Metastatic Hormone-refractory Prostate Cancer Patients Research Articles

Efficacy of 68Ga-PSMA PET/CT-derived whole-body volumetric parameters in predicting response to second-generation androgen receptor axis-targeted therapy, and the prognosis in metastatic hormone-refractory prostate cancer patients.

The present study investigates the role of 68Ga-PSMA PET/CT-derived whole-body metabolic and volumetric parameters in the prediction of treatment response and prognosis among metastatic hormone-refractory prostate cancer patients undergoing second-generation androgen receptor axis-targeted therapy (abiraterone or enzalutamide). This retrospective study included 44 metastatic hormone-refractory prostate cancer patients undergoing 68Ga-PSMA PET/CT, including 29 enzalutamide-treated and 15 abiraterone-treated patients. Of the 44 patients included in the study, 29 received enzalutamide and 15 received abiraterone. During treatment, the changes in PET parameters were correlated with the PSA (biochemical) response. More specifically, a positive correlation was noted between PSA response and percent change in TLP (ΔTLP) response, and there was concordance between the results (r = 0.652, k = 0.42, P < 0.001). Baseline PSA (P =0.05), high MTVw (P = 0.005), the increase in ΔPSA (P = 0.036), ΔTLP (P = 0.039) and percent change in MTV (ΔMTV) (P = 0.049) values were identified as factors associated with mortality risk.Multivariate analysis showed that PSA1 [odds ratio (OR): 1.005, 95% confidence interval (CI) 1.002-1.008, P = 0.004], ΔPSA (OR: 14.7, 95% CI 1.50-143.7, P = 0.02) and MTVw1 (OR: 11.4, 95% CI 1.11-116, 6, P = 0.04) were independent prognostic factors associated with mortality risk. A statistically significant concordance and correlation was noted between 68Ga-PSMA PET/CT-derived whole-body metabolic parameters (ΔTLP and ΔMTV) and ΔPSA. In addition, the baseline PSA, ΔPSA, ΔTLP, ΔMTV and TMTV were identified as predictive factors for mortality risk.

Progression of bone metastases in patients with prostate cancer - automated detection of new lesions and calculation of bone scan index

BackgroundThe objective of this study was firstly to develop and evaluate an automated method for the detection of new lesions and changes in bone scan index (BSI) in serial bone scans and secondly to evaluate the prognostic value of the method in a group of patients receiving chemotherapy.MethodsThe automated method for detection of new lesions was evaluated in a group of 266 patients using the classifications by three experienced bone scan readers as a gold standard. The prognostic value of the method was assessed in a group of 31 metastatic hormone-refractory prostate cancer patients who were receiving docetaxel. Cox proportional hazards were used to investigate the association between percentage change in BSI, number of new lesions and overall survival. Kaplan-Meier estimates of the survival function were used to indicate a significant difference between patients with an increase/decrease in BSI or those with two or more new lesions or less than two new lesions.ResultsThe automated method detected progression defined as two or more new lesions with a sensitivity of 93% and a specificity of 87%. In the treatment group, both BSI changes and the number of new metastases were significantly associated with survival. Two-year survival for patients with increasing and decreasing BSI from baseline to follow-up scans were 18% and 57% (p = 0.03), respectively. Two-year survival for patients fulfilling and not fulfilling the criterion of two or more new lesions was 35% and 38% (n.s.), respectively.ConclusionsAn automated method can be used to calculate the number of new lesions and changes in BSI in serial bone scans. These imaging biomarkers contained prognostic information in a small group of patients with prostate cancer receiving chemotherapy.

Constructing a Conceptual Framework of Patient-Reported Outcomes for Metastatic Hormone-Refractory Prostate Cancer

Objective A conceptual framework for patient-reported outcomes (PROs) is a structured representation of outcome concepts and issues. Our aim was to develop a conceptual framework of PROs for hormone-refractory prostate cancer (HRPC) to support measurement clarity. Methods Relevant outcome issues were identified from review of recent clinical trials. This provided content for an interview with 15 metastatic HRPC patients and a survey of 10 practitioners. All participants were asked about the relevance and importance of 26 outcomes and were allowed to nominate new outcomes. Practitioners were also asked to determine which outcomes endorsed by patients were attributable to the disease (symptoms) versus treatment (side effects). Analyses of archived clinical trial data were used to verify and augment the interview and survey results. Results Patients endorsed 11 concerns as relevant and important to HRPC including general pain, bone pain, urinary problems, fatigue, appetite loss, constipation, erectile dysfunction, peripheral neuropathy, diarrhea, PSA anxiety, and changes in self image. Practitioner judgments helped classify each concern into one of four categories, disease symptom, treatment side effect, both symptom and side effect, or psychological concern. Additionally, patients endorsed (and practitioners confirmed) the relevance and importance of several general domains of quality of life. Analyses of archived data confirmed the importance of these issues and suggested two additional concerns. Conclusion Findings were used to propose a conceptual framework of PROs for metastatic HRPC. Such frameworks can be used to help specify targets for assessment in clinical studies such as treatment trials.

A dose-escalating phase I study of biweekly docetaxel in older men with hormone refractory prostate cancer (HRPC)

e16117 Background: Docetaxel has been shown to be effective and is used in the treatment of HRPC. This phase I study is designed to investigate the maximum tolerated dose, tolerability and activity of docetaxel administered on a biweekly schedule in older patients with HRPC. This study will also explore the feasibility of a self-report geriatric assessment tool in this population. Methods: HRPC patients with progression of metastatic disease during hormonal therapy received docetaxel q 2 wks at dose levels of 40 (level 0), 45 (level 1), 50 (level 2), or 55 mg/m2 (level 3). The trial is a conventional phase I 3+3 dose-escalation design. Treatment was continued until progression, refused further treatment, or unacceptable toxicity. Patients were given the Vulnerable Elders Survey (VES-13) for completion every 4 weeks. Results: 16 patients were enrolled in the study. All are evaluable for toxicity, 10 for response. Pts had a median (range) age 76 (72–87). Median doses administered was 6 (range 3–19). The maximum tolerated dose (MTD) was not reached in the study. No dose limiting side effects were reported for any of the dosing levels in the 8 week assessment period. Five patients had a ≥50% decline in serum PSA on two consecutive measurements taken at least 2 weeks apart. Of the 10 patients with measureable disease, 2 patients (one at dose level 0 and one at dose level 3) achieved a complete response, 2 patients (one at dose level 1 and one at dose 2) achieved a partial response, and 3 patients had stable disease (one each at dose levels 1, 2, and 3). At the time of entry onto the study, 4 patients required narcotic analgesics for bone pain; after treatment, 1 (25%) discontinued their pain medications. The completion rate of the Vulnerable Elders Survey (VES-13) was 94.6%. Conclusions: Biweekly docetaxel can be safely administered in older metastatic HRPC patients and showed activity. For phase II evaluation, a bi-weekly dose of 55 mg/m2 appears to be suitable. The administration of the VES-13 was feasible in this population. [Table: see text]

Estimating Clinically Meaningful Changes for the Functional Assessment of Cancer Therapy—Prostate: Results from a Clinical Trial of Patients with Metastatic Hormone-Refractory Prostate Cancer

Objective To determine clinically meaningful changes (CMCs) for the Functional Assessment of Cancer Therapy–Prostate (FACT–P). Methods We obtained data from a Phase III trial of atrasentan in metastatic hormone-refractory prostate cancer patients (n = 809). We determined anchor-based differences using Karnofsky Performance Status (KPS), bone alkaline phosphatase (BAP), hemoglobin, time to disease progression (TTP), adverse events (AE), and survival. One-third and one-half standard deviation and standard error of measurement (SEM) were used as distribution-based criteria for CMCs. Comparison across baseline FACT–P domains and derived scales [FACT–P total score, Trial Outcome Index (TOI) score, prostate cancer subscale (PCS) score, pain-related score, and FACT Advanced Prostate Symptom Index (FAPSI)] were conducted for KPS, BAP, and hemoglobin using Student's t tests. Twelve-week change scores were compared for TTP, AE, and survival using ANCOVA. Results CMCs were estimated as 6 to 10 for FACT–P total score, 5 to 9 for FACT–P TOI score, 2 to 3 for FACT–P PCS, 1 to 2 for the 4 PCS pain-related questions, and 2 to 3 for FAPSI. CMCs were also estimated using distribution-based criteria. Kappa statistics were computed to determine the degree of correspondence between the recommended guideline of 1.0 SEM and empirically derived standards. Most of the kappas for health-related quality of life domains and SEM standards had “substantial” to “almost perfect” concordance. Conclusions The significant relationship between clinical and quality of life data provides support for the use of CMCs to increase interpretability of FACT–P scores.

Platelet Microparticles: A Potential Predictive Factor of Survival in Hormone-Refractory Prostate Cancer Patients Treated with Docetaxel-Based Chemotherapy

BackgroundSeveral studies suggest a causal relationship between platelet activation and cancer metastasis. Activated platelet microparticles (PMPs) release vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), which play a major role in angiogenesis. ObjectiveWe conducted a prospective, nonrandomised, single-centre study in hormone-refractory prostate cancer (HRPC) patients to determine the impact of PMPs on the outcome. Design, setting, and participantsEligible chemonaive and metastatic HRPC patients received docetaxel-based chemotherapy and a low dose of prednisone. InterventionPMPs in whole blood were quantified before the start of chemotherapy through flow cytometry using an anti-CD41a monoclonal antibody, and plasma VEGF and bFGF were determined with an enzyme-linked immunosorbent assay. MeasurementsThe primary end point was to evaluate the impact of the PMPs on overall survival (OS). We also studied the statistical interaction between PMPs and platelets and their relationship with OS. The median PMP value was used to sort patients into two groups. Results and limitationsData of 43 consecutive HRPC patients treated in a single French centre were analysed. Significant correlations were observed between Eastern Cooperative Oncology Group performance status (ECOG PS), platelets, and PMP level. The median OS was significantly shorter for patients with >6867 PMPs per μl of whole blood than for those with lower values (16.7 vs 26.4 mo, p=0.013). A significant relationship was found between OS and PMPs, whereas a statistical interaction term between PMPs and platelets was significantly associated with OS (p=0.019). No association was found between OS and plasma VEGF and bFGF. In the multivariate analysis, only baseline prostate-specific antigen (PSA) and ECOG PS remained significantly predictive of risk of death. ConclusionsIn HRPC patients, PMPs and their interaction with platelets were predictive of outcome. A biologic association between PMPs and the OS of HRPC patients, independent of chemotherapy regimen, should be demonstrated by confirmatory prospective studies.

Docetaxel re-treatment for metastatic hormone refractory prostate cancer

16066 Background: Recent clinical trials have established three-weekly docetaxel chemotherapy along with prednisolone (3wD+P) as standard of care for patients with metastatic hormone refractory prostate cancer (MHRPC). A significant proportion of patients receiving first- line 3wD chemotherapy (CT) will be eligible for second-line CT on biochemical disease progression (BDP), however, there are no other licensed CT options. The efficacy and toxicity with 3wD CT re-treatment has not been previously reported in patients who respond to docetaxel and then progress after a period of biochemical remission. Methods: A total of43 patients with MHRPC were treated at our institution with 3wD 75 mg/m2 + P 10 mg daily. The median patient age was 73 years and the median PSA at CT initiation was 182 (range 19.9->1500) ng/ml. Of 43 patients, 10 were re-treated with 3wD+P (2nd line CT) on BDP. A further 3 out of these 10 patients received 2nd re-treatment with 3wD+P (3rd line CT) on BDP. We assessed PSA response, toxicity, overall survival for first-line docetaxel CT and subsequent re-treatment. Results: Of 43 patients, 37% had PSA decline of >50% and 14% had PSA declines of 30–50% of pre-treatment levels; 19% had stable disease and 23% had progressive disease. On 1st re-treatment, 7 out of 10 patients who had responded to first-line CT responded again with a PSA reduction >50%. 3 out of these 7 patients received 2nd re-treatment, with all 3 patients achieving PSA reduction >50% of pre-treatment levels. The median treatment-free interval prior to 1st and 2nd re-treatments was 24 and 26 weeks, respectively. The median overall survival was 16 (range 1–35) months. There was a significant rise in the incidence of grade 3/4 neutropenia with re-treatment, though no treatment-related deaths. Conclusions: To our knowledge, this is the first evidence supporting 3wD re-treatment, demonstrating that MHRPC patients responding to 1st line docetaxel CT maintain their intrinsic sensitivity to subsequent re-treatment. Analogous to intermittent androgen ablation, intermittent administration of CT is an attractive proposition which may offer patients improved quality of life during treatment-free periods. Based on these results, the role of intermittent 3wD CT needs to be prospectively evaluated in clinical trials. No significant financial relationships to disclose.

Prostate-specific antigen doubling time before onset of chemotherapy as a predictor of survival for hormone-refractory prostate cancer patients

Background: We evaluated the possible use of prostate-specific antigen doubling time (PSA-DT) before chemotherapy initiation as a surrogate marker of survival in hormone-refractory prostate cancer (HRPC) patients.Patients and methods: Data from 250 consecutive metastatic HRPC patients treated with chemotherapy between February 2000 and November 2006 were retrospectively analysed. At least three PSA assays were required within 3 months before chemotherapy. PSA-DT was calculated as ln 2 divided by the slope of the log PSA line, and the difference between two log PSA levels was divided by the time interval. The primary endpoint was overall survival (OS). Survival rates according to PSA-DT were stratified on chemotherapy regimen. Multivariate Cox regression analysis was performed to isolate the impact of PSA-DT on OS, controlling for associate prognostic covariates.Results: Patients received docetaxel- (82%) or mitoxantrone-based chemotherapy. The median PSA-DT was 45 days (range 4.7–1108 days). There were 174 deaths (70%). The median survival was 16.5 months (95% confidence interval [CI]=12.5–20.5) and 26.4 months (95% CI=20.3–32.4) for patients with a PSA-DT < 45 and ≥45 days, respectively. In the multivariate setting, the adjusted hazard ratio (HR) was 1.39 (95% CI=1.03–1.89; P=0.04), stratified by chemotherapy regimen.Conclusion: A short PSA-DT before onset of chemotherapy in HRPC patients was associated with an increased risk of death. This could be useful as a stratification parameter in trials with new drugs in a metastatic setting.

Mapping FACT-P and EORTC QLQ-C30 to Patient Health Status Measured by EQ-5D in Metastatic Hormone-Refractory Prostate Cancer Patients

Objective To construct and validate a prediction model of preference-adjusted health status (EQ-5D) for metastatic hormone-refractory prostate cancer (HRPCA) patients using cancer-specific health-related quality of life (HRQoL) measures. Methods Data were obtained from a multicenter, multinational observational study of metastatic HRPCA patients conducted during 2002 to 2004. In addition to clinical and resource utilization, preference-adjusted health status (EQ-5D) and HRQoL (Functional Assessment of Cancer Therapy—Prostate [FACT-P] and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire [EORTC QLQ-C30]) data were collected. Predictive validity of ordinary least square (OLS) and median regressions of various model specifications were tested using cross-validation samples. The selected specification was thenfurther refined and tested for alternative model specifications and restrictions. Results OLS regression with both HRQoL measures as individual components and patient demographics was the best-performing model. It explained 58.2% of the observed EQ-5D variation in the validation sample. A model including only the prostate cancer-specific HRQoL measure, FACT-P, explained 53.5% of the observed EQ-5D variation. Conclusion The models developed have good predictive validity. These algorithms enable researchers to translate cancer-specific HRQoL measures to preference-adjusted health status in metastatic HRPCA patients. The findings will help perform health status adjustments in cost-utility analyses.

A retrospective analysis of cardiovascular morbidity in metastatic hormone-refractory prostate cancer patients on high doses of the selective COX-2 inhibitor celecoxib

This data were previously presented in February 2007 at the American Society of Clinical Oncology’s Prostate Cancer Symposium in Orlando, FL, USA. COX-2 inhibition has shown promise in treating prostate cancer, but concerns exist regarding the risk profile associated with this class of drugs. This study analyzes the cardiovascular and cerebral vascular morbidity associated with high doses of the COX-2 inhibitor, celecoxib, in patients with metastatic hormone-refractory prostate cancer (mHRPC). We retrospectively reviewed 67 patients with mHRPC who were treated at our institution between 1999 and 2005. All charts were reviewed for cardiac risk factors and the clinical course whilst on therapy and post-treatment was analyzed. This study included 34 patients who were on protocols that involved celecoxib 400 mg b.i.d.. Treatment ranged from 21 to 355 days, with a median of 118.5 days. There were three myocardial infarctions (MIs) – two in the study group and one in the control group. One patient had a MI while on treatment, but he had a significant cardiac disease history. There were also two cerebral vascular accidents (CVAs) in each group, although none in any patient who was on-study. Although this is a small study, these findings, in the context of other published data, suggest that some patients with advanced malignancies may still benefit from therapies involving COX-2 inhibitors without clinically significant increase in risk for MI or CVA.

Elevated plasma TIMP-1 levels predict reduced survival in metastatic hormone-refractory prostate cancer patients

5143 Background: Tissue inhibitor of metalloproteinase-1 (TIMP-1) has been shown to have parodoxical multifunctional roles in tumorigenesis: inhibition of the catalytic activity of MMPs, growth promotion, inhibition of apoptosis, and regulation of angiogenesis. Increased TIMP-1 has been associated with an unfavorable prognosis in many cancers including breast, colorectal, gastric, head and neck, lung cancer, and lymphomas. Methods: EDTA plasma TIMP-1 was determined from 60 hormone-refractory prostate cancer (HRCaP) patients using the TIMP-1 ELISA from Oncogene Science / Bayer HealthCare, Cambridge, MA. Patients were identified from an institutional database and had metastatic, HRCaP at the time of blood collection, which ranged from &lt;1 month to 14 yrs. after the start of androgen-deprivation therapy (ADT); some patients had also received several chemotherapy regimens by the time of blood collection. Median follow-up was 17 mo. after blood collection and 27/60 patients had died. Overall survival was analyzed using Kaplan-Meier method and Cox modeling on tertiles of the TIMP-1 distribution. Results: The median EDTA plasma TIMP-1 level from the 60 HRCaP patients was 335 ng/ml (range 21 - 1391 ng/ml). Median survival since time of blood collection was 14 mo. Survival differed across TIMP-1 levels (P&lt;0.01, logrank test), in particular the upper tertile of plasma TIMP-1 had a significantly reduced overall survival from the time of blood collection compared to the lowest tertile: A larger confirmatory study which will include a multivariate analysis of known prognostic factors is planned. Conclusions: Elevated plasma TIMP-1 tertile level predicted reduced survival in HRCaP patients. Soluble TIMP-1 deserves further study to determine its predictive and prognostic biomarker potential in a larger cohort of prostate cancer patients. [Table: see text] [Table: see text]

Evaluation and significance of circulating epithelial cells in patients with hormone‐refractory prostate cancer

To determine the feasibility of using flow cytometry fluorescence-activated cell sorting (FACS) analysis for detecting circulating epithelial cells (CECs) in patients with hormone-refractory prostate cancer (HRPC), and to determine whether CECs can be used to predict survival in these patients. Several prognostic models that include routinely used clinical and laboratory variables for predicting survival in men with HRPC have been reported; the presence of CECs measured by reverse transcriptase-polymerase chain reaction for prostate-specific antigen (PSA) in patients with HRPC is an independent prognostic factor for survival. CECs detected by FACS analysis correlate with advanced stage and poor survival outcome. A retrospective study was conducted to assess the presence of CECs by FACS analysis in metastatic HRPC patients initiating systemic chemotherapy with a taxane-based regimen. The association between clinical variables previously described and the presence of CECs along with the effect of the magnitude of CECs on survival was calculated, in 41 patients with HRPC, all of whom had peripheral blood collected for FACS analysis. Except for four patients, all those with metastatic HRPC had detectable CECs. Among these patients, the number of CECs/mL was correlated with age, serum PSA level and serum alkaline phosphatase (ALP). Higher serum levels of PSA and ALP predicted a poor survival outcome. Similarly, patients with < or =1.8 CECs/mL had a significantly longer survival than those with more CECs/mL (P = 0.02). With a median follow-up of 15.4 months, the median overall survival for all patients was 18.4 months. The presence of more CECs in patients with metastatic HRPC was associated with a poorer survival outcome; levels of > or =1.8 CECs/mL were associated with a shorter survival in patients with metastatic HRPC.

Combination Therapy of Personalized Peptide Vaccination and Low-Dose Estramustine Phosphate for Metastatic Hormone Refractory Prostate Cancer Patients: An Analysis of Prognostic Factors in the Treatment

The aim of this study was to investigate prognostic factors of patients with metastatic hormone refractory prostate cancer (HRPC) under combined administration of personalized peptide vaccination and low-dose estramustine phosphate (EMP). From February 2001 to July 2004, 58 men with metastatic HRPC received the combination therapy of personalized peptide vaccination and low-dose EMP. Conducted immune monitorings for those patients were peptide-specific cytotoxic T lymphocyte (CTL) precursor analysis by interferon-gamma production and peptide-reactive immunoglobulin G (IgG) by an enzyme-linked immunosorbent assay. Clinical responses and survival times were also evaluated. The combination therapy was well tolerated with no major adverse effects. Increased levels of CTL precursors and IgG responses to the vaccinated peptides were observed in 29 of 37 (78%) patients and in 36 of 41 (88%) patients tested, respectively. A prostate-specific antigen decline of at least 50% occurred in 24% of patients. The median survival time was 17 months (95% confidence interval, 12-25 months). Cox proportional hazards analysis showed that a low number of lymphocytes (p = 0.0075, odds ratio 2.700), a negative immunological activity response after the vaccination (p = 0.0185, odds ratio 2.658), and poor performance status (p = 0.0347, odds ratio 2.569) were independent predictors of disease death. These encouraging results show the need for further evaluation of the combination of personalized peptide vaccination and low dose of EMP for metastatic HRPC patients.

Corrected area under prostate-specific antigen (PSA) curve and PSA half-time dynamics during chemotherapy. A new prognostic classification for hormone-refractory prostate cancer (HRPC) patients

4641 Background: The PSA half-time (PSA HT) dynamics and corrected area under PSA curve (PSA c-AUC) during chemotherapy (CT) predict overall survival (OS) probability among metastatic HRPC patients (ASCO 2003, abstract 1673; ASCO 2004, abstract 9579). This has motivated the search of a new prognostic classification to identify these patients (pts) at risk, with a poor outcome. The manner in which these parameters were combined could have a major survival impact. Methods: Based on their PSA c-AUC values (< 60 or ≥ 60 ng/mL) and PSA HT categories [initial progressers (IP), late progressers (LP) and responders (R)], a new prognostic classification was defined (Table). Analysis was done according to the OS as primary end point, stratified by first-line CT regimen. Log-rank test was used to determine the equality of the groups over the survival distribution estimates. Results: Two hundred-eighteen metastatic HRPC pts treated with docetaxel (77%) or mitoxantrone (23%) based CT were included in this exploratory analysis. Pts characteristics: median age 68 years (range 51–91 years), median PSA follow-up duration of 26.8 months (range 2–184 months). The 3-year OS for the entire cohort was 26% with a median of 20 months [95% confidence interval (CI) 17.5–22.5 months)]; 137 (73%) pts have died. Our classification identified three major risk groups with predicted 3-year survival rates of 45%, 28% and 16% (Table). There was an significant difference in OS (log-rank, P=0.00003) according to prognostic groups. Conclusions: The PSA c-AUC and PSA HT are predictive factors for overall survival independently of chemotherapy regimen. Combination of both parameters is more powerful, being capable to stratify patients according to survival probabilities. Such model could assist in assessing the results of newer therapies, by comparing predicted survival to achieved survival. No significant financial relationships to disclose.

Docetaxel versus mitoxantrone as first-line chemotherapy for hormone-refractory prostate cancer (HRPC) patients. A meta-analysis of 3-year overall survival results

4634 Background: Docetaxel (DTX) based chemotherapy is considered the standard treatment for metastatic HRPC patients (pts), with a median survival advantage of 2 months, compared to mitoxantrone (MT). DTX advantage at long term is not defined and further evaluations are needed. Methods: We conducted a meta-analysis to assess the effect of DTX chemotherapy (CT) on overall survival (OS) compared to MT for metastatic HRPC pts. OS probabilities at 12, 18, 24, 30 and 36 months, were considered as the endpoints of interest. Subgroups analysis were performed to evaluate the impact on OS of DTX dose intensity (DI), between dose-dense (q1w) and dose-intense (q3w) schedules. Estimates of the effectiveness of CT were expressed as relative risk reduction (RRR), using a fixed effects model. Associated statistics with 95% confidence interval (CI) were calculated based on adjusted number of pts at risk and events (according to the extent of follow-up) using EasyMA software. Results: Three randomized controlled trials comparing DTX with MT-based CT in HRPC pts were selected (Tannock, Petrylak, NEJM 2004; Oudard, JCO 2005). A total of 1807 pts were included, 1092 allocated to DTX and 715 allocated to MT. The follow-up range was 13.9–58.5 months. No differences were found according to Gleason score, performance status and sites of metastasis. Overall analysis demonstrates a significant OS benefit for DTX at any time points, without any significant heterogeneity (Table). There was a significant difference in OS in favor of DTX dose-intense arm comparing to MT, with no OS benefit for DTX dose-dense schedule. The rank test for publication bias were not significant. Conclusions: This meta-analysis shows on a large data set that DTX-based CT significantly reduced the risk of death by 8–21%, a benefit persisting 3 years later after the start of CT. The benefit of DTX over MT was related to DTX schedule and dose-intense model. No significant financial relationships to disclose.

Multicenter Randomized Phase II Study of Two Schedules of Docetaxel, Estramustine, and Prednisone Versus Mitoxantrone Plus Prednisone in Patients With Metastatic Hormone-Refractory Prostate Cancer

Mitoxantrone-corticosteroid is currently the standard palliative treatment in hormone-refractory prostate cancer (HRPC) patients. Recent clinical trials documented the high activity of the docetaxel-estramustine combination. We conducted a randomized phase II study to evaluate prostate-specific antigen (PSA) response (primary end point) and safety of two docetaxel-estramustine-prednisone (DEP) regimens and mitoxantrone-prednisone (MP). One hundred thirty metastatic HRPC patients were randomly assigned to receive docetaxel (70 mg/m2 on day 2 or 35 mg/m2 on days 2 and 9 of each 21-day cycle) and estramustine (280 mg p.o. tid on days 1 through 5 and 8 through 12) or mitoxantrone 12 mg/m2 every 3 weeks; all patients received prednisone (10 mg daily). One hundred twenty-seven patients were assessable for PSA response and safety. A > or = 50% PSA decline was found in a greater percentage of patients in the docetaxel arms (67% and 63%) compared with MP (18%; P = .0001). Median time to PSA progression was five times longer with DEP than with MP (8.8 and 9.3 v 1.7 months, respectively; P = .000001). Overall survival was better in the docetaxel arms (18.6 and 18.4 months) compared with the MP arm (13.4 months), but not significantly so (P = .3). Crossover rates differed significantly among treatment arms (16%, 10%, and 48% in arms A, B, and C, respectively; P = .00001). Treatment-related toxicities were mild and mainly hematologic. The results of this randomized phase II study showed significantly higher PSA decline < or = 50% and longer times to progression in HRPC patients receiving DEP-based chemotherapy than MP, and that DEP could be proposed in this setting.

A multiple ascending dose, open-label, phase IIa study evaluating the safety and tolerability of PCK3145 administered intravenously in patients with metastatic hormone refractory prostate cancer (HRPC)

4636 Background: PCK3145 is a synthetic 15-mer peptide derived from the prostate secretory protein (PSP94) sequence. PCK3145 has demonstrated antiproliferative and antitumoral activity in the PC3 xenograft mouse model and the Dunning rat R-3327 MLL model. No drug related toxicities were found in the animal studies. The objectives of PCK3145-UK-2001 clinical trial were to evaluate the safety and tolerability, the pharmacokinetics, and efficacy of PCK3145 in metastatic HRPC patients. Methods: Dose-escalation study in which successive cohorts of 4 patients received 4 ascending doses (5, 20, 40 and 80 mg/m2) of PCK3145. One cycle consist of IV administration of PCK3145, three time per week for 4 weeks followed by a 7-day post-treatment observation period. Pharmacokinetics of PCK3145 was determined for all patients at day 1 and day 26. Tumours were assessed by CT-Scan prior to and after the PCK3145 treatment. Results: Median age is 67 y (53–75) and the median time from HRPC to enrolment is 16.2 months (3–33). Sites of disease were mainly bone and lymph node. No drug related Adverse Event was observed for patients treated at 5, 20 and 40 mg/m2 but two patients treated at 80 mg/m2 experienced Serious Adverse Event (tachycardia and vasovagal reaction) possibly related to study medication. Preliminary results indicate that the half-life of PCK3145 is 20 minutes and tumor assessments suggest that the patients are having stable disease at least after one cycle. Five patients showed a decline in PSA levels (one of them by almost 50%). All patients that had plasma MMP-9 levels over 100 ug/L before treatment had reductions ranging from 34% to 90% after the first cycle while those with levels below 100 ug/L remained low. Conclusions: This clinical trial indicated that PCK3145 has an excellent safety profile for patients treated at 5, 20 and 40 mg/m2. Some toxicities, possibly related were observed at 80 mg/ m2. The marked reduction in plasma MMP-9 levels of patients receiving PCK3145 treatment indicates a biological effect, possibly related to control of metastasis. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Procyon Biopharma, Inc. Procyon Biopharma, Inc. Procyon Biopharma, Inc. Procyon BioPharma, Inc.

The addition of imatinib mesylate to estramustine/docetaxel (E/D) for the treatment of hormone refractory prostate cancer (HRPC) patients: Results of a phase I trial

4617 Background: The E/D combination is used widely to treat metastatic HRPC. Imatinib mesylate inhibits the platelet-derived growth factor receptor which is overexpressed in HRPC, and is synergistic with docetaxel in preclinical models. A phase I trial of E/D was therefore undertaken to determine the maximum tolerated dose of docetaxel in this combination. Methods: Metastatic HRPC patients with progressive disease by Consensus Criteria and no prior chemotherapy or investigational therapy were treated in a standard phase I design. All patients received therapy every 21 days consisting of fixed doses of estramustine phosphate, (280 mg po tid D 1–5) dexamethasone (8 mg po bid D 1–3), warfarin (2 mg po qd) and imatinib (400 mg po qd D 1–21). Docetaxel on day 1 was dose-escalated by cohort from 50 to 60 to 70 mg/m2 iv. Results: A total of 13 patients were treated. On dose level 3 (400 mg qd imatinib, 70 mg/m2 docetaxel), 2 patients experienced grade 3 elevated prothrombin times attributed to the interaction between imatinib and warfarin, so an additional 3 patients were treated at an intermediate level utilizing 300 mg qd imatinib and 60 mg/m2 docetaxel. While this dose level was initially established as the recommended phase II level, overall in the entire study, 5/13 patients had unacceptable toxicity as defined by the protocol, which exceeded pre-specified boundaries, mandating study closure. These events were thromboembolic in nature and included 2 cerebrovascular accidents, 1 myocardial infarct, 1 mesenteric ischemia and 1 deep vein thrombosis. Conclusions: The combination of estramustine, docetaxel and imatinib results in excessive thromboembolic toxicity, potentially due to interactions between estramustine, a known thrombogenic agent, and imatinib. This toxicity precludes the use of this combination in HRPC patients. No significant financial relationships to disclose.

A multiple ascending dose, open-label, phase IIa study evaluating the safety and tolerability of PCK3145 administered intravenously in patients with metastatic hormone refractory prostate cancer (HRPC)

4636 Background: PCK3145 is a synthetic 15-mer peptide derived from the prostate secretory protein (PSP94) sequence. PCK3145 has demonstrated antiproliferative and antitumoral activity in the PC3 xenograft mouse model and the Dunning rat R-3327 MLL model. No drug related toxicities were found in the animal studies. The objectives of PCK3145-UK-2001 clinical trial were to evaluate the safety and tolerability, the pharmacokinetics, and efficacy of PCK3145 in metastatic HRPC patients. Methods: Dose-escalation study in which successive cohorts of 4 patients received 4 ascending doses (5, 20, 40 and 80 mg/m2) of PCK3145. One cycle consist of IV administration of PCK3145, three time per week for 4 weeks followed by a 7-day post-treatment observation period. Pharmacokinetics of PCK3145 was determined for all patients at day 1 and day 26. Tumours were assessed by CT-Scan prior to and after the PCK3145 treatment. Results: Median age is 67 y (53–75) and the median time from HRPC to enrolment is 16.2 months (3–33). Sites of disease were mainly bone and lymph node. No drug related Adverse Event was observed for patients treated at 5, 20 and 40 mg/m2 but two patients treated at 80 mg/m2 experienced Serious Adverse Event (tachycardia and vasovagal reaction) possibly related to study medication. Preliminary results indicate that the half-life of PCK3145 is 20 minutes and tumor assessments suggest that the patients are having stable disease at least after one cycle. Five patients showed a decline in PSA levels (one of them by almost 50%). All patients that had plasma MMP-9 levels over 100 ug/L before treatment had reductions ranging from 34% to 90% after the first cycle while those with levels below 100 ug/L remained low. Conclusions: This clinical trial indicated that PCK3145 has an excellent safety profile for patients treated at 5, 20 and 40 mg/m2. Some toxicities, possibly related were observed at 80 mg/ m2. The marked reduction in plasma MMP-9 levels of patients receiving PCK3145 treatment indicates a biological effect, possibly related to control of metastasis. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Procyon Biopharma, Inc. Procyon Biopharma, Inc. Procyon Biopharma, Inc. Procyon BioPharma, Inc.

Bone alkaline phosphatase doubling time and outcome in metastatic hormone-refractory prostate cancer patients

Bone alkaline phosphatase doubling time and outcome in metastatic hormone-refractory prostate cancer patients