Hormone Refractory Prostate Cancer Pts Research Articles

1014 poster EFFICACY OF KETOCONAZOLE AND DIETHYLSTILBESTROL IN HORMONE REFRACTORY PROSTATE CANCER

Purpose: Diethylstilbestrol (DES), a synthetic ethynyl estrogen, and intermediate dose ketoconazole (IDK) and hydrocortisone, a combination of antimycotic and corticosteroid, are often used as salvage therapy after several hormone manipulations. We investigated their efficacy in patients with hormone refractory prostate cancer (HRPC). Materials: A retrospective review of medical records of 32 HRPC pts receiving IDK and 19 pts receiving DES from Jan 2005 to Dec 2009. Results: Prior to IDK, patients received four lines of hormonal therapy. The median baseline serum PSA level was 75.8 ng/ml (range 1.75-563.3). A PSA response (defined by ≥ 50% decline in baseline PSA) or any PSA decline were observed in 5 (17.9%) and 11 (39.3%) pts, respectively.For the entire study group, the median time to progression (TTP) was 2.25 months (interquartile range (IQR) 2.0-5.75 mths), and the median survival was 11 months (IQR 5-21 mths). In PSA responders, TTP was significantly longer (7 mths) than in PSA non-responders (2.0 mths) (p=0.014). TTP was also significantly longer (6 mths) in patients with any PSA decline than in the group without decline (2.0 mths)(p 50% decline were observed in 11 (68.7%) and 6 (37.5%) pts, respectively. The median TTP was 7.25 months (IQR 4.0-9.25 mths) and the median overall survival was 12 months (IQR 7.4-17.5 mths). Using the >50% response criteria, the median TTP for responders was 8.25 mths compared to 4.5 mths for non-responders (p=0.093). DES toxicity was reported in only one patient. Conclusions: Diethylstilbestrol and ketoconazole are a valuable option for HRPC patients. DES can induce prolonged responses and is well tolerated. Early identified PSA responders to IDK will benefit from this therapy. A substantial proportion of patients discontinue therapy due to intolerable side effects. Long responses are more likely to occur in men initiating IDK or DES early in the course of their disease.

1015 poster EVALUATION OF ROTATIONAL IMRT FOR THE TREATMENT OF PROSTATE CANCER PATIENTS WITH PROSTHETIC HIP

Purpose: Diethylstilbestrol (DES), a synthetic ethynyl estrogen, and intermediate dose ketoconazole (IDK) and hydrocortisone, a combination of antimycotic and corticosteroid, are often used as salvage therapy after several hormone manipulations. We investigated their efficacy in patients with hormone refractory prostate cancer (HRPC). Materials: A retrospective review of medical records of 32 HRPC pts receiving IDK and 19 pts receiving DES from Jan 2005 to Dec 2009. Results: Prior to IDK, patients received four lines of hormonal therapy. The median baseline serum PSA level was 75.8 ng/ml (range 1.75-563.3). A PSA response (defined by ≥ 50% decline in baseline PSA) or any PSA decline were observed in 5 (17.9%) and 11 (39.3%) pts, respectively.For the entire study group, the median time to progression (TTP) was 2.25 months (interquartile range (IQR) 2.0-5.75 mths), and the median survival was 11 months (IQR 5-21 mths). In PSA responders, TTP was significantly longer (7 mths) than in PSA non-responders (2.0 mths) (p=0.014). TTP was also significantly longer (6 mths) in patients with any PSA decline than in the group without decline (2.0 mths)(p 50% decline were observed in 11 (68.7%) and 6 (37.5%) pts, respectively. The median TTP was 7.25 months (IQR 4.0-9.25 mths) and the median overall survival was 12 months (IQR 7.4-17.5 mths). Using the >50% response criteria, the median TTP for responders was 8.25 mths compared to 4.5 mths for non-responders (p=0.093). DES toxicity was reported in only one patient. Conclusions: Diethylstilbestrol and ketoconazole are a valuable option for HRPC patients. DES can induce prolonged responses and is well tolerated. Early identified PSA responders to IDK will benefit from this therapy. A substantial proportion of patients discontinue therapy due to intolerable side effects. Long responses are more likely to occur in men initiating IDK or DES early in the course of their disease.

Impact of age at diagnosis on survival of hormone-refractory prostate cancer (HRPC) patients

e16050 Background: Conflicting data exist for age as a determinant of overall survival (OS) in pts with HRPC. We hypothesize that young (<55) HRPC pts represent a more aggressive biological phenotype and therefore have a decreased OS. Methods: A retrospective chart review was conducted on 334 consective HRPC pts treated between 1995–2005. Summary statistics for demographic and clinical factors were generated, and Kaplan-Meier (KM) OS curves were created. Bivariate Cox Proportional-Hazards regression was used to test the association of age at diagnosis while adjusting for a covariate, with significant covariates entered into multivariate models. Results: Overall median survivals in the age stratified categories (<55, ≥55–65, ≥65–75, ≥75) were 5.5, 6.9, 7.9, and 4.3 yrs, with 5 yr survivals 51.9%, 67.4%, 67.0%, and 34.9%, respectively. KM curves showed divergence with an overall significant log-rank test (p < 0.0001). Compared to pts ≥65–75, the hazard ratios (HR) for HRPC pts <55 and ≥75 were 1.40 (95% CI 0.90–2.60) and 2.52 (95% CI 1.67–3.82), respectively. However, following multivariate analysis HRs for HRPC pts <55 and ≥75 were 1.60 (95% CI 0.98–2.62) and 1.25 (95% CI 0.71–2.20). Pts <55 and ≥75 presented with advanced stage at diagnosis and progressed to bone metastasis earlier. Pts ≥75 had decreased performance status, more comorbidities, higher PSA at diagnosis, shorter duration of hormone sensitive disease, and were less likely to receive chemotherapy than pts <75. The percentage of rapid PSA doubling times was highest in the <55 cohort. In multivariate analysis with age as a categorical variate, ECOG 3–4 (HR 2.65), time from diagnosis to both HRPC (HR 0.78) and bone metastasis (HR 0.80), and duration of response to androgen ablation (HR 0.86) remained highly predictive. Conclusions: Age at diagnosis influences OS in HRPC with a bimodal survival curve. Pts <55 and ≥75 present with more aggressive disease, translating into reduced median and 5 yr survivals. Other covariates, especially ECOG status, likely account for the decreased OS in the ≥75 cohort. Conversely, pts <55 had an adjusted HR of 1.60 (p = 0.06). Our study supports a growing body evidence that suggests a poor prognosis in younger men; correlating these differences at the molecular level could lead to better targeted therapies. No significant financial relationships to disclose.

Impact of nail toxicity on survival of patients with hormone-refractory prostate cancer (HRPC) treated with docetaxel

e16122 Background: Docetaxel is the standard first-line treatment for patients (pts) with metastatic HRPC. Taxanes are a well known cause of nail toxicity but docetaxel-related nail toxicity is rarely explored. Methods: Eligible HRPC pts included in the current analysis were from a phase II, multicentre, case-control study (Scotte F et al, J Clin Oncol 2005). Pts were treated with docetaxel 75 mg/m2 every 3 weeks and oral prednisone 10 mg daily. Nail toxicity was graded according to NCI CTC version 2 (0: absence of toxicity; 1: minor changes; 2: onycholisis). The endpoint of interest was the impact of nail toxicity on overall survival (OS) using Cox regression analysis as the main statistical method. OS was the time from the start of chemotherapy to death or last follow-up. Results: Data from 23 HRPC pts treated in two French centres were analyzed. The median age was 68 years, 91% of pts had bone metastases, 84% had a single metastatic site, 49% had a Gleason score of ≥ 8 and 91% had an ECOG performance status (PS) of 0 or 1. Median OS was 16.7 months [95% confidence interval (CI), 5.7–27.6 months], all pts died. There were differences in OS between nail toxicity categories (see Table). Median OS was 10.6 months (95% CI, 9.5–11.7) and 22.7 months (95% CI, 15.1–30.3) for pts without and with nail changes, respectively. Nail changes severity was significantly related to OS: hazard ratio (HR)=0.50 (95% CI, 0.28–0.92), P=0.027 (univariate analysis). The multivariate analysis adjusted by ECOG PS (the second covariate associated with prognosis) showed a 63% reduction in the risk of death for pts with nail toxicities: HR=0.29 (95% CI, 0.09–0.82), P=0.049. Conclusions: Our results suggest that pts with docetaxel-related nail toxicity have a better OS than those with no nail toxicity. This demonstrates that nail changes in HRPC pts treated with docetaxel are predictive of OS; these findings should be validated in a large cohort of pts. [Table: see text] No significant financial relationships to disclose.

Granulocyte macrophage: Colony stimulating factor (GM-CSF), ketoconazole, and mitoxantrone as second-line therapy in patients (Pts) with progressive hormone refractory prostate cancer (HRPC)

e16033 Background: A variety of docetaxel regimens have been tested in HRPC pts, yielding response rates between 38% - 69%. Docetaxel therapy has been widely used as first line therapy. Second line therapies, which are non - taxane based with comparable activities do not exist. This trial is built on the significant body of work which has demonstrated anti-tumor activity of GM-CSF, Ketoconazole and Mitoxantrone alone and in combination in pts with HRPC. The trial is designed to assess the combination of all three agents. Methods: No more than two prior chemotherapy regimens (one which contained docetaxel), progressive disease, and adequate marrow / organ function. Treatment consisted of: Ketoconazole daily 400mg po tid, GM-CSF subcutaneous 250mcg / m2 (14 days on/ 7 days off) and Mitoxantrone 12mg / m2 every 3 weeks (maximum cumulative dose of 140mg / m2), until either the completion of Mitoxantrone or maximum anti-tumor benefit. Pts continued Ketoconazole/ GM-CSF until disease progression. PSA was evaluated every 3 weeks and radiographic studies were performed every 9 weeks. Results: 31 pts were enrolled; 4 pts with PSA only, 9 bone only, 5 soft tissue only, and 13 bone and soft tissue. 2 pts withdrew from study due to toxicity. 8 pts had a PSA response of ≥ 50%, 5 pts had a PSA response of ≥ 80%, and 7 pts had a PSA response of ≥ 90%. 9 pts progressed. The majority of pts had stabilization of their bone and soft tissue involvement and 2 pts with nodal involvement demonstrated a radiographic CR. Significant adverse events included grade III/IV neutropenia, thrombocytopenia, and nausea. Median duration of treatment was 6.22 months (range 2 months - 20.5 months). Conclusions: GM-CSF, Ketoconazole and Mitoxantrone in combination demonstrate significant anti-tumor activity and reversible toxicity in pts who have failed prior docetaxel therapy. Information regarding PSA response, radiographic outcome and adverse event data will be presented. This data warrants further investigation such as a randomized phase II study. [Table: see text]

High response to docetaxel (D)/carboplatin (C) based chemotherapy as salvage therapy in patients with docetaxel-resistant metastastic hormone-refractory prostate cancer (HRPC)

e16041 Background: Presently, there is no standard treatment for prostate cancer (PC) patients who are resistant to docetaxel therapy. While previous reports support the use of C in combination with D in these patients (pts), the optimal regime is still unknown. Methods: Metastatic HRPC pts with clinical and/or radiographic evidence of progression while on docetaxel were included in our retrospective analysis. Between February 2005 and December 2008, 30 pts received treatment with C AUC 5 q3wks in combination with D 75 mg/m2 q3wks or D 35 mg/m2 d1, d8, d15 q4wks. All pts were assessed for PSA response and clinical outcome. Results: 27 pts were evaluable for response. Median age was 69 years (range 56–77) and median baseline performance status was ECOG 1 (range 0–2). The median number of prior therapies was 1 (range 1–3) with a median of 7 cycles of D therapy (range 3–34) administered. Median PSA at baseline was 297.15 ng/ml (range 12.33–6,446). Serum chromogranin A and neuron-specific enolase (NSE) were elevated in 24/24 and 8/25 cases, respectively. The median follow-up was 8.9 months (range: 0–38) with a median number of 6 cycles DC administered (range: 2–35). PSA declines of ≥50% (= PSA-response) was achieved in 14 of 27 pts (52%, 95% C.I. 0.32, 0.71) and PSA stabilization in 9 pts (33%). 4 pts (15%) progressed without PSA response. 6 PSA responders had a PSA reduction of >90%. The median duration of PSA response was 20.7 wks (95% C.I. 18.4, 59 wks). TTP was significantly longer in PSA responders vs. PSA non-responders (64.7 wks vs 15 wks, p<0.0001). 10 of 16 pts with measureable disease were evaluable for response. 3 of 6 PSA responders had a PR and 3 SD, while 2/4 pts with PSA non-response had PD and 2 SD. At the time of analysis, 2 PSA responders and 7 PSA non-responders have died. Median OS of all patients was 69.7 weeks with 79.9 wks for PSA responders vs. 38 wks for PSA non-responders (p=0.0034). The most common grade 3/4 toxicities were neutropenia in 42%, anemia in 23% and thrombocytopenia in 15% of pts. 17 of 30 pts had blood transfusions due to anemia. Conclusions: This retrospective analysis supports the usefulness of C plus weekly D chemotherapy as ≥second-line chemotherapy in docetaxel-resistant PC patients. No significant financial relationships to disclose.

Dose finding and safety analysis of inecalcitol in combination with a docetaxel-prednisone regimen in hormone-refractory prostate cancer (HRPC) patients

5151 Background: Inecalcitol is a novel synthetic vitamin D3 analogue with potent antiproliferative effects in human cancer cell lines and a 100-fold lower hypercalcemic activity than calcitriol in animal models. Methods: Escalating dosages of inecalcitol were combined to chemotherapy in naive HRPC patients (pts). Safety and efficacy were evaluated in groups of 3–6 patients receiving oral inecalcitol daily or every other day on a 21-day cycle in combination with docetaxel (75mg/m2 q3w) and oral prednisone (5mg bid). Biphosphonates were prohibited during the first cycle. Patients received up to six cycles unless unacceptable toxicity or disease progression. Primary endpoint was dose limiting toxicity (DLT) defined as grade 3 hypercalcemia within the first cycle. Calcemia, creatininemia and CBC were assessed weekly; biochemistry, ECG and PSA every 3 weeks. Efficacy endpoint was PSA response defined as ≥30% decline within 3 months. Results: Five dose levels: 40, 80, 160, 300, 600 μg have been evaluated in 34 pts; 9 pts are still being treated at 600 μg; 25 pts have completed 6 cycles (13 bone metastases; 3 extrasqueletic metastasis, 8 bone and extrasqueletic metastases; 1 PSA-only disease). Median age was 72 years (range, 53–87), median Gleason score (Gs) 7 (36% Gs 10–8, 64% Gs 7–6) and median PSA 41.5 ng/mL (range, 0.9–962.4). No increased calcemia was reported. Most adverse events (AE) were G1–2, asthenia (19pts), constipation (14pts), diarrhea (13pts). G3–4 AEs were neutropenia (11pts) lymphopenia (9pts), asthenia (3pts), arrhythmia (2 pts), general health deterioration (2pts) and diarrhea (1pt). None of these AEs was considered related to inecalcitol. Of the 23 evaluable pts for PSA response, 20 (87%) had ≥30% PSA decline. Conclusions: Results from this ongoing study show the safe profile of inecalcitol when given daily in in HRPC pts. PSA responses with this combination are encouraging. As DLT was not reached, a higher dose of inecalcitol (1000 μg/day) will be further tested. [Table: see text]

An open label phase II trial of BI 2536, a novel Plk1 inhibitor, in patients with metastatic hormone refractory prostate cancer (HRPC)

14547 Background: BI 2536 is a novel, highly selective, potent inhibitor of Polo-like kinase 1 (Plk1), a key regulator of mitotic progression. BI 2536 has demonstrated favorable tolerability and antitumor activity in Phase I trials. We investigated the activity, safety and pharmacokinetics of BI 2536 in patients (pts) with metastatic HRPC. Methods: This open label, single arm Phase II study used a modified Gehan two-stage design. The primary objective was to determine the PSA response rate at 12 weeks according to Prostate Specific Antigen Working Group (PSAWG) criteria. HRPC pts with castrate testosterone levels, PSA progression and a PSA of >10 ng/ml were entered. 15 pts had to complete ≥4 courses to be evaluable for Stage 1 analysis. In case of at least two PSA responders, 35 additional pts were planned for Stage 2. Pts were treated with 200 mg BI 2536 given as a 1h i.v. infusion on Day 1 every 3 weeks. The dose was escalated to 250 mg from cycle 2 onwards in pts with <Grade 2 drug related non-hematologic and <Grade 3 hematologic toxicity. Results: 20 men with a median age of 70 years (range: 56–76) and a median Gleason score of 9 were treated. The median PSA at study entry was 47 ng/ml. Of the 15 evaluable pts entered into Stage 1, 3 were docetaxel pretreated and 11 were chemonaive. There were no PSAWG criteria PSA responders; 9 pts progressed, 6 pts had stable disease with 1 pt achieving a 25% PSA reduction. RECIST evaluation showed stable disease in 5 pts after 4 courses. Overall, BI 2536 was very well tolerated. Neutropenia was the main toxicity observed. At 200 mg dosing, Grade 3/4 neutropenia was observed in 20%, and after escalation to 250 mg, in 73% of pts. There were 2 cases of neutropenic infection requiring hospitalization in the Stage 1 population. Due to the lack of PSA responders the accrual did not continue beyond Stage 1 analysis. Conclusions: BI 2536 was very well tolerated in metastatic HRPC pts, with some indications of antitumor activity by PSA reduction and radiologically stable disease. As the Stage 1 study objectives were not reached, BI 2536 will not be assessed further as a single agent. Ongoing preclinical work is assessing the potential for synergy of BI 2536 in combination therapy. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Boehringer Ingelheim Pharma GmbH & Co. KG Boehringer Ingelheim

Outcome of second-line chemotherapy with a combination of docetaxel and carboplatin (DC) in docetaxel-resistant (DR) hormone refractory prostate cancer (HRPC) patients

16090 Background: Docetaxel is the standard chemotherapy for HRPC. However, a standard protocol has not yet been defined for patients with DR disease. Initial reports support the use of carboplatin (C) in combination with docetaxel (D) in these patients (pts). Methods: Metastatic HRPC pts that were resistant to treatment with D were included in our retrospective analysis. Between February 2005 and December 2007, 17 pts received treatment with C AUC 5 q3wks in combination with D 75 mg/m2 q3wks or D 35 mg/m2 d1, d8, d15 q4wks. 3 pts additionally received estramustine 140 mg on 3 consecutive days in parallel to weekly applications of D. All pts were assessed for PSA response and clinical outcome. Results: Seventeen pts were identified at our institution for analysis. The median follow-up was 13 months (range: 0–31) with a median number of 4 cycles administered (range: 1–16). PSA reduction >50% was achieved in 9 pts (53%) and PSA stabilization in 5 pts (29%). 4 pts (24%) progressed without PSA response. The median duration of PSA response was 19 wks. Pts with PSA normalization or >90% reduction tended to achieve a longer PSA response (median 79 wks, range: 18–80) compared to pts with PSA stabilization or reduction by 50–90% (20 wks, range: 4–57). The most common grade 3/4 toxicities were neutropenia in 29% and thrombocytopenia in 11% of pts. Conclusions: This retrospective analysis supports the usefulness of second-line chemotherapy in HRPC. DC shows promising activity in DR pts with clinically meaningful responses. Patient Characteristics ECOG 0, No. of patients (%) 13 (76%) ECOG 1, No. of patients (%) 3 (18%) ECOG 2, No. of patients (%) 1 (6%) Liver metastases, No. of patients (%) 4 (24%) Visceral or lymphatic metastases, No. of patients (%) 6 (35%) Pain, No. of patients (%) 12 (71%) ≥2 metastatic sites, No. of patients (%) 7 (41%) Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration sanofi-aventis

Satraplatin in patients with advanced hormone-refractory prostate cancer (HRPC): Overall survival (OS) results from the phase III satraplatin and prednisone against refractory cancer (SPARC) trial

5003 Background: Satraplatin is a novel oral platinum compound previously reported to reduce risk of disease progression among HRPC pts progressing after prior CT. Herein the impact of satraplatin on OS is reported. Methods: SPARC is a multinational, randomized, double blind, placebo-controlled trial comparing Satraplatin 80 mg/m2/day po x 5 q 5 weeks) + prednisone 5 mg po bid [S] vs placebo + prednisone [P] in patients with metastatic HRPC progressing after prior CT. Progression-free survival (PFS) and OS were co-primary endpoints. Secondary and exploratory endpoints included time to pain progression (TPP), pain response, duration of pain response, objective tumor response, and PSA response. Efficacy analyses were conducted on an intent-to-treat (ITT) basis. Results: 950 pts were randomized 2:1 to S (n=635) and P (n=315). Baseline characteristics were well-balanced across groups. Of all pts, 51% received prior docetaxel and 47% received post-SPARC CT. As reported, S was associated with statistically significant improvements in PFS; TPP; PSA response, objective tumor response, pain response, and duration of pain response. These improvements did not translate into an OS benefit: median OS was 61.3 weeks and 61.4 weeks in the S and P groups respectively (HR = 0.97; 95% CI: 0.83, 1.13). Trends for improved OS was observed in the subgroup of pts who received prior docetaxel (HR = 0.78; 95% CI: 0.61, 0.99; medians 66.1 vs. 62.9) as well as pts who reported a PPI score 2–5 at baseline (HR = 0.88; 95% CI: 0.67, 1.16; medians 45.7 vs. 43.0) when models were adjusted for baseline prognostic factors. In the S group; myelosuppression was the most common toxicity; grade 4 neutropenia was detected in 4% and only one patient experienced grade 4 thrombocytopenia. Grade 3/4 non- hematologic side effects in the S group included infection (4.5%), vomiting (1.6%) and diarrhea (1.9%). Conclusions: Satraplatin is well tolerated and reduces risk of disease progression for men with HRPC progressing after prior CT. Ongoing analyses are planned to define relationships between PFS, pain response, and OS, as well as to elucidate factors (including post-SPARC CT) that may have confounded the ITT survival analysis. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration GPC-Biotech GPC-Biotech GPC-Biotech

What is the real impact of bone pain on survival of hormone-refractory prostate cancer (HRPC) patients treated with docetaxel?

5149 Background: Docetaxel is currently the standard of care for HRPC patients (pts). The moment of docetaxel initiation according to the presence or absence of the bone pain was less explored. Methods: Eligible HRPC pts were required to have a baseline bone pain evaluation using the rank-scores as follows: no pain or minimal pain (0), mild (1), moderate and severe pain (2), respectively. The main endpoint was to explore the overall survival (OS) impact of the bone pain (presence and intensity) using the Cox regression analysis, stratified by chemotherapy regimen. OS was calculated between start of chemotherapy and death or last follow-up for censored pts. Secondary endpoint was to evaluate the relationship between PSA doubling time (DT) and survival of pts with minimal or no pain. Results: Data of 145 consecutive HRPC pts treated in a single French center were analyzed. Chemotherapy was docetaxel (67%) or mitoxantrone-based. The median age was 68 years and 93% of pts had bone metastases, 55% with minimal or no pain at baseline. Median OS was 17.3 months (95% CI, 14.6–20) and 93% of pts died. There were OS differences between pain categories ( Table ). Pain intensity was significantly related with OS: hazard ratio=1.50 (95% CI, 1.20–1.88), P=0.0001 at the univariate analysis. Multivariate analysis adjusted by ECOG PS, hemoglobin and number of metastatic sites showed a 16% rise of the risk of death for pts with severe and mild pain. Pts with minimal or no pain at baseline have a different outcome depending of PSA DT (≥ 45 and &lt; 45 days): median OS 32.4 months (95% CI, 16.2–48.7) and 16.5 months (95% CI, 10–22.9), respectively. Conclusions: Our results suggest that HRPC pts with minimal or without bone pain can experience a better OS with docetaxel-based therapy. This motivates the use of docetaxel early, before bone pain apparition. The OS benefit was even higher for asymptomatic pts with a longer PSA DT. [Table: see text] No significant financial relationships to disclose.

Molecular analysis of hormone refractory prostate cancer biopsies supports the rationale of using mTOR inhibitors

21126 Background: The aim of our group is to identify molecular signatures in samples of hormone refractory prostate cancer (HRPC) patients (pts) that lead to novel rationales for medical treatment. We have previously shown that transurethral resections (TUR) of the prostate in HRPC pts are useful specimens for gene expression profiling using microarrays (ASCO 2006). Aim of this study was to prove the feasibility of gene expression profiling on prostate biopsies and to develop a standardised tissue handling protocol in order to facilitate multicenter research. Methods: Biopsy material and corresponding TUR chips or classical specimens from 8 pts with HRPC, 13 pts with localized PCA, 6 pts with benign prostatic hyperplasia (BPH) and 11 pts without cancer or BPH were investigated and compared. The tumor type and content was evaluated by a pathologist. Tissues were preserved in liquid nitrogen or RNAlater. Different tissue lysis and RNA purification methods were compared by the quantity (NanoDrop measurement) and quality (Bioanalyser, Agilent) of isolated RNA. Gene expression profiling occurred on Affymetrix HG-FOCUS arrays. Results: Most reliable gene expression results were obtained by biopsy lysis in Trizol using the QIAshredder. A total of more than 1 μg RNA was isolated from one biopsy. RNA quality fulfilled pre-defined criteria such as a 28S/18S rRNA ratio of &gt; 0.8, an area under the curve of &gt; 10% and a RNA integrity number &gt; 6.5. A comparison of HRPC and PCA samples clearly confirmed previous results of a deregulation of protein biosynthesis (translation initiation and elongation factors, ribosome biogenesis) and PI3K signalling pathway components. Conclusions: Gene expression profiling supports the induction of the PI3K-AKT-mTOR pathway in HRPC. A standardised protocol for gene expression profiling from prostate biopsy samples applicable for translational research programs within multicenter clinical trials is now available. As a part of a clinical phase II trial that aims to investigate survival benefits on HRPC pts treated with docetaxel ± RAD001, a translational research program is now set up in parallel to identify biomarkers for response prediction using microarray gene expression analysis from prostate biopsies. No significant financial relationships to disclose.

Chromogranine A and neuron-specific enolase as the main predictors of survival for hormone-refractory prostate cancer (HRPC) patients

15594 Background: Clinical studies suggested that the extent of neuro-endocrine differentiation in prostate cancer increases with tumor progression and the development of androgen refractory status. Chromogranine (CgA) and neuron-specific enolase (NSE) are currently explored as surrogate markers. Methods: Eligible chemonaive HRPC patients (pts) were required to have an ECOG performance status (PS) ≤ 2. Before chemotherapy initiation, we quantified NSE, CgA and PSA in the venous blood using commercial kits. We evaluated the impact of baseline NSE, CgA and PSA on overall survival (OS) using multivariate Cox regression analysis, stratified by chemotherapy regimen. Secondary, we studied the correlation between NSE, CgA, PSA and other important variables as age, Gleason score, hemoglobin, number of metastatic sites and ECOG PS. Results: Data of 39 consecutive HRPC pts treated between December 01–06 in a single French center were analyzed. Chemotherapy was docetaxel-based in 92% of pts. Median age was 71 years (range 51–86) and 79% of pts had bone metastases. Elevated NSE, CgA and PSA were observed in 6, 9 and 30% of pts and median levels were 10.8, 67 and 23.3 ng/mL, respectively. Gleason 8–10 was present in 49% of pts. Significant correlations were observed between NSE and the number of metastatic sites and between CgA and age, hemoglobin and ECOG PS. The baseline PSA was only correlated with Gleason score. Median OS for the entire cohort was 24.4 months (95% CI, 18.8–29.9). Two-year OS was 15% and only 19% of patients are dead. Univariate Cox regression analysis showed only a significant relationship between OS and baseline NSE: hazard ratio= 1.09 (95% CI, 1.03–1.16), P=0.006. No other known prognostic factors are related to outcome. A multivariate model including baseline NSE, CgA, ECOG PS and Gleason score showed a 15% rise of the risk of death related to NSE (borderline P value). Conclusions: NSE was the most powerful predictor of survival for HRPC pts. Our results emphasize the theory that cells secreting NSE are chemoresistant, with a negative impact on OS. No significant financial relationships to disclose.

Gefitinib (G) plus prednisone (P) versus placebo (pl) plus prednisone in the treatment of hormone-refractory prostate cancer (HRPC): A randomized phase II trial

5070 Background: In spite of EGF-R overexpression in 40%-80% of pts with HRPC, the results achieved so far with G, a selective EGF-R tyrosine kinase inhibitor have been dismal. This trial was designed to investigate the activity of G when combined with P, a common therapeutic option for HRPC pts. Methods: HRPC pts unresponsive to antiandrogen withdrawal were given P (10 mg/d) plus G (250 mg/d) or pl. On progression, pts initially assigned to pl were offered the possibility to receive G. This was a one-stage trial, and 37 pts per arm were required. Best PSA response (any decrease = 50% in baseline PSA confirmed 4 wks apart) was the primary end-point. Time to disease progression, OS and toxicity were secondary end-points. Results: 82 pts were enrolled (GP: 38; plP: 44). Groups were well balanced in respect to median age (75 vs 74 yrs); WHO PS (0 in both); baseline PSA (52 vs 44 ng/ml); bone disease (87% vs 84%) Gleason score 7 (58% vs 52%); prior treatment. At a median follow-up time of 29 mos (26–32), overall 77 pts progression and 51 died. PSA resp was recorded in 16% and 11% of pts in GP and plP groups. Median time to progression was 4.0 (3.5–4.5) and 4.5 (3.5–5.0) mos, respectively. In both groups, median PSA level increased during the first 8 wks of treatment (GP:13%; plP: 32%) while it decreased thereafter. Median time to death was 26.5 (16–37) and 20.5 (14–27) mos in the GP and plP groups, respectively (HR: 0.69, 0.39–1.23; p=.2). However, OS of pts given either early or delayed treatment with G was significantly longer (26.5 vs 17.5 mos; HR: 0.49, 0.28–0.87, p=.01). This advantage was maintained also after multivariate analysis by Gleason score, baseline PSA, Hb and PAL, WHO PS and pain score. AEs (any grade) occurred in 19 pts in each arm. However diarrhea and skin rash were more common in the GP group (12% vs 0% and 14% vs 2%, respectively). Conclusions: G when combined to P showed a moderate toxicity, achieved PSA control and prolonged pts survival. The efficacy of GP in HRPC warrants to be further investigated. [Table: see text] No significant financial relationships to disclose.

Suberoylanilide hydroxamic acid (vorinostat) post chemotherapy in hormone refractory prostate cancer (HRPC) patients (pts): A phase II trial by the Prostate Cancer Clinical Trials Consortium (NCI 6862)

5132 Background: Histone deacetylases (HDACs) are key regulators of histone acetylation status, which is critical to expression of genes implicated in the regulation of cell survival, proliferation, differentiation and apoptosis. Vorinostat is a potent oral HDAC inhibitor with anti-tumor activity in PC models and in phase I clinical trials. A phase II trial is assessing vorinostat in HRPC pts. Methods: Eligible pts had disease progression on 1 prior chemotherapy for HRPC, a PSA of ≥ 5ng/ml, and adequate organ function. Vorinostat was administered orally at 400 mg daily in 21-day cycles. Response was assessed every 12 weeks. The primary endpoint is proportion of pts without progression at 6 months by objective and biochemical measures. This study is designed to accrue 29 pts (80% power at the 5% significance level to distinguish between a rate of 10% vs 30%). If ≥ 7/29 pts are progression-free at 6 months, the drug will be recommended for further study. Secondary endpoints include safety, rate of PSA decline, objective response rate and overall survival. Correlative studies assessing the effect of vorinostat on serum levels of IL-6, soluble IL-6 receptor and gp130 levels were conducted. Results: To date 23/29 pts have been accrued. Median age is 68 years (range 54–77), 70% had performance status 1 and 78% are white. At registration disease progression was defined by: PSA in 83%, bone in 74% and soft tissue in 43%. Median number of cycles is 2 (range 1–6), 57% of pts required at least 1 dose reduction. At time of this report 39% of pts remain on therapy. 19 pts are toxicity evaluable. Most common treatment related adverse events (AEs) were: fatigue (74%), anorexia (63%), nausea (58%), diarrhea (32%), dehydration, taste alteration and vomiting (26% each). There was 1 grade (G) 4 thrombosis and 11 pts had G 3 AEs, the most common were: fatigue (32%) and nausea and anorexia (11% each). 3/9 response evaluable pts achieved stable disease. Conclusions: Vorinostat is feasible post chemotherapy in pts with HRPC, however it is associated with significant toxicities requiring dose reductions. Final efficacy, safety and correlative studies will be reported. Support: CTEP, N01-CM-62201, PC051375, PC 051382 No significant financial relationships to disclose.

Results of a randomized phase II study of irofulven in hormone-refractory prostate cancer patients that have failed first-line docetaxel treatment

5068 Background: Currently, no available treatments demonstrate an increase in survival for patients (pts) with hormone- refractory prostate cancer (HRPC) who have failed treatment with docetaxel-based regimens. Previous monotherapy and combination Phase I/II trials with irofulven (IROF) have shown antitumor effects in pts with HRPC, including those with resistance to docetaxel. A randomized phase II study was undertaken in HRPC pts with documented resistance to docetaxel to evaluate the efficacy and safety of IROF regimens compared to mitoxantrone (MITOX). Methods: Pts with metastatic HRPC with documented progression by RECIST or PSA Working Group criteria during or within 3 months of prior docetaxel were randomized to 1 of 3 arms in a 2:2:1 ratio: Arm A: IROF (0.45 mg/kg, Day [D]1, 8 every [q] 3 weeks [w]) and prednisone (PRED; 10 mg qd); Arm B: IROF (0.4 mg/kg D1, 15), capecitabine (CAPE; 2,000 mg/m2 D1–15 q4w) and PRED; Arm C: MITOX (12 mg/m2 q3w) and PRED. Pts were stratified by baseline pain status. Efficacy endpoints included time to progression (TTP), overall survival (OS), and response. Results: Enrollment of 134 treated pts was completed as of Jan 2006 (Arm A/B/C: 53/54/27). Median age: 64/66/63 years, median KPS: 80/90/80, median baseline PSA (ng/mL): 144/136/243, disease-related pain at baseline: 65%/57%/59%, and median number of metastatic sites: 1/1/2. Median pre-study PSA doubling time (days) was 42/44/50. Efficacy: As of Jan 2007, median OS (mos) was 10.1/9.5/7.4 in Arms A/B/C (based on 73% of pt deaths). Preliminary median TTP (mos) was 2.2/3.8/1.8, based mainly on PSA progression. PSA and RECIST responses were 10%/22%/0% and 10%/10%/13%, respectively. Safety: Treatment was well tolerated in all arms. The most frequent Grade 3–4 toxicities (% pts) were asthenia (8%/15%/0%), and vomiting (4%/11%/0%). Grade 3–4 hematological events included neutropenia (22%/15%/61%) and thrombocytopenia (23%/21%/4%). Conclusions: Results to date indicate longer survival, longer TTP, and greater PSA response for IROF/PRED and IROF/CAPE/PRED compared to MITOX/PRED. Based on these data, a larger randomized trial of irofulven in docetaxel resistant HRPC patients is warranted. No significant financial relationships to disclose.

Phase I study of picoplatin and docetaxel (D) with prednisone (P) in patients (pts) with chemotherapy-naive metastatic hormone refractory prostate cancer (HRPC)

15546 Background: Picoplatin is a sterically hindered platinum analogue specifically developed to overcome platinum resistance and to improve on the safety and efficacy of other platinum-based drugs. In &gt;600 pts, picoplatin had single-agent activity in prostate, lung, ovarian and other malignancies with rare clinically significant nephro-, oto-, or neurotoxicity (∼2% grade 3 and 0% grade 4), even in platinum pretreated pts. An objective response rate of 20% and a PSA response rate of 25% were observed following 120 mg/m2 picoplatin q 3 wk in 20 chemotherapy-naïve pts with HRPC. D + P leads to superior survival, increased PSA response and improved quality of life in HRPC pts. Picoplatin has demonstrated synergy with taxanes in pre-clinical studies. Thus the current study is designed to investigate D + P + picoplatin in chemotherapy-naïve pts with metastatic HRPC. Methods: Pts with documented progression of metastatic disease during adequate hormonal therapy, ECOG performance status of 0 or 1 and preserved organ function received D, 60 mg/m2 q 3 wks + P, 5 mg, po bid + picoplatin. Picoplatin has been given to date to sequential cohorts of subjects at 60 mg/m2, 80 mg/m2 and 100 mg/m2. Results: 16 pts have been enrolled and have received up to 8 cycles of therapy. Therapy has been well tolerated. No dose limiting toxicity has been observed. Dose reduction for thrombocytopenia has been required in 1 pt, but there has been no cumulative myelotoxity. 7 pts in the first 3 dose cohorts have been evaluated for efficacy after 4 cycles (12 weeks): at doses below the maximum tolerated dose, there were 3 PSA responses and 1 objective partial response. Dose escalation continues. Conclusion: Picoplatin can be safely administered with D + P in chemo-naïve pts with HRPC. A phase 2 study of this combination will begin when an optimal, safe dose is defined. No significant financial relationships to disclose.

Is the natural history of prostate cancer different according to serum neuroendocrine profile?

15536 Background: Elevated neuron-specific enolase (NSE) and chromogranine (CgA) values correlate with poor prognosis in prostate cancer (PC) patients (pts). They are correlated with the histological phenotype and a short hormone-sensitivity interval. The impact on the outcome was less explored. Methods: Eligible PC pts were required to have serial CgA and NSE specimens after the initial diagnosis in the venous blood, using commercial kits. Markers were defined as abnormal (+) or normal (-) with a threshold of 20,6 and 100 ng/mL for NSE and CgA, respectively. The endpoint was to evaluate the clinical impact of serum NSE and CgA on the natural history (NH) of the PC using the multivariate Cox regression analysis, stratified by Gleason score and adjusted by age at diagnosis. NH was calculated between the initial diagnosis and death or last follow-up for censored pts. Results: Blood samples were obtained from 213 PC pts, 53% with a metastatic hormone-refractory disease at the moment of the analysis. Seven, 36% and 10% of pts had either an abnormal NSE, CgA or both. Normal serum NSE and CgA were found in 47% of all pts and only in 35% of metastatic hormone-refractory PC pts. Median age was 64 years (range 41–82), 41% of pts had a Gleason score 8–10. Median NSE and CgA levels were 13.3 and 92 ng/mL, respectively. The median of the NH was not reached yet. The adjusted risk of death was multiplied by 3.1 for pts with abnormal NSE or/and CgA (HR=3.5, unadjusted for age). A borderline relationship was observed at the multivariate analysis between NH and the neuroendocrine profile ( Table ). Conclusions: NSE was the most powerful predictor of the NH in PC pts, regardless the moment of the rise during the NH. A systematic NSE and CgA assessment could be proposed for all pts. [Table: see text] No significant financial relationships to disclose.

A prospective study of carboplatin-etoposide in docetaxel-pretreated patients with hormone-refractory prostate cancer (HRPC): Clinical activity and correlation with neuroendocrine features

5151 Background: There is currently no standard of care for patients (pts) with HRPC and disease progression after docetaxel-based chemotherapy. Platin compounds have demonstrated activity in this setting and in vitro evidence of synergy between carboplatin and etoposide has previously been reported. A significant proportion of advanced HRPC exhibit neuroendocrine features but there are limited data on whether these patients should be treated differently or not. Methods: Pts with HRPC who experienced failure after first-line docetaxel-based chemotherapy were prospectively treated with carboplatin (AUC 5 day 1) and etoposide (80 mg/m2 day 1 to 3), repeated every 3 weeks as second-line chemotherapy. The response rate (defined as a serum PSA decline of = 50%), progression-free survival (PFS) and overall survival (OS) were evaluated using consensus criteria (Bubley JCO 1999). Pain relief was evaluated using a visual analogic scale. Serum chromogranin A and neurone specific enolase (NSE) levels were measured at baseline. Toxicity was evaluated according to NCI criteria. Results: Forty-one HRPC pts, previously treated with docetaxel with (n=24) or without (n=17) estramustine, prospectively received carboplatin-etoposide as second-line chemotherapy. A PSA response was obtained in 9 pts (22%). Pain relief was achieved in 18 pts (45%). Median progression-free survival was 9 weeks and median overall survival was 19 months. Toxicity included grade 3–4 anemia in 25% and febrile neutropenia in 2%. Biological neuroendocrine features (e.g. elevated baseline serum chromogranin A and NSE) were not associated with response or PFS. The response rate was 18% and 31% in pts with normal and elevated baseline chromogranin A, respectively. Conclusions: The carboplatin-etoposide regimen is active and well-tolerated as second-line chemotherapy after docetaxel-based chemotherapy in HRPC patients. Activity was detected in both tumors with and without neuroendocrine features. No significant financial relationships to disclose.

Clinical outcome of taxane-resistant (TR) hormone refractory prostate cancer (HRPC) patients (pts) treated with subsequent chemotherapy (ixabepilone (Ix) or mitoxantrone/prednisone (MP)

4558 Background: The clinical course of TR HRPC pts has not previously been evaluated in a large, prospective study. No standard treatment exists for this pt population, although MP is frequently used. Ix is an epothilone B analogue with activity against TR cell lines. Methods: Metastatic HRPC pts with disease progression during or within 60 days of stopping T chemotherapy were eligible. In a 2-arm, non-comparative randomized phase II study, pts were assigned to receive either: 1) M 14 mg/m2 IV q3wks and P 5 mg PO BID or 2) I × 35 mg/m2 IV q3wks. Crossover was allowed for progression or toxicity. The study’s primary endpoint was to detect a ≥ 50% PSA decline by Consensus Criteria in at least 25% of 2nd-line pts (H0 = 10%, α = 0.04, β = 0.18 for each arm). Pts were followed for survival. Results: Forty-one evaluable pts each were accrued to Ix and to MP. The median follow-up is 5.0 months (range: 0.3–19.5). The median number of cycles administered to each 2nd-line arm is 3 (range: Ix: 1–8, MP: 1–12). Median survival from protocol entry is 13.0 months with Ix and 12.5 months with MP. Confirmed 2nd-line post-therapy (rx) ≥50% PSA declines were observed in 17% of Ix pts (95% CI = 7–32) and 20% of MP pts (95% CI = 9–35). Of pts with measurable disease, partial responses were observed in 1/18 pts on 2nd-line Ix (6%; 95% CI = 0.1–27.3) and in 1/15 pts on 2nd-line MP (7%; 95% CI = 0.2–31.9). Median duration on 2nd-line Ix and MP was 2.2 months and 2.3 months, respectively. Crossover to 3rd-line rx occurred in 39% of Ix pts and 68% of MP pts. Confirmed 3rd-line post-rx ≥50% PSA declines were observed in 3/24 Ix pts and in 4/13 MP pts. The most common grade 3/4 toxicity associated with 2nd-line rx was neutropenia as previously reported (41% of Ix pts, 54% of MP pts). Conclusions: This prospective trial has characterized TR HRPC pts as having an observed median survival of approximately 1 year. This may be a useful reference for the screening of effective agents in the 2nd-line setting for TR HRPC. Both Ix and MP appear to have only modest activity as 2nd- and 3rd-line rx in this highly selected TR HRPC population. This study was supported by Bristol-Myers Squibb and the Prostate Cancer Foundation. No significant financial relationships to disclose.