Emmanuel S Antonarakis

Johns Hopkins University, Baltimore, Maryland, United States

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Publications (78)465.21 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: BACKGROUND The optimal sequencing of the multiple active agents now available for metastatic castration-resistant prostate cancer (mCRPC) is unclear. Prior reports have suggested diminished responses to sequential lines of androgen receptor (AR)-targeted therapies, but it is unknown whether subsequent taxane-based chemotherapy may be more effective than sequential AR-targeting treatment. We sought to evaluate the clinical activity of enzalutamide versus docetaxel in men with mCRPC who progressed on abiraterone.METHODS We performed a single-institution retrospective analysis of consecutive mCRPC patients who had progressed on abiraterone therapy and subsequently received either enzalutamide (n = 30) or docetaxel (n = 31). We evaluated clinical outcomes including prostate-specific antigen decline of >30% (PSA30) or >50% (PSA50), PSA-progression-free survival (PSA-PFS), and clinical/radiographic PFS. We performed multivariable modeling to control for baseline and on-treatment differences between groups.RESULTSCompared to subjects who received enzalutamide post-abiraterone, subjects who received docetaxel post-abiraterone had more bone metastases, more visceral metastases, higher baseline PSA, and had more frequent PSA tests while on-treatment. There were no significant differences in PSA30 (41% for enzalutamide vs. 53% for docetaxel) or PSA50 (34% vs. 40%) response rates between the two groups; there remained no difference after stratifying by presence/absence of prior response to abiraterone. Median PSA-PFS was 4.1 versus 4.1 months for the enzalutamide and docetaxel cohorts, respectively (HR 1.35, 95% CI, 0.53–3.66, P = 0.502). Median PFS was 4.7 versus 4.4 months, respectively (HR 1.44, 95% CI, 0.77–2.71, P = 0.257). PSA-PFS and PFS did not differ after stratifying by prior response to abiraterone. In multivariable analyses, there were no significant differences in PSA-PFS or PFS between the two groups.CONCLUSIONS Treatment with either enzalutamide or docetaxel produced modest PSA responses and PFS intervals in this abiraterone-pretreated mCRPC population. In this retrospective study with small sample size, no significant differences in outcomes were observed between groups. Therefore, either enzalutamide or docetaxel may be a reasonable option in men who have progressed on abiraterone. Prostate © 2014 Wiley Periodicals, Inc.
    The Prostate 07/2014; · 3.84 Impact Factor
  • Daniel L Suzman, Emmanuel S Antonarakis
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    ABSTRACT: Medical oncologists who treat men with castration-resistant prostate cancer (CRPC) have seen an abundance of new agents approved by the United States Food and Drug Administration in the last decade for a disease that was previously difficult to treat after becoming resistant to androgen-deprivation therapy. Advances in understanding of the mechanisms of castration-resistance and prostate cancer progression have highlighted several pathways and targets that appear promising to better treat CRPC. As the majority of CRPC appears to continue to rely on the androgen receptor for growth and progression, several of these agents directly or indirectly target the androgen receptor. A novel microtubule-targeted agent, cabazitaxel, has demonstrated an overall survival benefit following progression on docetaxel. Other agents target tumor immunogenicity and immune checkpoint pathways to attempt to harness the host immune system. The recently approved radiopharmaceutical, radium-223 dichloride, has demonstrated impressive results in patients with extensive bony metastases with minimal toxicity. Lastly, further understanding of the pathways underlying CRPC progression has led to late-phase clinical trials with the novel agents: custirsen, tasquinimod and cabozantinib. This article reviews the approved therapies for CRPC, the agents currently in late-phase clinical trials, and notable early-phase trials of novel therapies and their combinations, with particular attention to trials incorporating novel biomarkers and intermediate endpoints to better identify those men who may or may not benefit from specific therapies.
    Therapeutic advances in medical oncology. 07/2014; 6(4):167-79.
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    ABSTRACT: The development of noninvasive methods to detect and monitor tumors continues to be a major challenge in oncology. We used digital polymerase chain reaction-based technologies to evaluate the ability of circulating tumor DNA (ctDNA) to detect tumors in 640 patients with various cancer types. We found that ctDNA was detectable in >75% of patients with advanced pancreatic, ovarian, colorectal, bladder, gastroesophageal, breast, melanoma, hepatocellular, and head and neck cancers, but in less than 50% of primary brain, renal, prostate, or thyroid cancers. In patients with localized tumors, ctDNA was detected in 73, 57, 48, and 50% of patients with colorectal cancer, gastroesophageal cancer, pancreatic cancer, and breast adenocarcinoma, respectively. ctDNA was often present in patients without detectable circulating tumor cells, suggesting that these two biomarkers are distinct entities. In a separate panel of 206 patients with metastatic colorectal cancers, we showed that the sensitivity of ctDNA for detection of clinically relevant KRAS gene mutations was 87.2% and its specificity was 99.2%. Finally, we assessed whether ctDNA could provide clues into the mechanisms underlying resistance to epidermal growth factor receptor blockade in 24 patients who objectively responded to therapy but subsequently relapsed. Twenty-three (96%) of these patients developed one or more mutations in genes involved in the mitogen-activated protein kinase pathway. Together, these data suggest that ctDNA is a broadly applicable, sensitive, and specific biomarker that can be used for a variety of clinical and research purposes in patients with multiple different types of cancer.
    Science translational medicine 02/2014; 6(224):224ra24. · 10.76 Impact Factor
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    ABSTRACT: Taxanes may partly mediate their effect in castration-resistant prostate cancer (CRPC) through disruption of androgen-receptor trafficking along microtubules. This raises the possibility of cross-resistance between androgen-directed agents and docetaxel. To evaluate docetaxel efficacy after abiraterone treatment in CRPC patients. This was a single-institution, retrospective analysis in CRPC patients (N=119) who either received abiraterone before docetaxel (AD) (n=24) or did not receive abiraterone before docetaxel (docetaxel-only; n=95). Men initiated docetaxel between December 2007 (the date abiraterone was first used at our center) and May 2013. The primary efficacy end points were prostate-specific antigen progression-free survival (PSA-PFS) and clinical/radiographic progression-free survival (PFS) on docetaxel. Differences between groups were assessed using univariate and multivariable analyses. Men in the AD group had a significantly higher risk for progression than those in the docetaxel-only group. Median PSA-PFS was 4.1 mo in the AD group and 6.7 mo in the docetaxel-only group (p=0.002). Median PFS was also shorter in the AD group (4.4 mo vs 7.6 mo; p=0.003). In multivariable analysis, prior abiraterone treatment remained an independent predictor of shorter PSA-PFS (hazard ratio [HR]: 3.48; 95% confidence interval [CI], 1.36-8.94; p=0.01) and PFS (HR: 3.62; 95% CI, 1.41-9.27; p=0.008). PSA declines ≥50% were less frequent in the AD group (38% vs 63%; p=0.02). The small size and retrospective nature of this study may have introduced bias. Men receiving abiraterone before docetaxel were more likely to progress on docetaxel and less likely to achieve a PSA response than abiraterone-naïve patients. Cross-resistance between abiraterone and docetaxel may explain these findings; however, larger, more definitive studies are still needed to confirm this. We examined the efficacy of docetaxel in castration-resistant prostate cancer patients who either did or did not receive prior abiraterone. We found that men receiving abiraterone before docetaxel were less likely to achieve a PSA response and were more likely to progress sooner on docetaxel than abiraterone-untreated patients. This may be due to cross-resistance.
    European Urology 01/2014; · 10.48 Impact Factor
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    Michael T Schweizer, Emmanuel S Antonarakis
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    ABSTRACT: Advanced prostate cancer has been recognized as being responsive to androgen deprivation since the 1940s when Charles Huggins first described the role of surgical castration in managing these patients. However, androgen deprivation only results in transient disease control for the vast majority of men, with those progressing in spite of castrate testosterone levels labeled as having castrate-resistant prostate cancer (CRPC). Until 2004, the therapeutic arena for these patients had remained stagnant, with no agent having shown a survival gain in the CRPC setting. Two landmark publications changed the prostate cancer treatment landscape by providing 'level-1 evidence' that docetaxel-based chemotherapy led to prolongation in overall survival (OS). This was followed by the approval of cabazitaxel in 2010 on the basis of Phase III data demonstrating its efficacy in patients pretreated with docetaxel. More recently, a number of next-generation androgen-directed agents (e.g. abiraterone and enzalutamide) have also been shown to lead to a survival benefit in men with CRPC. With so many new treatment options available, a number of questions remain. These include: how to best sequence chemotherapy with these newer hormonal agents, the clinical implication of cross-resistance between taxanes and androgen-directed agents and which subsets of patients may benefit most from early use of chemotherapy. This review will provide an overview of the evolving role of chemotherapy in the management of advanced prostate cancer in the current era.
    Asian Journal of Andrology 01/2014; · 2.14 Impact Factor
  • Jocelyn L Wozney, Emmanuel S Antonarakis
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    ABSTRACT: Treatments that target the androgen axis represent an effective strategy for patients with advanced prostate cancer, but the disease remains incurable and new therapeutic approaches are necessary. Significant advances have recently occurred in our understanding of the growth factor and signaling pathways that are active in prostate cancer. In conjunction with this, many new targeted therapies with sound preclinical rationale have entered clinical development and are being tested in men with castration-resistant prostate cancer. Some of the most relevant pathways currently being exploited for therapeutic gain are HGF/c-Met signaling, the PI3K/AKT/mTOR pathway, Hedgehog signaling, the endothelin axis, Src kinase signaling, the IGF pathway, and angiogenesis. Here, we summarize the biological basis for the use of selected targeted agents and the results from available clinical trials of these drugs in men with prostate cancer.
    CANCER AND METASTASIS REVIEW 01/2014; · 9.35 Impact Factor
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    ABSTRACT: Background Anticoagulants have been postulated to possess antitumor activity, although clinical data supporting this claim are conflicting. No definitive data exist on the clinical impact of anticoagulant therapy in patients with prostate cancer. The aim of this study was to investigate the association between therapeutic anticoagulant use and survival in men with metastatic castration-resistant prostate cancer (CRPC) receiving docetaxel chemotherapy. Patients and Methods We retrospectively reviewed the records of 247 consecutive patients with metastatic CRPC who received first-line docetaxel chemotherapy between 1998 and 2010 at a single institution. Among them, 29 patients (11.7 %) received therapeutic anticoagulation (low-molecular-weight heparin (LMWH) or warfarin) for the treatment of venous thromboembolism. Univariate and multivariable Cox proportional hazards regression models were used to investigate the effect of anticoagulant use on overall survival. Results In univariate analysis, anticoagulant use was associated with improved survival (hazard ratio [HR], 0.61; P=0.024). Median survival was 20.9 months in the anticoagulation group versus 17.1 months in the control group (P=0.024). In multivariable analysis, anticoagulant use remained a significant predictor of survival after adjusting for other baseline prognostic factors (HR, 0.49; P=0.023). When each anticoagulant was considered separately in the multivariable model, LMWH remained significantly prognostic for survival (HR, 0.48; P=0.035) while warfarin use did not. Conclusions Anticoagulant use (LMWH in particular) is an independent predictor of improved survival in men with metastatic CRPC receiving docetaxel. These data provide the impetus to further explore the antitumor properties of anticoagulants in patients with prostate cancer and warrant validation in prospective studies.
    Clinical Genitourinary Cancer 01/2014; · 1.43 Impact Factor
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    ABSTRACT: Nearly three-quarters of a million American men who have been treated with prostatectomy and/or radiation therapy experience an increasing prostate-specific antigen level known as biochemical recurrence. Although androgen-deprivation therapy remains a reasonable option for some men with biochemical recurrence, deferring androgen ablation or offering nonhormonal therapies may be appropriate in patients in whom the risk of clinical or metastatic progression and prostate cancer-specific death is low. A risk-stratified approach informed by the patient's prostate-specific antigen kinetics, comorbidities, and personal preferences is recommended to determine the best management approach.
    Hematology/oncology clinics of North America 12/2013; 27(6):1205-19. · 2.05 Impact Factor
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    ABSTRACT: Background:Outcomes in men with National Comprehensive Cancer Network (NCCN) high-risk prostate cancer (PCa) can vary substantially-some will have excellent cancer-specific survival, whereas others will experience early metastasis even after aggressive local treatments. Current nomograms, which yield continuous risk probabilities, do not separate high-risk PCa into distinct sub-strata. Here, we derive a binary definition of very-high-risk (VHR) localized PCa to aid in risk stratification at diagnosis and selection of therapy.Methods:We queried the Johns Hopkins radical prostatectomy database to identify 753 men with NCCN high-risk localized PCa (Gleason sum 8-10, PSA >20 ng ml(-1), or clinical stage T3). Twenty-eight alternate permutations of adverse grade, stage and cancer volume were compared by their hazard ratios for metastasis and cancer-specific mortality. VHR criteria with top-ranking hazard ratios were further evaluated by multivariable analyses and inclusion of a clinically meaningful proportion of the high-risk cohort.Results:The VHR cohort was best defined by primary pattern 5 present on biopsy, or 5 cores with Gleason sum 8-10, or multiple NCCN high-risk features. These criteria encompassed 15.1% of the NCCN high-risk cohort. Compared with other high-risk men, VHR men were at significantly higher risk for metastasis (hazard ratio 2.75) and cancer-specific mortality (hazard ratio 3.44) (P<0.001 for both). Among high-risk men, VHR men also had significantly worse 10-year metastasis-free survival (37% vs 78%) and cancer-specific survival (62% vs 90%).Conclusions:Men who meet VHR criteria form a subgroup within the current NCCN high-risk classification who have particularly poor oncological outcomes. Use of these characteristics to distinguish VHR localized PCa may help in counseling and selection optimal candidates for multimodal treatments or clinical trials.Prostate Cancer and Prostatic Disease advance online publication, 5 November 2013; doi:10.1038/pcan.2013.46.
    Prostate Cancer and Prostatic Diseases 11/2013; · 2.81 Impact Factor
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    ABSTRACT: To determine whether the pretreatment neutrophil-to-lymphocyte ratio (NLR), a measure of systemic inflammatory response, is associated with overall survival (OS) in men receiving chemotherapy with docetaxel for metastatic castration-resistant prostate cancer (mCRPC). Records from 238 consecutive patients who were treated with first-line docetaxel-containing chemotherapy for mCRPC at a single high-volume centre from 1998 to 2010 (and who had adequate information to enable calculation of NLR) were reviewed. Univariable and multivariable Cox regression models were used to predict OS after chemotherapy initiation. In univariable analyses, the NLR as a discrete variable (optimal threshold 3.0) was significantly associated with OS (P = 0.001). In multivariable analyses, a lower NLR (≤3.0) was associated with lower risk of all-cause mortality (P = 0.002). In Kaplan-Meier analysis, the median OS was higher (18.3 vs 14.4 months) in patients that did not have an elevated NLR than in those with an elevated NLR (log-rank; P < 0.001). Men who were treated with first-line docetaxel for mCRPC who had a low pretreatment NLR (≤3.0) had significantly longer OS. NLR may be a potentially useful clinical marker of systemic inflammatory response in predicting OS in men with mCRPC who receive docetaxel and may be helpful to stratify patients for clinical trials. These findings derived from a retrospective analysis need to be validated in larger populations in prospective studies, and in the context of different therapies.
    BJU International 10/2013; · 3.05 Impact Factor
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    ABSTRACT: Background:PSA doubling time (PSADT) is an attractive intermediate end point for assessing novel therapies in biochemically recurrent prostate cancer (BRPC). This study explores whether PSADT calculations are influenced by frequency/duration of PSA measurements, and whether statistical variability leads investigators to find false significant results.Methods:In retrospective analyses of two BRPC cohorts: Johns Hopkins Hospital (JHH) patients who deferred therapy and placebo patients on a randomized clinical trial (RCT), we calculated changes in PSADT from early measurements to later measurements using subsets of available PSAs for patients with 6 and 9 PSAs. We simulated hypothetical single-arm trials using randomly selected, 50-patient subsets and simulated two-arm RCTs.Results:JHH cohort (n=205) had median follow-up 58 months, median age 61 years and median Gleason 7. PSA variability changed with duration of PSA measurement as median within-patient PSADT increases for men with >6 PSAs ranged from 1.0 to 1.4 months by PSA subset while increases for men with 9 PSAs ranged from 3.9 to 4.1 months. Frequency of measurement did not change PSA variability as PSADT increase was unchanged when odd values were used instead of all values. Approximately 30% of JHH men experienced >200% increases in PSADT. Up to 62% of 50-patient single-arm simulations detected a significant PSADT change, whereas simulated RCTs did not. Results were supported in the RCT placebo cohort; 46% of patients experienced PSADT increases >200%.Conclusions:These data suggest that calculated PSADT in BRPC may naturally increase over time in the absence of therapy and may be influenced by duration of PSA follow-up. As a result, single-arm trials could show false significant increases despite the lack of active treatment of these patients. Placebo-controlled RCTs including clinical end points are recommended to screen novel agents in men with BRPC to mitigate bias because of natural PSADT variability.Prostate Cancer and Prostatic Disease advance online publication, 8 October 2013; doi:10.1038/pcan.2013.40.
    Prostate cancer and prostatic diseases 10/2013; · 2.10 Impact Factor
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    ABSTRACT: Clinical trials in men with biochemically recurrent prostate cancer (BRPC) have been hampered by long survival times, making overall survival (OS) a difficult end point to reach. Intermediate end points are needed in order to conduct such trials within a more feasible time frame. This is a retrospective analysis of 450 men with BRPC following prostatectomy treated at a single institution between 1981 and 2010, of which 140 developed subsequent metastases. Androgen deprivation therapy (ADT) was deferred until after the development of metastases. Cox regression models were developed to investigate factors influencing OS. Median metastasis-free survival (MFS) was 10.2 years [95% confidence interval (CI) 7.6-14.0 years]; median OS after metastasis was 6.6 years (95%CI 5.8-8.4 years). Multivariable Cox regressions identified four independently prognostic variables for OS: MFS (HR 0.77; 95% CI 0.63-0.94), number of metastases (≤3 versus ≥4; HR 0.50; 95% CI 0.29-0.85), pain (absent versus present; HR 0.43; 95% CI 0.25-0.72), and bisphosphonate use (yes versus no; HR 0.60; 95% CI 0.37-0.98). MFS emerged as an independent predictor of OS in men with BRPC treated with deferred ADT after the development of metastases. MFS may be a reasonable intermediate end point in future clinical trials. This observation requires prospective validation.
    Annals of Oncology 08/2013; · 7.38 Impact Factor
  • Jatinder Goyal, Emmanuel S Antonarakis
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    ABSTRACT: Treatment of castration-resistant prostate cancer remains an area of unmet medical need. Evidence suggests that this entity continues to be driven by androgens and androgen receptor (AR) signaling. Abiraterone acetate, a pregnenolone derivative, is an oral selective and irreversible inhibitor of the key steroidogenic enzyme CYP17. It possesses dual 17-α hydroxylase and C17,20-lyase blocking activity, the result of which is decreased gonadal and extra-gonadal androgen synthesis. Abiraterone was first approved by the US Food and Drug Administration (FDA) in 2011 following the demonstration of superior survival compared with placebo in the post-docetaxel population. Since that time, more evidence has been generated from preclinical studies and clinical trials which have considerably enhanced our understanding of this complex disease. In this paper, we review the development of abiraterone acetate, its pharmacological characteristics, and its effects on the androgen-AR signaling axis, along with the combined experience from clinical trials. We also discuss some of the ongoing trials using this agent, as well as potential mechanisms of abiraterone resistance, novel bio-marker development, and future directions using AR-directed therapies.
    Clinical medicine insights. Urology. 07/2013; 2013(7):1-14.
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    Rosa Nadal, Zsuzsanna H McMahan, Emmanuel S Antonarakis
    Clinical Genitourinary Cancer 06/2013; · 1.43 Impact Factor
  • Emmanuel S Antonarakis
    Translational andrology and urology. 06/2013; 2(2):119-120.
  • Emmanuel S Antonarakis, Mario A Eisenberger
    Journal of Clinical Oncology 04/2013; · 18.04 Impact Factor
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    ABSTRACT: Circulating tumor cells (CTCs) have received intense scientific scrutiny because they travel in the bloodstream and are therefore well situated to mediate hematogenous metastasis. However, the potential of CTCs to actually form new tumors has not been tested. Popular methods of isolating CTCs are biased towards larger, more differentiated, non-viable cells, creating a barrier to testing their tumor forming potential. Without relying on cell size or the expression of differentiation markers, our objective was to isolate viable prostate CTCs from mice and humans and assay their ability to initiate new tumors. Therefore, blood was collected from transgenic adenocarcinoma of the mouse prostate (TRAMP) mice and from human patients with metastatic castration-resistant prostate cancer (PCa). Gradient density centrifugation or red cell lysis was used to remove erythrocytes, and then leukocytes were depleted by magnetic separation using CD45 immunoaffinity beads. CTCs fractions from TRAMP mice and PCa patients were verified by immunocytochemical staining for cytokeratin 8 and EpCAM, and inoculated into immunodeficient mice. TRAMP tumor growth was monitored by palpation. Human tumor growth formation was monitored up to 8 months by ultrasensitive PSA assays performed on mouse serum. We found viable tumor cells present in the bloodstream that were successfully isolated from mice without relying on cell surface markers. Two out of nine immunodeficient mice inoculated with TRAMP CTCs developed massive liver metastases. CTCs were identified in blood from PCa patients but did not form tumors. In conclusion, viable CTCs can be isolated without relying on epithelial surface markers or size fractionation. TRAMP CTCs were tumorigenic, so CTCs isolated in this way contain viable tumor-initiating cells. Only two of nine hosts grew TRAMP tumors and none of the human CTCs formed tumors, which suggests that most CTCs have relatively low tumor-forming potential. Future studies should identify and target the highly tumorigenic cells.
    Oncotarget 03/2013; · 6.64 Impact Factor
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    ABSTRACT: Background. The antifungal drug itraconazole inhibits angiogenesis and Hedgehog signaling and delays tumor growth in murine prostate cancer xenograft models. We conducted a noncomparative, randomized, phase II study evaluating the antitumor efficacy of two doses of oral itraconazole in men with metastatic prostate cancer.Patients and Methods. We randomly assigned 46 men with chemotherapy-naïve metastatic castration-resistant prostate cancer (CRPC) to receive low-dose (200 mg/day) or high-dose (600 mg/day) itraconazole until disease progression or unacceptable toxicity. The primary endpoint was the prostate-specific antigen (PSA) progression-free survival (PPFS) rate at 24 weeks; a 45% success rate in either arm was prespecified as constituting clinical significance. Secondary endpoints included the progression-free survival (PFS) rate and PSA response rate (Prostate Cancer Working Group criteria). Exploratory outcomes included circulating tumor cell (CTC) enumeration, serum androgen measurements, as well as pharmacokinetic and pharmacodynamic analyses.Results. The high-dose arm enrolled to completion (n = 29), but the low-dose arm closed early (n = 17) because of a prespecified futility rule. The PPFS rates at 24 weeks were 11.8% in the low-dose arm and 48.0% in the high-dose arm. The median PFS times were 11.9 weeks and 35.9 weeks, respectively. PSA response rates were 0% and 14.3%, respectively. In addition, itraconazole had favorable effects on CTC counts, and it suppressed Hedgehog signaling in skin biopsy samples. Itraconazole did not reduce serum testosterone or dehydroepiandrostenedione sulfate levels. Common toxicities included fatigue, nausea, anorexia, rash, and a syndrome of hypokalemia, hypertension, and edema.Conclusion. High-dose itraconazole (600 mg/day) has modest antitumor activity in men with metastatic CRPC that is not mediated by testosterone suppression.
    The Oncologist 01/2013; · 4.10 Impact Factor
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    ABSTRACT: PURPOSE: KX2-391 is an oral non-ATP-competitive inhibitor of Src kinase and tubulin polymerization. In phase 1 trials, prostate-specific antigen (PSA) declines were seen in patients with advanced prostate cancer. We conducted a single-arm phase 2 study evaluating KX2-391 in men with chemotherapy-naïve bone-metastatic castration-resistant prostate cancer (CRPC). METHODS: We treated 31 patients with oral KX2-391 (40 mg twice-daily) until disease progression or unacceptable toxicity. The primary endpoint was 24-week progression-free survival (PFS); a 50 % success rate was pre-defined as clinically significant. Secondary endpoints included PSA progression-free survival (PPFS) and PSA response rates. Exploratory outcomes included pharmacokinetic studies, circulating tumor cell (CTC) enumeration, and analysis of markers of bone resorption [urinary N-telopeptide (uNTx); C-telopeptide (CTx)] and formation [bone alkaline phosphatase (BAP); osteocalcin]. RESULTS: The trial closed early after accrual of 31 patients, due to a pre-specified futility rule. PFS at 24 weeks was 8 %, and median PFS was 18.6 weeks. The PSA response rate (≥30 % decline) was 10 %, and median PPFS was 5.0 weeks. Additionally, 18 % of men with unfavorable (≥5) CTCs at baseline converted to favorable (<5) CTCs with treatment. The proportion of men with declines in bone turnover markers was 32 % for uNTx, 21 % for CTx, 10 % for BAP, and 25 % for osteocalcin. In pharmacokinetic studies, median C (max) was 61 (range 16-129) ng/mL, and median AUC was 156 (35-348) ng h/mL. Common toxicities included hepatic derangements, myelosuppression, fatigue, nausea, and constipation. CONCLUSION: KX2-391 dosed at 40 mg twice-daily lacks antitumor activity in men with CRPC, but has modest effects on bone turnover markers. Because a C (max) of ≥142 ng/mL is required for tubulin polymerization inhibition (defined from preclinical studies), higher once-daily dosing will be used in future trials.
    Cancer Chemotherapy and Pharmacology 01/2013; · 2.80 Impact Factor
  • Daniel L. Suzman, Emmanuel S. Antonarakis
    Clinical Genitourinary Cancer 01/2013; · 1.43 Impact Factor

Publication Stats

520 Citations
465.21 Total Impact Points

Institutions

  • 2007–2014
    • Johns Hopkins University
      • Department of Radiation Oncology and Molecular Radiation Sciences
      Baltimore, Maryland, United States
  • 2013
    • Medical University of South Carolina
      • Division of Hematology/Oncology
      Charleston, SC, United States
    • University of Maryland, Baltimore
      Baltimore, Maryland, United States
  • 2012
    • University of Alabama at Birmingham
      • Department of Medicine
      Birmingham, AL, United States
  • 2006–2012
    • Johns Hopkins Medicine
      • • Department of Medical Oncology
      • • Department of Medicine
      Baltimore, Maryland, United States
    • University of Wales
      Cardiff, Wales, United Kingdom
  • 2010
    • Walter Reed National Military Medical Center
      Washington, Washington, D.C., United States