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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.  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
3.  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
4.  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
5.  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
6.  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
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.  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
9.  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
10.  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
11.  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
12.  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
13.  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
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.  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
16.  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
17.  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
18.  A Phase II Trial of Docetaxel with Rapid Androgen Cycling as a Treatment for Patients with Prostate Cancer 
Purpose
We evaluated rapid androgen cycling in combination with docetaxel for men with progressive non-castrate prostate cancers.
Methods
Non-castrate patients with ≤ 6 months of hormones were eligible. Cohort 1 (63 patients ) received 6 28-day cycles of docetaxel (75 mg/m2), leuprolide and 7 days of topical testosterone. Cohort 2 (39 patients) received 9 21-day cycles of docetaxel (70 mg/m2), leuprolide and 3 days of testosterone. The primary endpoint was the proportion of patients at 18 months who achieved non -castrate testosterone levels (>150 ng/dl) and an undetectable PSA (≤ 0.05, ≤0.5, or ≤2.0 ng/ml with prior prostatectomy, radiotherapy, or no definitive therapy, respectively). Cytochrome P450 3A4 (CYP3A4) activity and docetaxel pharmacokinetics were evaluated.
Results
A higher proportion of patients achieved the undetectable PSA outcome at 18 months in cohort 2 relative to cohort 1 (13% vs. 0%). The 16% incidence of febrile neutropenia was higher than observed in patients was castration-resistant disease, which may have been related to a 50% reduction in overall docetaxel clearance in the non-castrate group. There was no alteration in CYP3A4 activity (P=0.87) or docetaxel clearance (P=0.88) between cycles.
Conclusions
The undetectable PSA endpoint allows for a rapid screening of interventions for further study. Increasing the number of docetaxel cycles following a shorter period of testosterone repletion, and a longer duration of testosterone depletion, increased the proportion of men who achieved an undetectable PSA. The higher-than-expected incidence of febrile neutropenia may have been related to the reduced overall docetaxel clearance in patients with non-castrate vs castrate testosterone levels.
doi:10.1200/JCO.2007.15.1928
PMCID: PMC3051836  PMID: 18565882
19.  Antitumour activity of MDV3100 in castration-resistant prostate cancer: a phase 1-2 study 
Lancet  2010;375(9724):1437-1446.
Background
MDV3100 is a rationally-designed androgen receptor antagonist that blocks androgen receptor (AR) binding, nuclear translocation, and co-activator recruitment more effectively than the androgen receptor antagonists currently in use. MDV3100 is also unique in that it prevents DNA binding, induces apoptosis, and has no agonist activity when AR is overexpressed. Because growth of castration-resistant prostate cancer (CRPC) appears to depend upon continued androgen receptor signaling, we hypothesized that MDV3100 could be effective therapy for men with CRPC. Antitumor activity and safety were assessed in a phase 1-2 trial.
Methods
Eligible patients with progressive metastatic CRPC were enrolled in cohorts of 3-6 patients. Once the safety of a dose was established, cohorts were expanded to include at least 12 chemotherapy-naïve and 12 post-chemotherapy treated patients.
Findings
140 patients were treated with doses ranging from 30 to 600 mg daily. Positron emission tomography (PET) imaging to assess androgen receptor blockade showed decreased 18-fluorodihydrotestosterone binding at dosages of 60 mg/day and above. Antitumor effects were observed at all dosages including declines in serum PSA of 50% or more in 56% of patients, responses in soft tissue, stabilized bone disease, and conversion from unfavourable to favourable circulating tumour cell counts. The median time to progression was 47 weeks for radiological progression. The maximal tolerated dose for sustained treatment (>28 days) was 240 mg and the most common adverse event was dose-dependent fatigue, which generally resolved following dose reduction.
Interpretation
Encouraging antitumor activity on all outcomes assessed was observed for MDV3100 in both chemotherapy-naïve and post-chemotherapy patients with CRPC, establishing that patients with CRPC are not uniformly hormone-refractory. A phase 3 trial in patients with progressive disease after docetaxel treatment is underway.
doi:10.1016/S0140-6736(10)60172-9
PMCID: PMC2948179  PMID: 20398925
20.  Antiandrogens and androgen depleting therapies in prostate cancer: novel agents for an established target 
The lancet oncology  2009;10(10):981-991.
Summary
Activation of the androgen receptor is critical for prostate cancer growth at all points in the illness. Currently therapies targeting the androgen receptor, including androgen depletion approaches and antiandrogens, do not completely inhibit androgen receptor activity. Prostate cancer cells develop resistance to castration by acquiring changes such as AR overexpression that result in reactivation of the receptor. Based on understanding of these resistance mechanisms and androgen synthesis pathways, novel antiandrogens and androgen depleting agents have been tested. Notably, MDV3100, a novel antiandrogen designed for activity in prostate cancer model systems with overexpressed AR and, abiraterone acetate, a 17-α-hydroxylase/17,20 lyase inhibitor that blocks steroid biosynthesis in the adrenal gland and in the tumor, have demonstrated significant activity in early phase trials and are being tested in the phase III setting.
doi:10.1016/S1470-2045(09)70229-3
PMCID: PMC2935850  PMID: 19796750
21.  Fluorescence in situ Hybridization Analysis of Circulating Tumor Cells in Metastatic Prostate Cancer 
Purpose
To assess the feasibility of characterizing gene copy number alteration by fluorescence in situ hybridization of circulating tumor cells (CTC) isolated using the CellSearch system in patients with progressive castration resistant metastatic prostate cancer (CRPC).
Experimental Design
We used probe combinations that included the androgen receptor (AR) and MYC genes for FISH analysis of CTC samples collected from 77 men with metastatic CRPC.
Results
High-level chromosomal amplification of AR was detected in 37.5% of samples analyzed, and relative gain of MYC in 55.8%. No such abnormalities were detected in samples with CTC counts of less than 10, reflecting ascertainment difficulty in these lower count samples.
Conclusion
The CTC isolated from our patient cohort present a very similar molecular cytogenetic profile to that reported for late-stage tumors, and thus demonstrate that analysis of CTC can be a valuable, noninvasive surrogate for routine tumor profiling. Furthermore, we demonstrate that as many as 50% of these patients have substantial amplification of the AR locus, indicating that androgen signaling continues to play an important role in late-stage prostate cancer.
doi:10.1158/1078-0432.CCR-08-2036
PMCID: PMC2875199  PMID: 19276271
circulating tumor cells; prostate cancer; tumor markers; FISH; androgen receptor
22.  Pharmacokinetic Assessment of the Uptake of 16β-[18F]-Fluoro-5α Dihydrotestosterone (FDHT) in Prostate Tumors as Measured by PET 
Objective
The aim of this study was to develop a clinically applicable non-invasive method to quantify changes in androgen receptor (AR) levels based on 18F-FDHT PET in prostate cancer patients undergoing therapy.
Methods
Thirteen patients underwent dynamic 18F-FDHT PET scans over a selected tumor. Concurrent venous blood samples were acquired for blood metabolite analysis. A second cohort of 25 patients, injected with 18F-FDHT underwent dynamic PET imaging of the heart. These data were used to generate a population-based input function, essential for pharmacokinetic modeling. Linear compartmental pharmacokinetic models of increasing complexity were tested on the tumor tissue data. Four suitable models were applied and compared using the Bayesian Information Criterion (BIC). Model 1 consisted of an instantaneously equilibrating space followed by a unidirectional trap. Models 2a and 2b contained a reversible space between the instantaneously equilibrating space and the trap, into which metabolites were excluded (2a) or allowed (2b). Model 3 built upon Model 2b with the addition of a second reversible space preceding the unidirectional trap and from which metabolites were excluded.
Results
The half-life of the 18F-FDHT in blood was determined to be between 6-7 minutes. As a consequence, the uptake of 18F-FDHT in prostate cancer lesions reached a plateau within 20-minutes as the blood-borne activity was consumed. Radiolabeled metabolites were shown not to bind to AR in in-vitro studies with CWR22 cells. Model 1 produced reasonable and robust fits for all datasets and was judged best by the BIC for 16 out of 26 tumor scans. Models 2a, 2b and 3 were judged best in seven, two and one case, respectively.
Conclusion
Our study explores the clinical potential of using 18F-FDHT PET to make estimates of free AR concentration. This process involved the estimation of a net-uptake parameter such as Model 1’s ktrap that could serve as a surrogate measure of AR expression in metastatic prostate cancer. Our initial studies suggest a simple body-mass normalized standard uptake value (SUV) is reasonably well correlated to model based ktrap estimates, which we surmise may be proportional to AR expression. Validation studies to test this hypothesis are underway.
doi:10.2967/jnumed.109.066159
PMCID: PMC2866076  PMID: 20080885
23.  Circulating Tumor Cell Number as a Prognostic Marker in Progressive Castration-Resistant Prostate Cancer: Use in Clinical Practice and Clinical Trials 
The lancet oncology  2009;10(3):233-239.
SUMMARY
Background
To assess the use of circulating tumor cell (CTC) number as a continuous variable as a prognostic factor for survival, and for the clinical management of patients with progressive metastatic castration-resistant prostate cancer receiving first-line chemotherapy.
Methods
The study included 164 men with progressive metastatic castration-resistant prostate cancer. CTCs were isolated by immunomagnetic capture from blood samples drawn at baseline and after the initiation of first-line chemotherapy. Baseline variables including CTC number, prostate-specific antigen (PSA), and lactate dehydrogenase (LDH), and posttreatment variables (fold change in CTCs and PSA) were tested for association with survival using the Cox proportional hazards models. The concordance probability estimate was used to gauge the discriminatory strength of the informative factors in separating low- and high-risk patients.
Findings
At baseline, variables associated with increased risk of death were a high LDH (hazard ratio [HR] 6.44), CTC number (HR 1.58), and PSA (HR 1.26), low albumin (HR 0.10), and low hemoglobin (HR 0.72) (all p<0.001). At 4, 8, and 12 weeks posttreatment, changes in CTC number were strongly associated with risk (all p≤0.001), while changes in PSA were modestly associated (p=0.04 to 0.8). The combination of factors most predictive of survival were LDH and CTC number (concordance probability estimate 0.72–0.75). Time to CTC progression was modestly associated with time to death.
Interpretation
CTC number, analyzed as a continuous variable, was more predictive of survival than PSA at baseline and during patient follow-up, and can be used to monitor disease status. A model including baseline and posttreatment CTC, independent of discrete cutoff values, and baseline LDH was most predictive. The prospective evaluation of CTC number as an intermediate endpoint of survival in randomized prospective clinical trials is warranted.
Funding
The Prostate Cancer Foundation.
doi:10.1016/S1470-2045(08)70340-1
PMCID: PMC2774131  PMID: 19213602
circulating tumor cells; prostate cancer; PSA; LDH; prognosis
24.  Targeting the androgen receptor pathway in prostate cancer 
Current opinion in pharmacology  2008;8(4):440-448.
Summary of recent advances
When prostate cancers progress following androgen depletion therapy, there are currently few treatment options with only one, docetaxel, that has been shown to prolong life. Recent work has shown that castration resistant prostate cancers (CRPC) continue to depend on androgen receptor (AR) signaling which is reactivated despite low serum androgen levels. Currently available AR targeted therapy, including GnRH agonists and antiandrogens, cannot completely shut down AR signaling. Several mechanisms that enhance AR signaling in an androgen depleted environment have been elucidated. These include AR mutations that allow activation by low androgen levels or by other endogenous steroids, AR overexpression, increased local intracrine synthesis of androgens, and upregulation of tyrosine kinase pathways. This has led to the development of a number of novel agents targeting AR signaling pathway, including more effective antiandrogens, inhibitors of CYP17, an enzyme required for androgen synthesis, inhibitors of 5α-reductase, inhibitors of HSP90 which protects AR from degradation, inhibitors of histone deacetylases which is required for optimal AR mediated transcription, as well as inhibitors of tyrosine kinase inhibitors. Many of these strategies are currently being tested in clinical trials in CRPC.
doi:10.1016/j.coph.2008.07.005
PMCID: PMC2574839  PMID: 18674639
25.  Assessing Outcomes in Prostate Cancer Clinical Trials: A 21st Century Tower of Babel 
Cancer  2008;113(5):966-974.
Background
Due to the osseous distribution of prostate cancer metastases, progression is more readily identified than response in prostate cancer clinical trials. As a result, there is an increased focus on progression free survival (PFS) as a phase II endpoint. PFS, however, is vulnerable to inter-study design variability. We sought to identify and quantify this variability and the resultant error in PFS across prostate cancer clinical trials.
Methods
We reviewed phase II clinical trials of cytotoxic agents in castrate metastatic prostate cancer over 5-years to evaluate the policies determining extent of disease and the definitions of disease progression. A simulation model was created to define the degree of error in estimating PFS in 3 hypothetical cohorts (median PFS of 12, 24, and 36 weeks) when the frequency of outcome assessments varies.
Results
Imaging policies for trial entry were heterogeneous, as were the type, timing, and indications for outcome assessments. In the simulation, error in the reported PFS varied according to the interval between assessments. The difference between the detected and the true PFS could vary as much as 6.4 weeks per cycle, strictly resulting from the variability of assessment schedules tested.
Conclusions
Outcome assessment policies are highly variable in phase II studies of castration-resistant prostate cancer patients, despite published guidelines designed to standardize authenticating disease progression. The estimated error in PFS can exceed 6 weeks per cycle, just due to variations in the assessment schedules. Comparisons of PFS times from different studies must be made with circumspection.
doi:10.1002/cncr.23719
PMCID: PMC2708077  PMID: 18661513
prostate cancer; phase II clinical trials; outcome assessments; endpoints; progression-free survival

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