Correlation of increased eosinophil count following sipuleucel-T treatment with outcome in patients (pts) with metastatic castrate-resistant prostate cancer (mCRPC).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 4650-4650 ◽  
Author(s):  
Douglas G. McNeel ◽  
Daniel W. Lin ◽  
Thomas Gardner ◽  
Nadeem A. Sheikh ◽  
James Boyd Whitmore ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Hypereosinophilic Syndrome ◽  
Phase Iii ◽  
Cellular Immunotherapy ◽  
Cancer Specific Survival ◽  
Phase Iii Trials ◽  
Castrate Resistant ◽  
Humoral Responses ◽  
The Impact ◽  
Eosinophil Counts

4650 Background: Sipuleucel-T is the first autologous cellular immunotherapy approved for asymptomatic or minimally symptomatic mCRPC. In the IMPACT trial, pts treated with sipuleucel-T had transient increases in eosinophil counts compared with control. In this retrospective analysis, we assess potential correlations between eosinophilia, overall survival (OS), prostate cancer-specific survival (PCSS) and immune response following sipuleucel-T. Methods: Data from three phase III trials (D9901, D9902A, and IMPACT) were pooled. The analysis included CBCs performed at baseline and wks 2–34. Eosinophilia was defined as either >ULN (with normal baseline), or a max change from baseline within the top quartile, at any time between wks 2–16. Results: Increased eosinophil counts were seen in sipuleucel-T pts by wk 6, decreasing to near baseline by wk 14; eosinophil counts in control pts were stable. Of 377 sipuleucel-T pts eligible for analysis, 105 (27.9%) had eosinophilia. Baseline disease characteristics associated with eosinophilia were indicative of better prognosis (i.e., longer Halabi predicted survival [p=0.007], lower PSA [P=0.033], higher Hgb [p<0.001], and no prior docetaxel [p=0.012]). In univariate analyses, eosinophilia correlated with improved OS (HR=0.75; 95%CI: 0.56–1.01; p=0.057) and PCSS (HR=0.71; 95%CI: 0.53–0.97; p=0.031); trends persisted after adjusting for Halabi. The magnitude of eosinophilia positively correlated with antigen-specific humoral responses (p ≤0.039 for wks 6, 14 and 26) and elevations in the cytokines at wk 6 (IL2 [p=0.011], IL5 [p=0.038] and TARC [p=0.001]). AEs occurring more frequently (p<0.05) in pts with eosinophilia were infusion-related: pyrexia (33.3 v 21.3%) and nausea (19.0 v 10.7%). No cases of hypereosinophilic syndrome were reported. Conclusions: Increases in eosinophils after sipuleucel-T correlated with improved OS and PCSS. Large increases in eosinophil counts were associated with humoral responses and Th2-type cytokine production. Further studies of eosinophilia as a biomarker for sipuleucel-T response, particularly in earlier disease settings, are of interest.

Impact of salvage therapy with APC8015F on the overall survival (OS) benefit achieved with sipuleucel-T in three phase III studies of metastatic castrate-resistant prostate cancer (mCRPC).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e15120-e15120
Author(s):  
Leonard G. Gomella ◽  
Chadi Nabhan ◽  
Todd DeVries ◽  
James Boyd Whitmore ◽  
Mark Walter Frohlich ◽  
...  
Keyword(s):  
Treatment Effect ◽  
Salvage Therapy ◽  
Failure Time ◽  
Phase Iii ◽  
Comparable Efficacy ◽  
Cellular Immunotherapy ◽  
Three Phase ◽  
Castrate Resistant ◽  
The Impact ◽  
Phase Iii Studies

e15120 Background: Sipuleucel-T is an autologous cellular immunotherapy approved for asymptomatic or minimally symptomatic mCRPC. Three phase III sipuleucel-T trials (D9901, D9902A and D9902B [IMPACT]) allowed control patients (pts) to receive salvage treatment with an autologous product derived from previously frozen cells (APC8015F). We previously reported that salvage therapy with APC8015F demonstrated no deleterious effect and may have improved outcomes in control pts, potentially reducing the observed survival benefit seen with sipuleucel-T. Thus, we performed an exploratory analysis of pooled data from phase III studies to estimate the impact of APC8015F treatment on the OS benefit conferred by sipuleucel-T. Methods: We analyzed the effect of salvage APC8015F therapy on OS, and used a rank-preserving structural failure time (RPSFT) model to estimate control arm OS if treatment with APC8015F had not occurred. This allows estimation of the effect of sipuleucel-T treatment on OS, adjusting for salvage effect. Results: Median OS from randomization in the three pooled trials was 25.4 months with sipuleucel-T (n=488) and 21.5 months with control (n=249). Of the control arm pts, 165 (66.3%) subsequently received APC8015F. Median OS from randomization in the control population was 23.6 months for pts receiving APC8015F and 12.7 months for those who did not. Using the RPSFT model, and assuming APC8015F was as effective as sipuleucel-T, the estimate of median OS for control pts was 17.3 months, representing an 8.1 month median increase in OS with sipuleucel-T. Results from extensions of the RPSFT model, where APC8015F is assumed to have less treatment effect than sipuleucel-T, will be presented. Conclusions: These analyses estimated a median OS benefit for sipuleucel-T between 3.9 and 8.1 months, assuming that APC8015F had either no efficacy or comparable efficacy to sipuleucel-T, respectively. The results suggest a possible greater treatment effect of sipuleucel-T than was reported in the three phase III studies. Future studies should account for potential crossover treatment bias as this may diminish estimates of OS benefit.

scholarly journals New Therapeutics to Treat Castrate-Resistant Prostate Cancer

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Ömer Acar ◽  
Tarık Esen ◽  
Nathan A. Lack
Keyword(s):  
Prostate Cancer ◽  
Late Stage ◽  
Endocrine Disruptor ◽  
Patient Survival ◽  
Abiraterone Acetate ◽  
Phase Iii ◽  
Bone Targeting ◽  
Phase Iii Trials ◽  
Castrate Resistant Prostate Cancer ◽  
Castrate Resistant

The effective treatment of castrate-resistant prostate cancer (CRPC) has proven to be very challenging. Until recently, docetaxel was the only therapeutic demonstrated to extend overall patient survival. Yet recently, a considerable number of new therapeutics have been approved to treat CRPC patients. These remarkable advances now give new tools for the therapeutic management of late-stage prostate cancer. In this review, we will examine mechanistic and clinical data of several newly approved therapeutics including the chemotherapeutic cabazitaxel, antiandrogen enzalutamide, endocrine disruptor abiraterone acetate, immunotherapy sipuleucel-T, and bone-targeting radiopharmaceutical alpharadin. In addition, we will examine other promising therapeutics that are currently in Phase III trials.

scholarly journals Apalutamide in the treatment of castrate-resistant prostate cancer: evidence from clinical trials

2018 ◽  
Vol 10 (12) ◽  
pp. 445-454 ◽  
Author(s):  
Vadim S. Koshkin ◽  
Eric J. Small
Keyword(s):  
Prostate Cancer ◽  
Clinical Trials ◽  
Specific Antigen ◽  
The United States ◽  
Phase Iii ◽  
Metastatic Progression ◽  
Free Survival ◽  
Phase Iii Trials ◽  
Castrate Resistant Prostate Cancer ◽  
Castrate Resistant

Apalutamide (ARN-509) is a second-generation androgen receptor (AR) antagonist that was developed to inhibit AR-mediated prostate cancer cell proliferation. Following the initial promising clinical efficacy results in phase I and II clinical trials of patients with metastatic castrate-resistant prostate cancer (CRPC), apalutamide has been investigated in several phase III trials. Particular interest has focused on the development of effective therapy for the prevention of disease progression in patients with nonmetastatic (nm or M0) CRPC, especially patients who have a rapid prostate-specific antigen (PSA) doubling time that is indicative of shorter bone metastasis-free survival and associated with significant morbidity and mortality. The results from the phase III SPARTAN trial were recently published and reported a significant benefit of apalutamide relative to placebo in patients with nmCRPC and a high risk of metastatic progression. The study noted marked improvement in the primary endpoint of metastasis-free survival as well as several relevant secondary clinical endpoints, including time to symptomatic progression. These results led to the United States Food and Drug Administration (US FDA) approval of apalutamide in the nmCRPC setting in February 2018. This review summarizes the clinical development of apalutamide, culminating with the pivotal SPARTAN trial as well as other phase III trials which may further expand potential indications for this agent in the near future.

scholarly journals Meta-Analysis Evaluating the Impact of Site of Metastasis on Overall Survival in Men With Castration-Resistant Prostate Cancer

2016 ◽  
Vol 34 (14) ◽  
pp. 1652-1659 ◽  
Author(s):  
Susan Halabi ◽  
William Kevin Kelly ◽  
Hua Ma ◽  
Haojin Zhou ◽  
Nicole C. Solomon ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Overall Survival ◽  
Liver Metastases ◽  
Lung Metastases ◽  
Phase Iii ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Phase Iii Trials ◽  
The Impact ◽  
Sites Of Metastases

Purpose Reports have suggested that metastatic site is an important predictor of overall survival (OS) in men with metastatic castration-resistant prostate cancer (mCRPC), but these were based on a limited number of patients. We investigate the impact of site of metastases on OS of a substantial sample of men with mCRPC who received docetaxel chemotherapy in nine phase III trials. Patients and Methods Individual patient data from 8,820 men with mCRPC enrolled onto nine phase III trials were combined. Site of metastases was categorized as lymph node (LN) only, bone with or without LN (with no visceral metastases), any lung metastases (but no liver), and any liver metastases. Results Most patients had bone with or without LN metastases (72.8%), followed by visceral disease (20.8%) and LN-only disease (6.4%). Men with liver metastases had the worst median OS (13.5 months). Although men with lung metastases had better median OS (19.4 months) compared with men with liver metastases, they had significantly worse median survival duration than men with nonvisceral bone metastases (21.3 months). Men with LN-only disease had a median OS of 31.6 months. The pooled hazard ratios for death in men with lung metastases compared with men with bone with or without LN metastases and in men with any liver metastases compared with men with lung metastases were 1.14 (95% CI, 1.04 to 1.25; P = .007) and 1.52 (95% CI, 1.35 to 1.73; P < .0001), respectively. Conclusion Specific sites of metastases in men with mCRPC are associated with differential OS, with successive increased lethality for lung and liver metastases compared with bone and nonvisceral involvement. These data may help in treatment decisions, the design of future clinical trials, and understanding the variation in biology of different sites of metastases in men with mCRPC.

Postdocetaxel treatment for castrate-resistant prostate cancer: The sequential use of abiraterone and cabazitaxe.

2013 ◽  
Vol 31 (6_suppl) ◽  
pp. 234-234 ◽  
Author(s):  
David Gareth Fackrell ◽  
Nicholas David James ◽  
Daniel Ford
Keyword(s):  
Prostate Cancer ◽  
Survival Benefit ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Free Survival ◽  
Select Group ◽  
Phase Iii Trials ◽  
Castrate Resistant Prostate Cancer ◽  
Castrate Resistant ◽  
The Uk

234 Background: Large phase III trials have shown both abiraterone (Abi) and cabazitaxel (Cbz) to have a survival benefit in patients with metastatic castrate resistant prostate cancer (mCRPC). They are now used routinely throughout the UK in this setting. The mechanisms of resistance of these drugs remain unclear and therefore, their sequential use is less recognised. We present data from patients who have been exposed to both therapies. Methods: In this retrospective study, we searched our own pharmacy databases to identify all patients that had been exposed to both Abi and Cbz. All patients were treated between April 2009 and October 2012. A total of 21 patients were reviewed and clinical data was collected. SPSS software was used to create Kaplan Meier curves. Results: 17 of the 21 patients received Abi before Caz. Median progression free survival for patients on the sequential regimes was 16.9 months (95% Confidence interval: 10.5-23.3). Reviewing the drugs individually found progression free survival was 5.1 months (4.4-6.0 months) with Abi and 7.1 months (5.1-9.1) with Cbz. Conclusions: In a select group of patients who are fit enough to receive both drugs, superior progression free survival is seen than can be expected on one drug alone. The data compares favourably to that seen in the TROPIC study where time to progression on Cbz was 2.8 months. Furthermore, lack of response to one drug did not preclude worthwhile response to the other agent. These findings are consistent with the drugs having separate mechanisms. At this stage the series is not mature enough to draw conclusions on survival benefit. An updated series, involving larger patient numbers, will be presented at the meeting.

Quality-of-life (QoL) assessment and reporting in prostate cancer: A systematic review of phase III trials published between 2012 and 2016.

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 219-219 ◽  
Author(s):  
Laura Marandino ◽  
Anna La Salvia ◽  
Cristina Sonetto ◽  
Emmanuele De Luca ◽  
Daniele Pignataro ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Phase Iii ◽  
Castration Resistant ◽  
Primary Endpoints ◽  
Phase Iii Trials ◽  
Eortc Qlq C30 ◽  
Hormone Sensitive ◽  
Eortc Qlq ◽  
The Impact

219 Background: We previously reported that QoL is not included among endpoints and QoL results are significantly underreported in a high proportion of recently published phase III trials in oncology. In this study our aim was to describe QoL prevalence and heterogeneity in QoL reporting in prostate cancer (PC) phase III trials. Methods: Whole database included all primary publications (P) of phase III trials evaluating anticancer drugs published between 2012 and 2016 by 11 major journals. For this analysis, we extracted the subset of PC trials. We analyzed QoL inclusion among endpoints, presence of QoL results and methodology of QoL analysis. Results: 35 P were identified (21 in castration-resistant [CRPC], 9 in advanced hormone sensitive [aHSPC], incl. both metastatic and biochemical relapsed, and 5 in earlier stages). In 13 (37.1%) QoL was not listed among study endpoints: 7/21 (33.3%) in CRPC, 3/9 (33.3%) in aHSPC, and 3/5 (60%) in earlier stages. Out of 22 primary P of trials including QoL among endpoints, QoL results were not reported in 9 (40.9%). Overall, no QoL data were available in 22/35 (62.9%) primary P (61.9% in CRPC, 44.4% in aHSPC and 100% in earlier disease). QoL data were not available in 15/25 (60%) trials with overall survival (OS) as primary endpoint, and in 7/10 (70%) trials with other primary endpoints. QoL data were not available in 7/16 (43.8%) trials with a positive result (25% in CRPC, 40% in aHSPC, 100% in earlier stages). In 18 trials with available QoL results (incl. secondary publications), most common QoL tools were FACT-P (11, 61.1%) and EORTC QLQ-C30 (6, 33.3%). Common methods of analysis were mean changes (6, 33.3%), mean scores over time (6, 33.3%), time to deterioration (6, 33.3%) and proportion of responders (3, 16.7%). QoL analysis was focused on the impact of toxicity in 10 cases (mostly in earlier stages), and on disease symptoms in 10 cases (mostly in CRPC). Conclusions: QoL is absent in a high proportion of recently published phase III trials in PC, although presence of QoL results is better in positive trials, especially in CRPC. Methodology of QoL analysis is heterogeneous in terms of type of instruments, analysis and presentation of results.

Oct1 regulates cell growth of LNCaP cells and is a prognostic factor for prostate cancer

2020 ◽  
Author(s):  
Lungwani Muungo
Keyword(s):  
Prostate Cancer ◽  
Prognostic Factor ◽  
Hazard Analysis ◽  
Critical Role ◽  
Immunohistochemical Analysis ◽  
Lncap Cells ◽  
Cancer Specific Survival ◽  
High Gleason Score ◽  
Castrate Resistant ◽  
Transcription Factor 1

The androgen receptor (AR) plays a critical role in the development and the progression of prostate cancer. Alterations in theexpression of AR coregulators lead to AR hypersensitivity, which is one of the mechanisms underlying the progression ofprostate cancer into a castrate-resistant state. Octamer transcription factor 1 (Oct1) is a ubiquitous member of the POUhomeodomainfamily that functions as a coregulator of AR. In our study, the contribution of Oct1 to prostate cancerdevelopment was examined. Immunocytochemistry analysis showed that Oct1 is expressed in the nuclei of LNCaP cells.siRNA-mediated silencing of Oct1 expression inhibited LNCaP cell proliferation. Immunohistochemical analysis of Oct1expression in tumor specimens obtained from 102 patients with prostate cancer showed a positive correlation of Oct1immunoreactivity with a high Gleason score and AR immunoreactivity (p 5 0.0042 and p &lt; 0.0001, respectively). Moreover,patients with high immunoreactivity of Oct1 showed a low cancer-specific survival rate, and those patients with highimmunoreactivities of both Oct1 and AR exhibited poorer cancer-specific prognosis. Multivariate hazard analysis revealed asignificant correlation between high Oct1 immunoreactivity and poor cancer-specific survival (p 5 0.012). These resultsdemonstrate that Oct1 can be a prognostic factor in prostate cancer as a coregulator of AR and may lead to the developmentof a new therapeutic intervention for prostate cancer.

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