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Purpose We report the long-term results of a prospective, Phase II study of long-term androgen deprivation (AD), pelvic radiotherapy (EBRT), permanent transperineal prostate brachytherapy boost (PB), and adjuvant docetaxel in patients with high-risk prostate cancer. Methods and Materials Eligibility included biopsy-proven prostate adenocarcinoma with the following: prostate-specific antigen (PSA) > 20 ng/ml; or Gleason score of 7 and a PSA >10 ng/ml; or any Gleason score of 8 to 10; or stage T2b to T3 irrespective of Gleason score or PSA. Treatment consisted of 45 Gy of pelvic EBRT, followed 1 month later by PB with either iodine-125 or Pd-103. One month after PB, patients received three cycles of docetaxel chemotherapy (35 mg/m 2 per week, Days 1, 8, and 15 every 28 days). All patients received 2 years of AD. Biochemical failure was defined as per the Phoenix definition (PSA nadir + 2). Results From August 2000 to March 2004, 42 patients were enrolled. The median overall and active follow-ups were 5.6 years (range, 0.9–7.8 years) and 6.3 years (range, 4–7.8 years), respectively. Grade 2 and 3 acute genitourinary (GU) and gastrointestinal (GI) toxicities were 50.0% and 14.2%, respectively, with no Grade 4 toxicities noted. Grade 3 and 4 acute hematologic toxicities were 19% and 2.4%, respectively. Of the patients, 85.7% were able to complete the planned multimodality treatment. The 5- and 7-year actuarial freedom from biochemical failures rates were 89.6% and 86.5%, and corresponding rates for disease-free survival were 76.2% and 70.4%, respectively. The 5- and 7-year actuarial overall survival rates were 83.3% and 80.1%, respectively. The 5- and 7-year actuarial rates of late Grade 2 GI/GU toxicity (no Grade 3–5) was 7.7%. Conclusions The trimodality approach of using 2 years of AD, external radiation, brachytherapy, and upfront docetaxel in high-risk prostate cancer is well tolerated, produces encouraging long-term results, and should be validated in a multi-institutional setting.

Purpose of review Prostate cancer remains a medical dilemma and a major cause of morbidity and mortality in many western countries. It represents the most common cancer in US men, with an estimated 192 280 new cases diagnosed in 2009. The median survival for men with metastatic castrate-resistant prostate cancer is 1-2 years, with improvements in survival seen primarily with docetaxel-based therapies. The purpose of this article is to discuss developments of novel agents in the field of metastatic castration-resistant prostate cancer (CRPC), including new cytotoxic agents, immune-based therapies, circulating tumor markers and targeting agents. Recent findings During this past year, several promising approaches yielded disappointing results in the phase III setting (GVAX); nonetheless, expectations for other agents (Abiraterone, MDV3100, Zibotentan, immunotherapy agents) still remain high. Summary Systemic therapy options are limited in CRPC and survival benefit remains to be seen with the new therapies. Circulating tumor cells continue to provide important prognostic information and will likely become an important aspect of future clinical decision-making.

Zibotentan (ZD4054) is a specific endothelin A receptor antagonist in clinical development for the treatment of hormone-resistant prostate cancer (HRPC). In a Phase II trial in patients with pain-free or mildly symptomatic metastatic HRPC, zibotentan was well tolerated with a promising signal for prolonged overall survival compared with placebo. As part of this trial, the impact of zibotentan compared with placebo on health-related quality of life (HRQoL) was assessed.Patients were randomized to receive once-daily oral zibotentan 10 or 15 mg, or matching placebo. Patients were allocated to one of two questionnaires; the Functional Assessment of Cancer Therapy-Prostate (FACT-P) or the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30), supplemented by PR25, specific for prostate cancer. Questionnaires were completed at baseline and every 4 weeks until disease progression when study treatment was discontinued.Compliance with questionnaire completion was90% (286 of 312 patients) of the intention-to-treat population at baseline. Of baseline completers who were available for assessment (i.e., had not clinically progressed), 89% (164 of 184) and 83% (73 of 88) completed questionnaires at 12 and 24 weeks, respectively. HRQoL scores from both questionnaires were high at baseline and remained high throughout the study, with scores being similar in the zibotentan and placebo groups. However, some floor and ceiling effects were seen in the EORTC QLQ-C30 questionnaire.High-baseline HRQoL scores were maintained throughout treatment with zibotentan. The FACT-P instrument was selected to further assess the impact of zibotentan on HRQoL in the Phase III clinical trial program.

PURPOSE Suramin is known to inhibit the growth of malignant prostate carcinoma cells in vitro. This led us to evaluate the effectiveness of suramin in the treatment of 38 patients with prostate carcinoma refractory to hormone therapy. PATIENTS AND METHODS Suramin was administered by continuous infusion at a rate designed to reach a peak of 300 micrograms/mL at the end of 14 days. Patients were given 8 weeks to recover from any toxicity before beginning the second cycle. Subsequent cycles were administered in the same manner except the starting dose rate was 280 mg/m2. RESULTS In 17 patients with measurable soft tissue disease, three had complete disappearance of soft tissue disease for 4, 5, and 11 months, whereas three patients had a greater than or equal to 50% decrease in the sum of the products of the diameters of all measurable disease for greater than or equal to 1 month. Of these 17 patients, pretreatment prostate-specific antigen (PSA) decreased by 75% or more in five (29%) and normalized in one (6%). The remaining 21 patients had disease limited to bone, and only one of these experienced resolution of more than 50% of all lesions on bone scan. Of these 21 patients, pretreatment PSA decreased by 75% or more in eight (38%) and normalized in five (25%). Median time to progression for all patients was 26.3 weeks, and median survival was 42.3 weeks. Patients with bone involvement alone exhibited a better survival than patients with soft tissue involvement (P2 = .02). Survival was strongly correlated (P2 = .0001) with a decline in the pretreatment PSA of greater than or equal to 75% by the eighth week on therapy, with nearly an 85% survival at 1 year compared with a 20% survival for those whose pretreatment PSA did not decline by that amount. CONCLUSION We conclude that suramin is an active agent in hormone-refractory prostate carcinoma.

Fifteen patients with previously untreated metastatic prostate cancer were treated on a pilot trial with a combination of maximal androgen blockade plus intermittent cytotoxic therapy after androgen priming to stimulate cell division. Androgen blockage was carried out using a gonadotropin-releasing hormone analog (leuprolide) plus a nonsteroidal antiandrogen (flutamide). Carboplatin (CBDCA) (800 mg/m2) was given intravenously every 28 days, preceded for 3 days and followed for 3 days by androgen treatment with fluoxymesterone (5 mg orally twice a day), during which time flutamide was discontinued. Three patients (20%) achieved a complete response (CR), and eight patients (53.3%) achieved a partial response (PR). Four patients (26.7%) had stable disease (SD). The median progression-free survival (PFS) time was 31 months. Nine of 15 patients (60%) remain alive with a median follow-up time of 42+ months (range, 22 to 54 months). Grade 4 thrombocytopenia and Grades 3 or 4 leukopenia were experienced in 87% and 80% of patients, respectively, requiring dose reductions of CBDCA in 85% of the cycles. Six of 15 patients experienced a flare in bone pain with androgen priming. There were no associated spinal cord compressions; however, exclusion of impending spinal cord compression was required before entrance on study.

We conducted a clinical trial of peptide prostate specific antigen (PSA): 154-163 (155L) vaccination in human leukocyte antigen (HLA)-A2 patients with detectable and rising serum PSA after radical prostatectomy for prostate cancer (Clinicaltrials.gov identifier NCT00109811). The trial was a single dose-level, phase 2 pilot trial of 1 mg of PSA: 154-163 (155L) emulsified with adjuvant (Montanide ISA-51). The primary endpoint was the determination of immunogenicity of the vaccine; secondary outcomes were determination of toxicity and effect on serum PSA. The vaccine was given subcutaneously 7 times on weeks 0, 2, 4, 6, 10, 14, and 18. Peptide-specific CD8 T-cell responses in the peripheral blood mononuclear cells (PBMC) of patients were measured by interferon (IFN)-gamma enzyme-linked immunosorbent spot assay. CD8 T-cell cultures were also established by in vitro stimulation with the peptide presented by autologous dendritic cells. Five patients were enrolled and completed all vaccinations. No IFN-gamma response to PSA: 154-163 (155L) was detected in unfractioned PBMC in any patient either before or after vaccination. Three of 5 patients demonstrated strong IFN-gamma responses to PSA: 154-163 (155L) and native PSA: 154-163 peptides in CD8 T-cell cultures derived from postvaccination PBMC. However, peptide-specific T cells failed to recognize HLA-A2 positive targets expressing endogenous PSA. There were no significant changes in serum PSA level in any subject. No serious adverse events were observed. PSA: 154-163 (155L) is not an effective immunogen when given with Montanide ISA-51. The PSA: 154-163 peptide is poorly processed from endogenous PSA and therefore represents a cryptic epitope of PSA in HLA-A2 antigen-presenting cells.

Purpose Pain from castration-refractory prostate cancer (CRPC) bone metastases is a common event. Although it is assumed that pain represents an adverse prognostic factor, this variable has not been extensively evaluated. The objective of this study was to determine whether men with CRPC who had higher pain interference scores at baseline had worse clinical outcomes compared with men who had lower pain scores. Patients and Methods Data from three randomized phase III multicenter trials conducted by the Cancer and Leukemia Group B from 1992 to 1998 were combined. Eligible patients had progressive CRPC adenocarcinoma of the prostate, an Eastern Cooperative Oncology Group performance status of 0 to 2, and adequate hematologic, renal, and hepatic functions. Seven items from the Brief Pain Inventory were used to assess the impact of pain on a range of daily activities and quality of life, each rated on a scale from 0 to 10. Results In 599 men, the median pain interference scores was 17 (interquartile range, 4 to 34), and 38% of the men had opioid analgesic use at baseline. There was a statistically significant association between pain interference scores and risk of death. The median survival times were 17.6 months (95% CI, 16.1 to 19.1 months) and 10.2 months (95% CI, 8.6 to 11.3 months; P < .001) in men with low (< 17) and high (≥ 17) pain scores, respectively. Pain was inversely associated with likelihood of prostate-specific antigen decline, objective response, and time to bone progression. Conclusion This analysis demonstrates that pain is a statistically significant predictor of overall survival in men with metastatic CRPC. These results need to be validated prospectively in future phase III trials.

e16032 Background: D improves survival in mCRPC, but benefits are modest. Emerging clinical data suggests mCRPC patients (pts) treated with anti-androgen therapy like abiraterone (AA) or enzalutami...

146 Background: Tivantinib is a putative non-ATP competitive inhibitor of c-MET receptor tyrosine kinase that has additional cytotoxic mechanisms including tubulin inhibition. Prostate cancer demonstrates higher c-MET expression as the disease progresses to more advanced stages and to castration resistance. Methods: 80 patients (pts) with asymptomatic or minimally symptomatic mCRPC were assigned (2:1) to either tivantinib 360 mg PO BID or placebo (P). The primary endpoint was progression free survival. PCWG2 guidelines were utilized for determining eligibility and progression. Results: Of the 80 pts enrolled, 78 (52 tivantinib, 26 P) received treatment and were evaluated. Median age was 67 yrs (range: 43 to 85). Baseline characteristics were balanced between arms for ECOG PS, Gleason score, PSA, LDH, hemoglobin, Alk Phos, prior treatment, bone and organ involvement. More African Americans and those with lymph node involvement were randomly assigned to placebo. Median follow up is 8.2 months (range: 1.4 to 27.6). To date 59 patients have progressed. Patients treated with tivantinib had significantly better PFS vs. those treated with placebo (medians: 5.6 mo vs 3.8 mo, respectively; HR = 0.53, 95% CI: 0.32 to 0.89; p=0.015). Toxicity was mild overall. Grade 3 febrile neutropenia was seen in 1 patient on tivantinib while grade 3 and 4 neutropenia were recorded in 1 patient each on tivantinib and placebo. Grade 3 sinus bradycardia was recorded in two men on the tivantinib arm. 8 deaths (3 P and 5 tivantinib) have been recorded and were all considered unrelated to therapy. Conclusions: Tivantinib significantly improved PFS in men with asymptomatic or minimally symptomatic mCRPC. Given the favorable toxicity profile and evidence of anti-tumor activity, investigation of tivantinib with other agents may be a rational strategy. Clinical trial information: NCT01519414.

235 Background: Docetaxel (D) improves overall survival in metastatic castrate-resistant prostate cancer (mCRPC), but benefits remain short-lived. Clinical data suggests patients (pts) with mCRPC treated with anti-androgen therapy like abiraterone (AA) or enzalutamide (ENZA) have decreased responses to subsequent therapy due to cross-resistance in the androgen pathway targeted by D, AA, or ENZA(van Soest et al, Eur J Cancer 49:18, 2013). Combining D with other agents, like cabozantinib (C), could target different cellular signaling pathways potentially minimizing tumor resistance. Methods: D naive pts receive 75 mg/m2 IV on day 1 of a 21 day cycle, and prednisone (P) 5 mg po q12 hours with C at 3 dose levels: 20, 40, or 60 mg po daily until maximum tolerated dose (MTD) is defined. In phase 2, pts who have progressed on AA or ENZA, enroll on a randomized 2 arm cohort comparing D plus C to D alone. Results: 20 pts have been accrued; 4 at 20 mg C, 8 at 40 mg C, and 7 at 60 mg C. On phase 2, 1 pt is randomized to D alone. Median age is 68 (44-84 yrs). Median baseline PSA is 94.7 (0.01-754.1 ng/mL). Gleason score is 9 (7-10). Median cycles is 9.5 (1-33). 8 pts have bone only disease, 12 pts have bone and soft tissue disease. Common grade 2 and grade 3 adverse events possibly related to C: hand/foot syndrome (4/16), oral mucositis (4/16), hypophosphatemia (4/16), and fatigue (3/16). The MTD of C is 40 mg daily with D. 15 pts were previously treated with AA or ENZA. In 13 patients previously treated with AA, median PFS has not been reached, with a median potential follow up of 12.4 months. Six month PFS is 77.8% and 9 month PFS is 60.5%. Conclusions: D plus P may have limited benefits after disease progression on AA as seen in 3 retrospective analyses demonstrating a median PFS survival of 4.6 months or less (Mezynski J, et al. Ann Oncol 23;11, 2012) (Aggarwal R, et al. Clin Genitourin Cancer 12;5, 2014) (Schweizer MT, et al. Eur Urol 66;4, 2014). PFS results seen in this trial compare favorably to previously published data of treatment with D after AA in mCRPC, suggesting the addition of C to D may help overcome acquired resistance. Further randomized trials will determine if C in combination with D will enhance clinical outcomes. Clinical trial information: NCT01683994.

Purpose Prostatectomy or radiation for localized prostate cancer (PC) can fail in up to 15% to 30% of patients. The purpose of this study was to determine feasibility, tolerability, and outcome of docetaxel followed by hormone therapy in men experiencing an increasing prostate-specific antigen (PSA) after their primary local treatments for PC. Patients and Methods Men with increasing serum PSA after prostatectomy or/and radiation were eligible. Serum PSA had to be ≥ 4 ng/mL and serum testosterone had to be in the noncastrate range. Treatment included docetaxel 70 mg/m2 every 3 weeks for up to six cycles, followed by total androgen suppression (luteinizing hormone-releasing hormone agonist plus bicalutamide) and peripheral androgen blockade (finasteride plus bicalutamide) for 12 to 20 months. Results Thirty-nine men were enrolled; 32 had PSA-only failure, seven also had clinical metastasis. Baseline median PSA was 13.7 ng/mL. Serum PSA decreased ≥ 50% in 17 of 35 patients (48.5%) and ≥ 75% in seven of 35 patients (20%) with docetaxel. The PSA decreased to a median of 0.1 ng/mL with subsequent hormone therapy. In 28 of 33 patients the PSA increased (median, 0.41 ng/mL) at a median follow-up of 2.3 months after treatment. In contrast, in five of 33 men the PSA remains at 0.1 ng/mL at a median of 18.9 months after therapy; three of these five men had soft tissue metastasis at entry but remain in complete remission. The most common grade 3 to 4 toxicity was neutropenia (61.5%). Conclusion Docetaxel followed by hormone therapy of limited duration may provide disease control in subgroups of men experiencing failure after local treatments for PC.

(1996). Hypertensive Reactions Associated with Paclitaxel. Cancer Investigation: Vol. 14, No. 4, pp. 340-342.

Total androgen deprivation is by many clinicians considered to be the optimal therapeutic regimen for hormone sensitive prostate cancer (1-2). Complete androgen blockade is usually accomplished with either orchiectomy or an LHRH agonist such as leuprolide, that inhibits testicular androgen production, together with an antiandrogen such as flutamide. Flutamide is a pure antiandrogenic compound that prevents the androgen receptor from binding testosterone and dihydrotestosterone (DHT) without exhibiting hormonal acivity of its own (3, 4).

Purpose: The epidermal growth factor receptor (EGFR) is overexpressed in 75 to 90% of renal cell carcinomas and may play a role in tumor initiation and progression. Gefitinib (Iressa, ZD1839) is a potent, selective EGFR-tyrosine kinase inhibitor. This trial was undertaken to assess the efficacy and toxicity of gefitinib in advanced renal cell carcinoma. Experimental Design: Oral gefitinib, 500 mg once daily, was given continuously. A single-dose reduction to 250 mg daily was allowed for toxicity. The primary end point was response rate (defined as complete remission + partial remission + stable disease). Secondary end points were progression-free survival, overall survival, toxicity, and correlation of response with EGFR status. Results: Twenty-one patients were enrolled on this study, and all are evaluable for response and toxicity. Patient characteristics were median age 61 (range, 35–78 years); 17 males, 4 females; median performance status 0 (range 0–2); median number of prior systemic therapies 1 (range, 0–3). The median and mean number of cycles of therapy received was 3 and 4.7 (range, 1–14+). The best response was stable disease in eight patients (38%). Median progression-free survival was 2.7 months. Median overall survival was 8.3 months. The difference in overall survival was significantly different between patients with progressive disease versus stable disease (6.1 months versus 16+ months; Log-Rank test P value < 0.0001). Three patients required a dose reduction, all for grade 3 diarrhea. There was no apparent correlation between EGFR status and stability of disease or progression of disease. Conclusions: Gefitinib is without significant conventional activity in renal cell carcinoma. The relation of “stable disease” to treatment or to disease-related prognostic heterogeneity remains to be defined.

PURPOSE OF REVIEW Androgen deprivation therapy is the cornerstone treatment for men with de novo or recurrent metastatic prostate cancer. Unfortunately, androgen deprivation therapy is primarily palliative, with nearly all men progressing to an androgen-independent state. Hormone-refractory prostate cancer presents significant management challenges and is the focus of this review. RECENT FINDINGS Investigations into the pathophysiology of hormone-refractory prostate cancer, the exploration of chemotherapeutic combinations, novel biological targets, skeletal protectants, and radiopharmaceuticals, as well as new prognostic tools are expanding the clinician's armamentarium and improving patient outcomes. SUMMARY Bisphosphonates and chemotherapy are providing effective palliative approaches. Phase II trials of taxane-based regimens show higher response rates and longer survival than has typically been achieved with existing standards. Two completed randomized phase III studies to be reported in mid-2004 will more definitively answer the question of whether currently available chemotherapy can improve survival.

Purpose Antiandrogen withdrawal (AAWD) results in a prostate-specific antigen (PSA) response (decline in PSA level of ≥ 50%) in 15% to 30% of androgen-independent prostate cancer (AiPCa) patients. Thereafter, adrenal androgen ablation with agents such as ketoconazole (K) is commonly utilized. The therapeutic effect of AAWD alone was compared with simultaneous AAWD and K therapy. Patients and Methods AiPCa patients were randomized to undergo AAWD alone (n = 132), or together with K (400 mg orally [po] tid) and hydrocortisone (30 mg po each morning, 10 mg po each evening; n = 128). Patients who developed progressive disease after AAWD alone were eligible for deferred treatment with K. Results Eleven percent of patients undergoing AAWD alone had a PSA response, compared to 27% of patients who underwent AAWD and simultaneous K (P = .0002). Objective responses were observed in 2% of patients treated with AAWD alone compared to 20% in patients treated with AAWD/K (P = .02). There was no difference in survival. PSA and objective responses were observed in 32% and 7%, respectively, of patients receiving deferred K, and were more common in patients with prior AAWD response. Treatment with K was well tolerated, and resulted in a decline in adrenal androgen levels, which rose at the time of disease progression. Conclusion K has modest activity in AiPCa patients, while AAWD alone has minimal activity. Adrenal androgen levels fall with treatment with K and then climb at the time of progression, suggesting that progressive disease while on K may be due to tachyphylaxis to the adrenolytic properties of K.

Biochemical-only recurrent prostate cancer presents the ideal setting for assessing novel agents or approaches for prostate cancer treatment. There is no clear evidence that delay in initiation of more definitive androgen-deprivation therapy is harmful, and a simple blood test--the prostate-specific antigen (PSA) level--is readily available to screen for potential antineoplastic activity. Current novel approaches include vaccines, cyclooxygenase-2 (COX-2) inhibitors, selective apoptotic antineoplastic drugs, endothelin-A receptor antagonists, chemotherapy, vitamin D, and peroxisome proliferator-activated receptor-gamma agonists. In this screening process, certain therapies have emerged as delaying PSA progression or decelerating PSA velocity. These therapies, such as the COX-2 inhibitors, will need to proceed to phase 3 trials to answer the more important question of whether this change in PSA dynamics translates into improved survival. Patients enrolling in these trials need to be clearly informed of the limited expectations of these novel exploratory approaches.

A multidisciplinary approach to prostate cancer has become the rule and not the exception. Involving the entire team, which includes a medical oncologist, from the time of initial diagnosis is optimal. This facilitates maximal patient education regarding treatment options and enhances informed decision making. A coordinated approach also promotes enrollment on clinical trials, which are often, multimodality, especially in high-risk early stage prostate cancer. Integrated therapeutic strategies throughout the patient's disease course can improve both patient care and satisfaction

Historically, the medical oncologist has been involved in the care of prostate cancer patients at the end of their lives; however, with newer chemotherapy interventions, clinical trials, more options, and increased involvement of patients in their medical care, the role of the medical oncologist should be revisited. A survey of the practice of British urologists clearly demonstrates the problem. “In clinical practice, 82% of urologists have close links with oncology, available through joint clinics or on-site referral. However

Platinum-based regimens have improved response rates and survival in patients with advanced transitional cell carcinoma (TCC) of the urothelial tract. However, the toxicities of platinum-based chemotherapy are considerable. Regimens with reduced toxicity that are applicable to a broader group of TCC patients without sacrificing activity therefore are of interest.Because gemcitabine, paclitaxel, and methotrexate have each been reported to possess single-agent activity in this disease, the authors evaluated the tolerability and efficacy of fixed doses of paclitaxel (100 mg/m(2) over 3 hours) and methotrexate (30 mg/m(2)) with escalating doses of gemcitabine (800-1000 mg/m(2)), all given on Days 1 and 8 every 21 days, in patients with previously untreated unresectable or metastatic TCC.Twenty-five patients were enrolled. Two patients were ineligible and were excluded from analysis. Because no dose-limiting toxicity occurred in the first 4 patients who were given gemcitabine at a dose of 800 mg/m(2), the gemcitabine dose was escalated to 1000 mg/m(2) in the next 21 patients. Of the 21 patients assessable for response, 6 had achieved a complete response (CR) and 6 had achieved a partial response, for an overall response rate of 57%. An additional patient was converted to a CR surgically. The median overall and progression-free survival times were 18 months and 9.2 months, respectively. Toxicity was predominantly neutropenia: Grade 3 in 9 patients (39%) and Grade 4 in 4 patients (17%) (according to the Southwest Oncology Group Toxicity Criteria, version 12/1994). One patient died of septic shock associated with febrile neutropenia after three cycles.The regimen of gemcitabine, paclitaxel, and methotrexate at this dose and schedule was found to possess activity in patients with locally advanced or metastatic TCC. Further studies of this regimen are warranted.

Summary Candida meningitis, a previously rare occurrence, has been increasing in prevalence and often is a result of complications of neurosurgery. We describe the case of a 49-year-old man who presented with headache, vertigo, intermittent blurred vision, and multiple episodes of nausea and vomiting. Computed tomography (CT) showed a left cerebellar hemorrhage with obliteration of the fourth ventricle causing hydrocephalus. He had an occipital craniotomy with transcondylar evacuation of the hemorrhage and placement of a temporary ventriculostomy. The hospital stay was prolonged because of postsurgical complications, and Candida tropicalis meningitis developed. Treatment was started with 400mg of fluconazole administered intravenously every 12h. In vitro susceptibility testing showed a minimum inhibitory concentration (MIC) to fluconazole of 1μg/mL. Fluconazole was therefore continued orally for a total of 60 days, and the patient remained asymptomatic for 2 years. He then presented with increased vertigo and ataxia. Cerebrospinal fluid cultures grew C. tropicalis , which again showed susceptibility to fluconazole with a MIC of 1μg/mL, identical to that in the previous infection. However, a second course of fluconazole failed to control the infection despite adequate cerebrospinal fluid levels.

A diversity of bone pathology is present in men with prostate cancer. Androgen deprivation therapy (ADT) can cause significant and progressive osteopoenia and osteoporosis. Bone is also the primary site for metastases leading to associated pain, skeletal fractures and hypercalcaemia. Bisphosphonate therapy decreases bone resorption, which may prevent or reverse loss of bone mineral density. Both pamidronate and zoledronic acid have proven efficacy in preventing ADT-induced bone loss. In a randomised, placebo-controlled trial, in men with hormone-refractory prostate cancer, there was a decreased incidence of skeletal- related adverse events in men receiving zoledronic acid. So far, randomised trials have failed to show improved pain control. Formalised guidelines are needed to help clinicians decide which patients should be treated with bisphosphonates, when to initiate therapy and for what duration.

Patients with cancer are increasingly incorporating complementary therapies into the overall treatment. We determine the prevalence and patterns of use of complementary therapies among patients with prostate cancer.Patients attending 6 urology institutions for prostate cancer management completed a self-administered questionnaire on complementary therapy. All men diagnosed with prostate cancer were eligible, regardless of age, stage of disease or treatment.A total of 1,099 patients returned the questionnaire. The overall response rate was 78.5%. Complementary therapies had previously been or were currently being used by 23.5% (258) and 18.2% (200) of patients, respectively. Higher levels of education and income were associated with greater use of complementary therapy (p0.002 by logistic regression). Patients with progressive disease or those primarily treated with hormones were most likely to use complementary therapy. Among the patients using complementary therapy 90% believed that it would help them live longer and improve quality of life, 60% believed it would relieve symptoms and 47% expected it to cure disease.Complementary therapies are used by a large number of patients with prostate cancer, particularly those with progressive disease or who have undergone multiple treatments. Health care providers need to recognize this growing pattern of use of complementary therapy. Among patients who use complementary therapy the perception of benefit is much greater than that supported by scientific data. Future research should aim to unravel the complex psychosocial dynamics that influence the decision to use complementary therapy by men with prostate cancer and to educate patients about the efficacy of such therapies.

In the search for an early measure of response in hormone refractory prostate cancer (HRPC), most have targeted changes in serum prostate-specific antigen (PSA). Up to this point, no one has targeted changes in serum hemoglobin during treatment. If dynamic changes in hemoglobin after treatment provide additive prognostic information to dynamic changes in PSA, then we should consider and test ways to incorporate serum hemoglobin into measures of response in HRPC.Our patients consisted of 321 men who were studied on Cancer and Leukemia Group B protocols 9181 and 9182. We fit serial values of PSA and hemoglobin with an exponential model: y = exp(alpha + beta*t + gamma*t(2)) with y symbolizing either PSA or hemoglobin and t denoting time. We then used the Cox proportional hazard model to relate the parameters of the model (alpha, beta, and gamma) to subsequent survival.We found that the exponential model fit serial measurements of both PSA and serum hemoglobin well, and all three of the parameters for both markers related closely to subsequent survival (Por = 0.003). The Cox model suggested a composite hazard score (HS) as a way to consolidate the information from serial measurements of both serum markers, and we observed that those with HS0 enjoyed a longer survival.Because serial measurements of serum hemoglobin during treatment of HRPC add prognostic information to serial measurements of PSA, we hypothesize that combining the dynamic changes in serum hemoglobin with those of PSA could lead to an improved measure of response in HRPC.

108 Background: Cabozantinib (C) is a multikinase inhibitor of c-Met, vascular endothelial growth factor receptor two and RET. C has shown activity in metastatic castrate resistant prostate cancer (mCRPC), with resolution of bone lesions on bone scan (BS), regression of soft tissue/visceral disease (STD), reductions in circulating tumor cells and bone biomarkers. Combining docetaxel (D) with other agents, without overlapping toxicities, can target different cellular signaling pathways necessary for tumor survival. Methods: Patients (pts), with no prior D for CRPC, receive a fixed dose of D (75 mg/m2 IV day one of each 21 day cycle) and prednisone (P) (5 mg po q12 hours) with C at three escalating dose levels: 20 mg, 40 mg, or 60 mg (all po daily). Using a standard three-plus-three design, three to six pts are treated at each dose level until the maximum tolerated dose (MTD) has been defined. Results: Thirteen pts have been accrued; four on dose level one, six on dose level two, and three on dose level three. Median age 69 (45 to 84). Four pts have an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of zero and nine pts have a PS of one. Median Gleason score is nine (7 to 10). Median on-study prostate-specific antigen (PSA) is 129.2 ng/mL (0.01-508.5 ng/mL). Median cycles is six (1 to 17). Grade 1 adverse events (AEs), possibly related to C; dysgeusia (4/12), oral mucositis (4/12), increased ALT (3/12), and epistaxis (3/12). Grade 2 AEs; nausea (2/12), hand/foot syndrome (2/12), fatigue (2/12), dysgeusia (2/12), oral mucositis (2/12), hypophosphatemia (2/12), and anemia (2/12). Grade 3 AE is hypophosphatemia (2/12). Grade 4 AE is neutropenia (1/12). MTD of C is 60 mg. Of nine evaluable pts, six have bone only disease. Of these six, three pts have PSA declines of less than 30% with improvement on BS (two pts) or stable BS (one pt). The other three pts have PSA declines of greater than 30% and bone scan improvement. Three pts have STD and bone disease; one patient had a PSA decline of greater than 30% with improvement on BS and SD by CT scan. One patient had an increase in PSA of less than 30% with improvement on BS and CT. The third pt had PD by CT and an increase in PSA equal to 30%. PFS probability at six months is 90.0% and is 67.5% at eight months and beyond. Conclusions: The addition of C to D and P, has an acceptable toxicity profile. CT scan and BS improvements did not correlate with PSA declines in all pts. An expansion cohort will combine D plus P with C at the MTD (60 mg) to determine clinical benefit. Clinical trial information: NCT01683994.

A survey of front line police officers' practices, perceptions and attitudes regarding detection of impaired driving, processing of driving while impaired (DWI) charges, criminal court proceedings and DWI sanctions was conducted across Canada. A sample of 1545 officers of all jurisdictions across the country, representative of different types of police services (i.e. national, provincial, municipal) and types of policing (i.e. traffic, general duty) were surveyed by mail. The results, based on a 71% response rate, indicate that: an average of 7.5 charges/year are laid by officers resulting mainly from erratic driving; videotaping and mobile breath testing could improve efficiency of DWI enforcement; it takes an average of 2 h 48 min to process each DWI charge; about 2/3 of officers say plea bargaining occurs at least sometimes; the average length of DWI trial is over 4 h; less than half of officers think Crown Attorneys are adequately prepared for DWI cases; about 3/4 of officers think the accused escapes conviction on a legal technicality at least sometimes; about 30% of officers say short-term licence suspensions and other forms of discretion are used at least sometimes; DWI places fifth in priority among 15 offences, up from eighth in a 1981 survey; DWI is a priority for most police management but human resources are not adequate; and there is greater support for administrative than for Criminal Code changes. Multiple regressions indicated that the number of DWI charges laid by officers depended mainly on the officers' personal priority regarding DWI enforcement. The results suggest that many officers want to enforce DWI laws but that the numerous procedural and legal barriers that they confront often force them to exercise discretion in the laying of DWI charges.

Although metastatic prostate cancer usually responds transiently to hormonal therapy, most patients eventually have progressive disease, and treatment options are limited. Suramin, a chemotherapeutic agent with immunomodulatory and tumor regressive properties, has shown promise in clinical trials as a second line treatment for advanced hormone refractory prostate cancer. We report on a patient with hormone refractory prostate cancer treated with suramin who had multiple benign keratoses that were clinically and histologically similar to skin cancer. CASE REPORT

PURPOSE To assess the efficacy and toxicity of suramin, hydrocortisone, leuprolide, and flutamide in previously untreated metastatic prostate cancer. PATIENTS AND METHODS Patients with stage D2 and poor-prognosis stage D1 prostate cancer were given suramin on a pharmacokinetically derived dosing schedule to maintain suramin concentrations between 175 and 300 micrograms/mL. Additionally, all patients received flutamide 250 mg orally three times daily, initiated on day 1 and continued until disease progression; depot leuprolide 7.5 mg intramuscularly begun on day 5 and repeated every 4 weeks indefinitely; and replacement doses of hydrocortisone. RESULTS Fifty patients were entered onto the study: 48 with stage D2 and two with stage D1 disease. The median age was 59 years (range, 42 to 79) and 31 patients had a Karnofsky performance status (KPS) of 100%. Forty-five patients had bone metastases and 25 had measurable soft tissue disease. Forty-one (82%) had severe disease. The overall response rate in 49 assessable patients was three complete responses (CRs) and 30 partial responses (PRs) for an overall response rate of 67%. Eighteen patients have died. The median survival time has not been reached, with a median potential follow-up duration of 44 months. Grade 3 to 4 toxicity was seen in 38% of patients and was predominantly hematologic and reversible. CONCLUSION The high response rate and prolonged survival in a poor-prognosis group of patients with metastatic prostate cancer warrant a phase III randomized comparison of this regimen versus hormonal therapy alone. Toxicity was moderate and reversible.

5047^ Background: Sipuleucel-T and AA + P are FDA-approved for asymptomatic/minimally symptomatic mCRPC. Suppression of the androgen axis can be immunostimulatory and AA suppresses circulating androgen levels; AA plus sipuleucel-T may therefore be synergistic. However P used with AA, which may be immunosuppressive, has not been studied with concurrent sipuleucelET and could impair sipuleucel-T production and/or immunologic response. P11-3 (NCT01487863) is the 1st study to evaluate the combination of sipuleucel-T and AA + P Methods: Patients (pts) with asymptomatic/minimally symptomatic mCRPC were randomized (1:1) to sipuleucel-T (3 infusions at approx 2-wk intervals) with up to 26 wks of AA + P (AA 1000mg QD + P 5mg BID) starting 1 day after the 1st sipuleucel-T infusion (concurrent, arm A) or at 10 wks following the 1st sipuleucel-T infusion (sequential, arm B). Endpoints included the effect of AA + P on product (sipuleucel-T) characteristics eg antigen presenting cell (APC) activation, measured as CD54 upregulation (primary endpoint), APC (measured as CD54+ cells) and total nucleated cell (TNC) counts, as well as safety and immunologic responses. Results: 31 pts in arm A and 32 pts in arm B completed sipuleucel-T treatment by the interim analysis (Nov 2012). Baseline characteristics were similar in the 2 arms. 60/63 pts received all 3 infusions of sipuleucel-T. No significant differences in median cumulative APC activation, APC count or TNC count were seen between the arms. Increased CD54 upregulation with the 2nd and 3rd treatments were indicative of a prime boost effect in both arms. Similar profiles of antigen-specific humoral and cellular immune responses were generated with no difference in magnitude of response between the arms (p>0.05). The incidence of adverse events (AEs) and serious AEs was similar in both arms. Conclusions: These data suggest sipuleucel-T can be successfully manufactured during concurrent AA + P. Product potency and prime boost effect were similar to sipuleucel-T alone. Immune responses and AEs were similar in both arms. It is not known if sipuleucel-T will provide similar efficacy with concurrent or sequential AA + P. Clinical trial information: NCT01487863.

e16017 Background: We have completed accrual of 63 patients (pts) to our study combining lenalidomide (L), with bevacizumab (B), docetaxel (D), and prednisone (P) (ART-P) in mCRPC. Due to the lack of improved survival and the increased toxicity of anti-angiogenic docetaxel combinations in the MAINSAIL and CALGB 90401 trials, we attempted to compare and contrast our studies with these failed phase III trials. Methods: Among the first 52 pts on ART-P, 3 received L 15 mg daily, 3 received 20 mg daily, and the others received 25 mg daily for 14 days of every 21−day cycle (C). We then enrolled 11 pts at L 15 mg. All pts received D 75 mg/m2 and B 15 mg/kg on day 1 with P 10 mg and enoxaparin daily. Pegfilgrastim was given on day 2. Patients on CALGB 90401 received D 75 mg/m2 and B 15 mg/kg on day 1, with P 10 mg. On MAINSAIL, pts received D 75 mg/m2, L 25 mg daily for 14 days of every 21−day cycle with daily P. Patients on CALGB 90401 and MAINSAIL did not receive enoxaparin or pegfilgrastim prophylactically. Results: The median number of Cs on ART-P is 18 (1-52). Median PFS is 19.1 months. Twenty-seven pts had a PR, and one pt with measurable disease had a CR. Two patients (3%) had deep vein thromboses. Of 1,334 Cs given, 14 cycles were complicated by febrile neutropenia (FN) (1%). There were no treatment related deaths. In comparison, median number of Cs in MAINSAIL L+DP arm was 6, with a PFS of 45 weeks and an OS of 77 weeks. Thirty-four pts (6.5%) developed pulmonary emboli and there were 2 deaths due to toxicity in the experimental arm. Nearly 12% of Cs were complicated by FN. In the experimental arm of CALGB 90401 trial, median OS was 22.6 months with median PFS of 9.9 months. The median number of Cs were 8 and 19 pts developed thrombosis/emboli (3.6%). In addition, 37 patients developed FN and treatment related deaths were reported at 4%. Conclusions: The use of supportive care allowed longer treatment duration with the ART-P combination as compared to D+L (MAINSAIL) and D+B (CALGB 90401), potentiating a longer PFS, RR and possibly OS with an improved safety profile. This data demonstrates the potential importance of supportive measures and is hypothesis generating for future combination studies. Clinical trial information: NCT00942578.

128 Background: We have recently completed accrual of 63 patients (pts) to our study combining lenalidomide (L), with bevacizumab (B), docetaxel (D), and prednisone (P) (ART-P). Due to the lack of improved survival and the increased toxicity of anti-angiogenic docetaxel combinations in the MAINSAIL and CALGB 90410 trials we attempted to contrast and compare our studies with the failed phase III trials. Methods: Among the first 52 pts on the ART-P, 3 received L 15 mg daily, 3 had 20 mg daily, and the rest had 25 mg daily for 14 days of every 21−day cycle (C). We later enrolled 11 more pts at L 15 mg. All pts received D 75 mg/m2 and B 15 mg/kg on day 1 with P 10 mg and enoxaparin daily throughout each C. Pegfilgrastim was given on day 2. Patients on CALGB 90410 received D 75 mg/m2 and B 15 mg/kg on day 1 with P 10 mg and on MAINSAIL received D 75 mg/m2, L 25 mg daily for 14 days of every 21−day cycle with daily P. Patients on CALGB 90410 and MAINSAIL did not receive enoxaparin or pegfilgrastim prophylactically. Results: Median number of Cs in ART-P was 16 (3−38). PFS was 22 months and median OS has not been reached. Pts with measurable disease had 1 CR and 25 PR (86.7% RR). Two patients (3%) had deep vein thromboses. Of 1,219 cycles given, 14 cycles were complicated by febrile neutropenia (FN) (1.1%). There were no treatment related deaths. In comparison, median number of Cs in MAINSAIL L+DP arm was 6, with a PFS of 45 weeks and an OS of 77 weeks. Thirty-four pts (6.5%) developed pulmonary emboli and there were 2 deaths due to toxicity in the experimental arm. Nearly 12% of Cs were complicated by FN. In the experimental arm of CALGB 90410 trial, median OS was 22.6 months with median PFS of 9.9 months. Median number of Cs was 8, and 19 pts developed thromboses/emboli (3.6%). In addition, 7% of patients developed FN and treatment related deaths were reported at 4%. Conclusions: The use of supportive care allows the ART-P combination to be given for more cycles than were given in MAINSAIL and CALGB 90401 potentiating a longer PFS, RR and possibly OS with an improved toxicity profile. This data demonstrates the potential importance of supportive measures and is hypothesis generating for future combination studies. Clinical trial information: NCT00942578.

This paper presents a retrospective review of 6 cases of severe neutropenia attributed to suramin, the response to granulocyte-colony stimulating factor (G-CSF) and the possible mechanism. Plasma suramin concentrations, G-CSF, platelet-derived growth factor-AB (PDGF-AB) and fibroblast growth factor basic (FGF basic) levels were measured and correlated with neutropenic course. The time course of neutropenia was unpredictable and occurred both during and following discontinuation of suramin. Neutropenia rapidly resolved with G-CSF. Neither the measured growth factor levels nor plasma suramin concentrations correlated with neutropenia. We conclude that neutropenia secondary to suramin is unpredictable and responds to G-CSF administration permitting further suramin therapy. The mechanism remains unknown.

Appropriate staging procedures for patients with hormone-refractory prostate cancer are poorly defined. In particular, there are no studies correlating prostate-specific antigen (PSA) with more traditional methods of staging. We have evaluated the abdominal/pelvic CT scan, bone scan, and PSA results following initial diagnosis of hormone-refractory prostate cancer in 177 consecutive patients (median age = 63.1 years, range 45-80). Thirty-four patients (19.2%) had measurable lesions (or = 2 cm) on CT scan compatible with metastatic disease. Of the patients with measurable lesions, 29/34 (85.3%) had retroperitoneal and/or pelvic adenopathy; 5 patients (14.7%) had measurable lesions in the liver. Other sites of metastatic disease were detected in less than 1% of the patients receiving scans. All patients had bone scan abnormalities compatible with metastatic disease. Results of these imaging studies were then compared to PSA serum concentration (Abbott IMx). The mean PSA concentration was not different in those patients with soft tissue disease as compared to those without soft tissue involvement and there was no correlation between PSA concentration and the presence or absence of measurable soft tissue disease. In contrast to previously published studies in hormone-naïve prostate cancer patients, these studies in hormone-refractory patients indicate that the detection of metastatic disease by standard radiological procedures cannot be predicted by measurement of serum PSA.

Background Sipuleucel-T is an FDA-approved autologous cellular immunotherapy for the treatment of asymptomatic or minimally symptomatic mCRPC. In the Phase 3 IMPACT trial, sipuleucel-T showed a 22% reduction in risk of death (p = 0.032) and a 4.1-month median OS improvement (25.8 vs 21.7 months) compared with control. OpenACT (P09-1; NCT00901342) is a Phase 2 open-label study to further evaluate the safety and immune responses of sipuleucel-T in patients (pts) with mCRPC. Methods Pts received sipuleucel-T at 2-week (wk) intervals for a total of 3 infusions. Sipuleucel-T is manufactured from autologous PBMCs isolated by leukapheresis at wks 0, 2 and 4, and activated with PA2024 (a recombinant fusion protein composed of prostatic acid phosphatase [PAP] linked to GM-CSF). Cell activation is measured by upregulation of the costimulatory molecule CD54. The primary endpoint was to evaluate the magnitude of immune responses to sipuleucel-T treatment. Results From October 2009–June 2010, 104 pts were enrolled; 101 pts received ≥1 leukapheresis and 98 pts received ≥1 infusion (safety population). Pts who had received prior docetaxel (D; 29.3% of enrolled pts) had a higher baseline prostate-specific antigen (90 vs 40ng/mL) and a greater proportion with a time from diagnosis of ≥6 years (93.5% vs 68.7%) compared with pts with no prior D exposure. Consistent with previous studies, CD54 upregulation and post-culture cytokine levels were significantly greater at wk2 and wk4 compared with wk0 (p Discussion Sipuleucel-T generates antigen-specific immune responses in patients with and without prior D exposure. However, product characteristics suggest that patients without prior D may generate sip-T products with higher TNC, which has previously been shown to correlate with prolonged survival, supporting earlier use in the mCRPC treatment paradigm. Disclosure J. Corman: On the Board of Directors for Benaroya Research Institute and employee of Virginia Mason Medical Center, N. Dawson: Corporate sponsored research for Dendreon Corporation, and participation in Speakers Bureau also for Dendreon Corporation, S. Hall: Corporate sponsored research for Dendreon and Medivation, C. Nabhan: Participation in corporate sponsored research and speakers bureau, A. Ferrari: Participation in advisory boards, A.J. Armstrong: Advisory boards for Bristol Myers Squibb, Bayer, Amgen; sponsored research for Dendreon, Sanofi Aventis, Medivation, Eli Lilly, Pfizer, Novartis, Janssen Biotech, Kanglaite Active Biotech/Ipsen; speaker for Dendreon, Sanofi Aventis, Amgen, Pfizer, F. Stewart: Employee and stock ownership in Dendreon Corporation, N. Sheikh: Employee of and stock ownership in Dendreon Corporation, D.P. Petrylak: Advisory boards for Amgen, Bayer, Pfizer, Ferring, Millenium, Novartis, Dendreon, Johnson and Johnson, GlaxoSmithKline; sponsored research Celgene, Dendreon, Sanofi, Pfizer, AstraZeneca, GlaxoSmithKline, Rogesen Institute, Boheringer Ingelheim, All other authors have declared no conflicts of interest.

Background Androgen deprivation therapy (ADT) is the standard treatment of hormone-sensitive metastatic prostate cancer (HSMPC). We performed a phase III multicentre trial to compare ADT alone with ADT plus docetaxel (D) in HNMPC. Methods Patients (pts) with HSMPC were randomly assigned to either arm A (ADT + D: 75mg/m q3w, up to 9 cycles) or arm B (ADT). The primary endpoint was overall survival (OS). The planned number of pts was 378 to detect an improvement in OS with a hazard ratio (HR) of 0.62, a power of 80% and an alpha risk of 0.05 (two-sided test). Secondary endpoints were biological progression-free survival (PFS) and clinical PFS. Data on toxicity and quality of life have been previously presented. Results From October 2004 to December 2008, 385pts were included. Baseline characteristics were well balanced between the two arms. Median age was 63 years (43-84), median PSA was 26.4 ng/ml (0.1-11900), Gleason score was ≥ 8 in 57%. Prognostic classification was as follows: good prognosis (49%), intermediate (29%) and poor (22%). The majority of pts had metastases at the time of diagnosis (72%), 28% developed metastases after local treatment failure. Median number of D cycles was 8 (range 0-9). The median follow-up was 50 months (mo) [95%CI: 49-54]. At 6 mo, a higher PSA response (≥ 50%) in arm A (94% vs 85%, p = 0.0096) and a higher PSA progression (≥ 25%) in arm B (10% vs 1%, p = 0.0015) were observed. Biological PFS was significantly longer in arm A: 22.9 vs 12.9 mo, HR; 0.72 [95%CI: 0.57-0.91] (p = 0.005). Clinical PFS was increase in arm A: 23.46 vs 15.44 mo, HR: 0.75 [95CI: 0.59-0.94] (0.015). OS was not significantly different (median: 58.9 mo in arm A and 54.2 mo in arm B, HR: 1.01 [95%CI: 0.75-1.36]. The median OS for each prognostic group was 69.1 [95%CI: 60.9-NR], 46.5 [95%CI: 37.7-NR] and 36.6 [95%CI9: 28.5-58.9] mo respectively in the good, intermediate, and poor prognosis groups (p = 0.001), with no difference between the two arms. At the cut-off time, 65% of pts from the ADT arm had received docetaxel since they developed castrate-resistant prostate cancer. Conclusion Combining docetaxel and ADT improves PFS over ADT alone in pts with HSMPC. However, no difference in OS was observed between the two arms. Disclosure G. Gravis: I have expert testimony to disclose: Sanofi Aventis, uncompensated. K. Fizazi: Participation to advisory boards and speaker for Sanofi-Aventis. F. Joly Lobbedez: advisory board/board of directors position: Sanofi, Roche, Pfizer, Novartis, Ferring; compensated consultant relationship: Roche, Novartis; honoraria: Sanofi, Roche, Pfizer, Novartis, Ferring, Ipsen,Takeda; travel remuneration: ASCO by Novartis, ESMO by Janssen. S. Oudard: I have an advisory relationship and honoraria to disclose: Pfizer Oncology, Bayer-Schering Pharma, Hoffman La Roche, Glaxo SmithKline, Novartis Pharma, Sanofi Aventis. D. Pouessel: Consultant role and honoraria: Sanofi, P. Beuzeboc: Presentations: Avantis, All other authors have declared no conflicts of interest.

4569 Background: Previously, we had shown the potent anti−tumor activity of dual anti-angiogenic therapy by combining bevacizumab (B) and thalidomide (T) with docetaxel (D) and prednisone (P) in mCRPC (Ning JCO 2010). We hypothesized that combining lenalidomide (L), an analogue of T, with B, D, and P would have a more favorable efficacy/toxicity profile. Methods: All patients (pts) had chemotherapy−naïve mCRPC. Among the first 52 pts, 3 received L 15 mg daily, 3 had 20 mg daily, and the rest had 25 mg daily for 14 days of every 21−day cycle (C). The protocol was recently amended to enroll 11 more pts at L 15 mg; 2 pts have now been enrolled in this expansion cohort. All pts received D 75 mg/m2 and B 15 mg/kg on day 1 with P 10 mg and enoxaparin daily throughout each C. Pegfilgrastim was given on day 2. PSA each C with imaging after C2 and after every 3C. Dental exams with mandible CT scan at baseline, after C5, and every 6C. Results: 54 of 62 pts have been enrolled. Median age 65.5 (51−82), Gleason score 8 (5−10), on−study PSA 85.2 ng/ml (0.15−3520), and pre−study PSA doubling time 1.49 months (0.52−6.73). Median number of Cs was 16 (3−38). PFS was 22 months and probability of survival at 12 months was 90%. Forty-six (85.2%) and 42 (77.8%) pts had PSA declines of ≥50% and ≥75%, respectively. Of 30 pts with measurable disease there were 1 CR and 25 PR (86.7% overall RR). 17/54 pts were off study for radiographic disease progression and 8/54 for other reasons. Grade ≥2 toxicities included neutropenia (34/54), anemia (23/54), thrombocytopenia (7/54), hypertension (12/54), perianal fistula (3/54), rectal fissure (1/54), myocardial infarction (1/54), and osteonecrosis of the jaw (ONJ) (12/54, 22.0%). At the time of diagnosis of ONJ, 7/12pts were on bisphosphonates (BP), 2/12 had used BP previously, and 3/12 never used BP. The incidence of ONJ was comparable to 18.3% reported by Ning et al. A recent study of carboplatin plus weekly docetaxel reported an incidence of 29.3%. Conclusions: Dual anti-angiogenic therapy with, B and L, plus D and P was associated with high PSA (85.2%) and tumor (86.7%) responses in mCRPC, with manageable toxicities. The incidence of ONJ is comparable to other studies.

4 Background: Castration resistance occurs in the vast majority of HSM1PC pts treated with AD, with a median survival of 2.5 years (y). It is in part an adaptive process with activation of genes resulting in the production of autocrine/paracrine growth factors that contribute to maintaining the viability of PC cells. Replacing androgens before castration resistance is hypothesized to maintain PC androgen-dependence. Preclinically IAD prolonged time to castration resistance and early clinical data indicated feasibility and potential for better quality of life. Methods: HSM1PC pts with performance status (PS) 0-2, PSA ≥ 5 ng/ml were treated with 7 months (m) of goserelin + bicalutamide. Pts achieving PSA ≤4 ng/ml on m 6 and 7 were stratified by prior neoadjuvant AD/finasteride, PS and disease extent (minimal, extensive) and randomized to CAD or IAD. Primary objective: To assess if overall survival (OS) with IAD is noninferior to CAD using a one-sided test with an upper bound hazard ratio=1.20, adjusting for stratification factors. Sample size: 756 pts/arm, type I and II error rates of 0.05 and 0.10. Results: 3,040 pts were accrued by SWOG, CALGB, ECOG, NCIC, and EORTC (5/95- 9/08). After 7 m of CAD, 1535 eligible pts achieved PSA ≤4.0 (median age 70 yrs, 4% PS 2, 48% extensive disease, 12% prior neoadjuvant AD) and were randomized to CAD (759 pts) or IAD (770 pts). Grade 3/4 related adverse events: IAD 30.3%, CAD 32.6%. Median follow-up was 9.2 yrs. Median and 10 yr OS: All eligible pts from study entry: 3.6 yrs, 17%; from randomization CAD: 5.8 yrs, 29%; IAD: 5.1 yrs, 23%, HR (IAD/CAD) = 1.09 (95% CI 0.95, 1.24). No interaction with therapy was significant (p>0.25) except suggestion with disease extent (p=0.08): extensive disease HR=0.96 (95% CI 0.79, 1.15, p=0.64); minimal disease: HR=1.23 (95% CI 1.02, 1.48, p=0.035). PC was cause of death in 56% of CAD and 64% IAD pts. OSby race was not different (p=0.44). Conclusions: In HSM1PC, IAD is not proven to be noninferior to CAD. For extensive disease pts IAD was noninferior; however, IAD was statistically inferior in minimal disease pts suggesting that CAD is the preferred treatment in this group.

207 Background: Angiogenesis may be vital to mCRPC. Previously, we had shown the potent anti−tumor activity of dual antiangiogenic therapy by combining thalidomide (T) and bevacizumab (B) with docetaxel (D) and prednisone (P) in mCRPC (Ning JCO 2010). We hypothesized that combining lenalidomide (L), an analogue of T, with B, D, and P would have a more favorable efficacy/toxicity profile. Methods: All patients (pts) had chemotherapy−naïve mCRPC. 3 pts received R 15 mg daily, 3 pts had 20 mg daily, and the rest had 25 mg daily for 14 days of every 21−day cycle (C). All pts received D 75 mg/m2 and B 15 mg/kg on day 1 with P 10 mg and enoxaparin daily throughout each C. Pegfilgrastim was given on day 2. PSA was assayed each C with imaging after C2 and then after every 3C. Results: 47 of the planned 51 pts have been enrolled. Median age was 66 (51−82), Gleason score 8 (5−10), on−study PSA 91.6 ng/ml (0.15−3520), pre−study PSA doubling time 1.43 months (0.52−6.73), number of Cs 14 (1−31), and PFS was 19.3 months as of this analysis. Among 45 pts who have completed ≥2 cycles, 39 (86.7%) and 30 (66.7%) had PSA declines of ≥50% and ≥75%, respectively. Of 29 pts with measurable disease there were 2 CR, 21 PR, and 6 SD (79.3% overall RR). 10/47 pts were taken off study for radiographic disease progression and 5/47 for other reasons. Grade ≥3 toxicities included neutropenia (24/47), anemia (9/47), thrombocytopenia (5/47), weight loss (1/47), hypertension (3/47), and febrile neutropenia (4/47). Other toxicities included perianal fistula (3/47), rectal fissure (1/47), myocardial infarction (1/47), and osteonecrosis of the jaw (ONJ) (16/47, 34.0%). At the time of diagnosis of ONJ, 9/16 pts were on bisphosphonates and 3/16 had used bisphosphonates previously. Although the incidence of ONJ was higher than the 18.3% reported by Ning, a recent study of carboplatin plus weekly docetaxel reported an incidence of 29.3%. Conclusions: Dual antiangiogenic therapy with, B and L, plus D and P was associated with high PSA (86.7%) and tumor (79.3%) responses with manageable toxicities. Further studies are underway to explore the high incidence of ONJ.