nature reviews. Clinical oncology  2013;10(4):225-234.
To improve future drug development and patient management for patients with castration-resistant prostate cancer (CRPC), surrogate biomarkers that are linked to relevant outcomes are urgently needed. A biomarker must be measurable, reproducible, linked to relevant clinical outcomes, and demonstrate utility. This is a rapidly evolving area, with recent trials in CRPC incorporating the detection of circulating tumour cells (CTCs), imaging, and patient-reported outcome biomarkers. We discuss the framework for the development of biomarkers for CRPC, including different categories and contexts of use. We also highlight the requirements of analytical validation, the sequence of trials needed for clinical validation and regulatory approval, and the future outlook for imaging and CTC biomarkers.
doi:10.1038/nrclinonc.2013.30
PMCID: PMC3790270  PMID: 23459624
25.  Phase II Multicenter Study of Abiraterone Acetate Plus Prednisone Therapy in Patients With Docetaxel-Treated Castration-Resistant Prostate Cancer 
Journal of Clinical Oncology  2010;28(9):1496-1501.
Purpose
Persistence of ligand-mediated androgen receptor signaling has been documented in castration-resistant prostate cancers (CRPCs). Abiraterone acetate (AA) is a potent and selective inhibitor of CYP17, which is required for androgen biosynthesis in the testes, adrenal glands, and prostate tissue. This trial evaluated the efficacy and safety of AA in combination with prednisone to reduce the symptoms of secondary hyperaldosteronism that can occur with AA monotherapy.
Patients and Methods
Fifty-eight men with progressive metastatic CRPC who experienced treatment failure with docetaxel-based chemotherapy received AA (1,000 mg daily) with prednisone (5 mg twice daily). Twenty-seven (47%) patients had received prior ketoconazole. The primary outcome was ≥ 50% prostate-specific antigen (PSA) decline, with objective response by Response Evaluation Criteria in Solid Tumors (RECIST) criteria, and changes in Eastern Cooperative Oncology Group (ECOG) performance status (PS) and circulating tumor cell (CTC) numbers. Safety was also evaluated.
Results
A ≥ 50% decline in PSA was confirmed in 22 (36%) patients, including 14 (45%) of 31 ketoconazole-naïve and seven (26%) of 27 ketoconazole-pretreated patients. Partial responses were seen in four (18%) of 22 patients with RECIST-evaluable target lesions. Improved ECOG PS was seen in 28% of patients. Median time to PSA progression was 169 days (95% CI, 82 to 200 days). CTC conversions with treatment from ≥ 5 to < 5 were noted in 10 (34%) of 29 patients. The majority of AA-related adverse events were grade 1 to 2, and no AA-related grade 4 events were seen.
Conclusion
AA plus prednisone was well tolerated, with encouraging antitumor activity in heavily pretreated CRPC patients. The incidence of mineralocorticoid-related toxicities (hypertension or hypokalemia) was reduced by adding low-dose prednisone. The combination of AA plus prednisone is recommended for phase III investigations.
doi:10.1200/JCO.2009.25.9259
PMCID: PMC3040042  PMID: 20159814

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