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Importance: Olaparib is a poly(adenosine diphosphate-ribose) polymerase inhibitor that provides benefit in combination with hormonal therapies in patients with metastatic prostate cancer who harbor homologous recombination repair (HRR) alterations. Its efficacy in the absence of androgen deprivation therapy has not been tested., Objective: To determine the activity of olaparib monotherapy among patients with high-risk biochemically recurrent (BCR) prostate cancer after radical prostatectomy., Design, Setting, and Participants: This phase 2, single-arm nonrandomized controlled trial enrolled genetically unselected patients across 4 sites in the US from May 2017 to November 2022. Eligible patients had BCR disease following radical prostatectomy, a prostate-specific antigen (PSA) doubling time of 6 months or shorter, an absolute PSA value of 1.0 ng/mL or higher, and a testosterone level of 150 ng/dL or higher., Intervention: Treatment was with olaparib, 300 mg, by mouth twice daily until doubling of the baseline PSA, clinical or radiographic progression, or unacceptable toxic effects., Main Outcome and Measure: The primary end point was a confirmed 50% or higher decline in PSA from baseline (PSA50). Key secondary end points were outcomes by HRR alteration status, as well as safety and tolerability., Results: Of the 51 male patients enrolled (mean [SD] age, 63.8 [6.8] years), 13 participants (26%) had a PSA50 response, all within the HRR-positive group (13 of 27 participants [48%]). All 11 participants with BRCA2 alterations experienced a PSA50 response. Common adverse events were fatigue in 32 participants (63%), nausea in 28 (55%), and leukopenia in 22 (43%), and were consistent with known adverse effects of olaparib., Conclusions and Relevance: In this nonrandomized controlled trial, olaparib monotherapy led to high and durable PSA50 response rates in patients with BRCA2 alterations. Olaparib warrants further study as a treatment strategy for some patients with BCR prostate cancer but does not have sufficient activity in those without HRR alterations and should not be considered for those patients., Trial Registration: ClinicalTrials.gov Identifier: NCT03047135.

Background: Prostate cancer (PCa) is the most common cancer in men in the US and androgen deprivation therapy (ADT) is the most frequently used systemic therapy for PCa. Data suggest that ADT is associated with an increased risk of new-onset diabetes mellitus (NODM) and cardiovascular complications. As the incidence and mortality of PCa are highest among the African American (AA) population, it is important to evaluate the difference in the incidence of NODM and ischemic heart disease (IHD) between AA men compared to Caucasian men., Methods: This is a retrospective cohort study utilizing the TriNetX database to assess NODM and IHD risk, risk difference, and risk ratio (RR) after recent ADT initiation in an AA cohort and a Caucasian cohort of patients with PCa. Propensity score matching (PSM) was performed by age, BMI, and confounding comorbidities., Results: After matching, the cohort included 1159 AA patients and 843 Caucasian patients with NODM after ADT initiation. The IHD cohort included 1269 AA patients and 1248 Caucasian patients. The risk of incidence of NODM is higher among AA men at 11.6% risk compared to Caucasian men at 7.4%. The risk difference is 4.1% (95% CI = 3.4, 4.9) p = 0.000. The RR is 1.56 (95% CI = 1.43, 1.70). In contrast, risk difference and risk ratio of IHD was not significant between AA and Caucasian groups., Conclusion: ADT exposure increases the risk of NODM in men with PCa, especially among AA men compared with Caucasian men. Men receiving ADT should be monitored routinely for signs and symptoms of metabolic syndrome and diabetes. Targeted close monitoring of AA men on ADT would be critical to prevent and treat metabolic complications with potential of reducing disparities in PCa morbidity., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: To report the impact of our 25-year multidisciplinary care delivery model experience on patients with muscle invasive bladder cancer treated at our National Cancer Institute (NCI)-designated Sidney Kimmel Cancer Center at Jefferson University. To our knowledge, our multidisciplinary genitourinary cancer clinic (MDC) is the longest continuously operating center of its kind at an NCI Cancer Center in the United States., Materials and Methods: We selected a recent group of patients with cT2-4 N0-1 M0 bladder cancer seen in the Sidney Kimmel Cancer Center Genitourinary Oncology MDC from January 2016 to September 2019. These patients were identified retrospectively. SEER-18 (Surveillance, Epidemiology, and End Results) database, November 2019 submission was queried to obtain patients with similarly staged disease diagnosed between 2015 and 2017. Completion rates of radical cystectomy, use of neoadjuvant therapies, and survival outcomes were compared between the two cohorts., Results: Ninety-one patients from the MDC form this time period were identified; 65.9% underwent radical cystectomy and 71.8% received neoadjuvant therapy in the form of chemotherapy, immune checkpoint inhibition or a combination of the two - higher than reported national trends for neoadjuvant therapies. Progression of disease was seen in 24.2% of patients. A total of 8675 patients met inclusion criteria in the SEER database. Rates of radical cystectomy were significantly higher in MCD patients when compared to SEER derived data (65.9% vs. 37.7%, p =< 0.001). MCD patients had significantly better cancer-specific survival (mean 20.4 vs. 18.3 months p = 0.028, median survival not reached)., Conclusion: Our long term experience caring for patients with genitourinary malignancies such as bladder cancer in a uniform multidisciplinary team results in a high utilization of neoadjuvant therapies. When compared to a contemporary SEER-derived cohort, multidisciplinary patients were more likely to undergo radical cystectomy and had longer cancer-specific survival.

We report the case of a 61-year-old male with metastatic prostate cancer who presented with urinary retention secondary to subdermal penile and corpora cavernosa metastases with neuroendocrine transformation of his metastatic hormone sensitive prostate cancer. We highlight the presentation, diagnosis, and management of this rare condition.

Background: Genomic classifiers (GC) have been shown to improve risk stratification post prostatectomy. However, their clinical benefit has not been prospectively demonstrated. We sought to determine the impact of GC testing on postoperative management in men with prostate cancer post prostatectomy., Methods: Two prospective registries of prostate cancer patients treated between 2014 and 2019 were included. All men underwent Decipher tumor testing for adverse features post prostatectomy (Decipher Biosciences, San Diego, CA). The clinical utility cohort, which measured the change in treatment decision-making, captured pre- and postgenomic treatment recommendations from urologists across diverse practice settings (n = 3455). The clinical benefit cohort, which examined the difference in outcome, was from a single academic institution whose tumor board predefined "best practices" based on GC results (n = 135)., Results: In the clinical utility cohort, providers' recommendations pregenomic testing were primarily observation (69%). GC testing changed recommendations for 39% of patients, translating to a number needed to test of 3 to change one treatment decision. In the clinical benefit cohort, 61% of patients had genomic high-risk tumors; those who received the recommended adjuvant radiation therapy (ART) had 2-year PSA recurrence of 3 vs. 25% for those who did not (HR 0.1 [95% CI 0.0-0.6], p = 0.013). For the genomic low/intermediate-risk patients, 93% followed recommendations for observation, with similar 2-year PSA recurrence rates compared with those who received ART (p = 0.93)., Conclusions: The use of GC substantially altered treatment decision-making, with a number needed to test of only 3. Implementing best practices to routinely recommend ART for genomic-high patients led to larger than expected improvements in early biochemical endpoints, without jeopardizing outcomes for genomic-low/intermediate-risk patients.

The management of men with prostate cancer (PCa) with biochemical recurrence following local definitive therapy remains controversial. Early use of androgen deprivation therapy (ADT) leads to significant side effects. Developing an alternative, clinically effective, and well-tolerated therapy remains an unmet clinical need. INO-5150 is a synthetic DNA therapy that includes plasmids encoding for prostate-specific antigen (PSA) and prostate-specific membrane antigen (PSMA), and INO-9012 is a synthetic DNA plasmid encoding for interleukin-12 (IL-12). This phase 1/2, open-label, multi-center study enrolled men with PCa with rising PSA after surgery and/or radiation therapy. Patients were enrolled into one of four treatment arms: arm A, 2 mg of INO-5150; arm B, 8.5 mg of INO-5150; arm C, 2 mg of INO-5150 + 1 mg of INO-9012; and arm D, 8.5 mg of INO-5150 + 1 mg of INO-9012. Patients received study drug with electroporation on day 0 and on weeks 3, 12, and 24, and they were followed for up to 72 weeks. Sixty-two patients were enrolled. Treatment was well tolerated. 81% (50/62) of patients completed all visits. 85% (53/62) remained progression-free at 72 weeks. PSA doubling time (PSADT) was increased when assessed in patients with day 0 PSADT ≤12 months. Immunogenicity was observed in 76% (47/62) of patients by multiple assessments. Analysis indicated that CD38 and perforin co-positive CD8 T cell frequency correlated with attenuated PSA rise (p = 0.05, n = 50)., (Copyright © 2020 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)

Background: The Veterans Affairs Cooperative Studies Program study #553 was designed to evaluate the efficacy of adjuvant chemotherapy added to the standard of care (SOC) for patients who are at high risk for relapse after prostatectomy., Objective: To test whether addition of chemotherapy to surgery for high-risk prostate cancer improves progression-free survival (PFS)., Design, Setting, and Participants: Eligible patients after prostatectomy were randomized to the SOC group with observation or to the chemotherapy group with docetaxel and prednisone administered every 3 wk for six cycles. Randomization was stratified for prostate-specific antigen, Gleason, tumor stage, and surgical margin status., Outcome Measurements and Statistical Analysis: The primary endpoint was PFS. Secondary endpoints included overall, prostate cancer-specific, and metastasis-free survival, and time to androgen deprivation therapy., Results and Limitations: A total of 298 of the planned 636 patients were randomized. The median follow-up was 59.1 mo (0.2-103.7 mo). For the primary endpoint, the two groups did not statistically differ in PFS (median 55.5 mo in the chemotherapy group and 42.2 mo in the SOC group; test adjusted for site via gamma frailty p=0.21; adjusted hazard ratio [HR] 0.80; 95% confidence interval [CI] 0.58-1.11; p=0.18). Prespecified subgroup analyses showed benefit in PFS for patients with tumor stage ≥T3b (HR 0.54, 95% CI 0.32-0.92; p=0.022) and patients with Gleason score ≤7 (HR 0.65, 95% CI 0.43-0.99; p=0.046). Secondary endpoint analyses are hampered by low event rates. The most common adverse events (≥grade 3 related or possibly related to chemotherapy) included neutropenia (43%), hyperglycemia (20%), and fatigue (5%), with febrile neutropenia in 2%., Conclusions: Adjuvant chemotherapy in high-risk prostate cancer using docetaxel and prednisone did not lead to statistically significant improvement in PFS for the intention-to-treat population as a whole. The analysis was challenged by lower power due to accrual limitation. Subgroup analyses suggest potential benefit for patients with Gleason grade ≤7 and stage≥pT3b (ClinicalTrials.gov number NCT00132301)., Patient Summary: In this randomized trial, we tested whether addition of chemotherapy to surgery for high-risk prostate cancer decreased the risk of prostate-specific antigen rise after surgery. We found no benefit from docetaxel given after radical prostatectomy, although some subgroups of patients may benefit., (Copyright © 2020 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Over the past 5 years, the advent of combination therapeutic strategies has substantially reshaped the clinical management of patients with advanced prostate cancer. However, most of these combination regimens were developed empirically and, despite offering survival benefits, are not enough to halt disease progression. Thus, the development of effective therapeutic strategies that target the mechanisms involved in the acquisition of drug resistance and improve clinical trial design are an unmet clinical need. In this context, we hypothesize that the tumour engineers a dynamic response through the process of cellular rewiring, in which it adapts to the therapy used and develops mechanisms of drug resistance via downstream signalling of key regulatory cascades such as the androgen receptor, PI3K-AKT or GATA2-dependent pathways, as well as initiation of biological processes to revert tumour cells to undifferentiated aggressive states via phenotype switching towards a neuroendocrine phenotype or acquisition of stem-like properties. These dynamic responses are specific for each patient and could be responsible for treatment failure despite multi-target approaches. Understanding the common stages of these cellular rewiring mechanisms to gain a new perspective on the molecular underpinnings of drug resistance might help formulate novel combination therapeutic regimens.

Purpose: Cabazitaxel has been demonstrated to improve the overall survival for men with metastatic castrate-resistant prostate cancer. The purpose of this study was to determine the maximum tolerated dose for concurrent cabazitaxel with androgen deprivation and intensity modulated radiation therapy in men with high-risk prostate cancer., Methods and Materials: Twenty men were enrolled in this institutuional review board-approved phase I clinical trial using a 3 + 3 design. Patients were followed prospectively for safety, efficacy, and health-related quality of life (Expanded Prostate Index Composite). Efficacy was assessed biochemically using the Phoenix definition., Results: With a median follow-up time of 56 months, the maximum tolerated dose of concurrent cabazitaxel was 6 mg/m 2 . The 5-year biochemical disease-free survival was 73%, despite 75% of patients having very high risk prostate cancer per the National Comprehensive Cancer Network guidelines. Four patients were unable to complete chemotherapy owing to dose-limiting toxicities (eg, rectal bleeding, diarrhea, and elevated transaminase). There was no significant minimally important difference in Expanded Prostate Index Composite patient-reported outcomes for either the urinary or bowel domains; however, there was a significant decrease in the sexual domain., Conclusions: This is the first clinical trial of prostate cancer to report on the combination of cabazitaxel and radiation therapy. The maximum tolerated dose of concurrent cabazitaxel with radiation and androgen deprivation therapy was determined to be 6 mg/m 2 . Despite the aggressive nature of the disease, robust biochemical control was observed., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Nuclear pore complexes (NPCs) regulate nuclear-cytoplasmic transport, transcription, and genome integrity in eukaryotic cells. However, their functional roles in cancer remain poorly understood. We interrogated the evolutionary transcriptomic landscape of NPC components, nucleoporins (Nups), from primary to advanced metastatic human prostate cancer (PC). Focused loss-of-function genetic screen of top-upregulated Nups in aggressive PC models identified POM121 as a key contributor to PC aggressiveness. Mechanistically, POM121 promoted PC progression by enhancing importin-dependent nuclear transport of key oncogenic (E2F1, MYC) and PC-specific (AR-GATA2) transcription factors, uncovering a pharmacologically targetable axis that, when inhibited, decreased tumor growth, restored standard therapy efficacy, and improved survival in patient-derived pre-clinical models. Our studies molecularly establish a role of NPCs in PC progression and give a rationale for NPC-regulated nuclear import targeting as a therapeutic strategy for lethal PC. These findings may have implications for understanding how NPC deregulation contributes to the pathogenesis of other tumor types., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Accelerated (also termed dose-dense, DD) chemotherapy regimens such as accelerated methotrexate, vinblastine, doxorubicin, and cisplatin have shown better efficacy and tolerability in the metastatic setting, and shortened the time to surgery in the neoadjuvant setting compared to standard-schedule regimens. We hypothesized that a DD schedule of gemcitabine and cisplatin (GC) would shorten the time to surgery and yield similar pathologic complete response rates (pT0) in patients with muscle-invasive bladder cancer (MIBC) compared with historical controls with standard GC., Objective: To determine the safety and efficacy of neoadjuvant DDGC in MIBC., Design Setting and Participants: Patients with cT2-4a, N0-1, M0 MIBC were eligible and received three 14-d cycles of DDGC with pegfilgrastim support followed by radical cystectomy with lymph node dissection. The primary end point was the pT0 rate. Molecular subtypes were assigned and correlated with survival., Results and Limitations: Thirty-one patients were evaluable for toxicity and response, of whom 58% had baseline clinical stage >T2N0M0; the median age was 69 yr. Ten patients (32%, 95% confidence interval [CI] 16-49%) achieved ypT0N0 status at cystectomy. Another four patients (13%, 95% CI 1-25%) were downstaged to non-muscle-invasive (

Objective: To determine long-term oncological outcomes of radical prostatectomy (RP) after neoadjuvant chemohormonal therapy (CHT) for clinically localised, high-risk prostate cancer., Patients and Methods: In this phase II multicentre trial of patients with high-risk prostate cancer (PSA level >20 ng/mL, Gleason ≥8, or clinical stage ≥T3), androgen-deprivation therapy (goserelin acetate depot) and paclitaxel, carboplatin and estramustine were administered before RP. We report the long-term oncological outcomes of these patients and compared them to a contemporary cohort who met oncological inclusion criteria but received RP only., Results: In all, 34 patients were enrolled and followed for a median of 13.1 years. Within 10 years most patients had biochemical recurrence (BCR-free probability 22%; 95% confidence interval [CI] 10-37%). However, the probability of disease-specific survival at 10 years was 84% (95% CI 66-93%) and overall survival was 78% (95% CI 60-89%). The CHT group had higher-risk features than the comparison group (123 patients), with an almost doubled risk of calculated preoperative 5-year BCR (69% vs 36%, P < 0.01). After adjusting for these imbalances the CHT group had trends toward improvement in BCR (hazard ratio [HR] 0.76, 95% CI 0.43-1.34; P = 0.3) and metastasis-free survival (HR 0.55, 95% CI 0.24-1.29; P = 0.2) although these were not statistically significant., Conclusions: Neoadjuvant CHT followed by RP was associated with lower rates of BCR and metastasis compared with the RP-only group; however, these results were not statistically significant. Because this treatment strategy has known harms and unproven benefit, this strategy should only be instituted in the setting of a clinical trial., (© 2014 The Authors BJU International © 2014 BJU International Published by John Wiley & Sons Ltd.)

Purpose: To test the hypothesis that a genomic classifier (GC) would predict biochemical failure (BF) and distant metastasis (DM) in men receiving radiation therapy (RT) after radical prostatectomy (RP)., Methods and Materials: Among patients who underwent post-RP RT, 139 were identified for pT3 or positive margin, who did not receive neoadjuvant hormones and had paraffin-embedded specimens. Ribonucleic acid was extracted from the highest Gleason grade focus and applied to a high-density-oligonucleotide microarray. Receiver operating characteristic, calibration, cumulative incidence, and Cox regression analyses were performed to assess GC performance for predicting BF and DM after post-RP RT in comparison with clinical nomograms., Results: The area under the receiver operating characteristic curve of the Stephenson model was 0.70 for both BF and DM, with addition of GC significantly improving area under the receiver operating characteristic curve to 0.78 and 0.80, respectively. Stratified by GC risk groups, 8-year cumulative incidence was 21%, 48%, and 81% for BF (P<.0001) and for DM was 0, 12%, and 17% (P=.032) for low, intermediate, and high GC, respectively. In multivariable analysis, patients with high GC had a hazard ratio of 8.1 and 14.3 for BF and DM. In patients with intermediate or high GC, those irradiated with undetectable prostate-specific antigen (PSA ≤0.2 ng/mL) had median BF survival of >8 years, compared with <4 years for patients with detectable PSA (>0.2 ng/mL) before initiation of RT. At 8 years, the DM cumulative incidence for patients with high GC and RT with undetectable PSA was 3%, compared with 23% with detectable PSA (P=.03). No outcome differences were observed for low GC between the treatment groups., Conclusion: The GC predicted BF and metastasis after post-RP irradiation. Patients with lower GC risk may benefit from delayed RT, as opposed to those with higher GC; however, this needs prospective validation. Genomic-based models may be useful for improved decision-making for treatment of high-risk prostate cancer., (Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: Zoledronic acid decreases the risk for skeletal-related events (SREs) in men with castration-resistant prostate cancer and bone metastases but its role earlier in the natural history of the disease is unknown. This phase III study evaluated the efficacy and safety of earlier treatment with zoledronic acid in men with castration-sensitive metastatic prostate cancer., Patients and Methods: Men with castration-sensitive prostate cancer and bone metastases whose androgen-deprivation therapy was initiated within 6 months of study entry were randomly assigned in a blinded 1:1 ratio to receive zoledronic acid (4 mg intravenously every 4 weeks) or a placebo. After their disease progressed to castration-resistant status, all patients received open-label treatment with zoledronic acid. The primary end point was time to first SRE, defined as radiation to bone, clinical fracture, spinal cord compression, surgery to bone, or death as a result of prostate cancer. Target accrual was 680 patients. Primary analysis was planned after 470 SREs. The study was discontinued prematurely (645 patients; 299 SREs) after the corporate supporter withdrew study drug supply., Results: Early zoledronic acid was not associated with increased time to first SRE. The median time to first SRE was 31.9 months in the zoledronic acid group (95% CI, 24.2 to 40.3) and 29.8 months in the placebo group (95% CI, 25.3 to 37.2; hazard ratio, 0.97; 95% CI, 0 to 1.17; one-sided stratified log-rank P = .39). Overall survival was similar between the groups (hazard ratio, 0.88; 95% CI, 0.70 to 1.12; P = .29). Rates of adverse events were similar between the groups., Conclusion: In men with castration-sensitive prostate cancer and bone metastases, early treatment with zoledronic acid was not associated with lower risk for SREs.

Purpose: Prognostic models for overall survival (OS) for patients with metastatic castration-resistant prostate cancer (mCRPC) are dated and do not reflect significant advances in treatment options available for these patients. This work developed and validated an updated prognostic model to predict OS in patients receiving first-line chemotherapy., Methods: Data from a phase III trial of 1,050 patients with mCRPC were used (Cancer and Leukemia Group B CALGB-90401 [Alliance]). The data were randomly split into training and testing sets. A separate phase III trial served as an independent validation set. Adaptive least absolute shrinkage and selection operator selected eight factors prognostic for OS. A predictive score was computed from the regression coefficients and used to classify patients into low- and high-risk groups. The model was assessed for its predictive accuracy using the time-dependent area under the curve (tAUC)., Results: The model included Eastern Cooperative Oncology Group performance status, disease site, lactate dehydrogenase, opioid analgesic use, albumin, hemoglobin, prostate-specific antigen, and alkaline phosphatase. Median OS values in the high- and low-risk groups, respectively, in the testing set were 17 and 30 months (hazard ratio [HR], 2.2; P < .001); in the validation set they were 14 and 26 months (HR, 2.9; P < .001). The tAUCs were 0.73 (95% CI, 0.70 to 0.73) and 0.76 (95% CI, 0.72 to 0.76) in the testing and validation sets, respectively., Conclusion: An updated prognostic model for OS in patients with mCRPC receiving first-line chemotherapy was developed and validated on an external set. This model can be used to predict OS, as well as to better select patients to participate in trials on the basis of their prognosis.

Nearly 40% of patients with non-invasive bladder cancer will progress to invasive disease despite locally-directed therapy. Overcoming the bladder permeability barrier (BPB) is a challenge for intravesical drug delivery. Using the fluorophore coumarin (C6), we synthesized C6-loaded poly(lactide-co-glycolide) (PLGA) nanoparticles (NPs), which were surface modified with a novel cell penetrating polymer, poly(guanidinium oxanorbornene) (PGON). Addition of PGON to the NP surface improved tissue penetration by 10-fold in intravesically-treated mouse bladder and ex vivo human ureter. In addition, NP-C6-PGON significantly enhanced intracellular uptake of NPs compared to NPs without PGON. To examine biological activity, we synthesized NPs that were loaded with the histone deacetylase (HDAC) inhibitor belinostat (NP-Bel-PGON). NP-Bel-PGON exhibited a significantly lower IC50 in cultured bladder cancer cells, and sustained hyperacetylation, when compared to unencapsulated belinostat. Xenograft tumors treated with NP-Bel-PGON showed a 70% reduction in volume, and a 2.5-fold higher intratumoral acetyl-H4, when compared to tumors treated with unloaded NP-PGON., From the Clinical Editor: These authors demonstrate that PLGA nanoparticles with PGON surface functionalization result in greatly enhanced cell penetrating capabilities, and present convincing data from a mouse model of bladder cancer for increased chemotherapy efficacy., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: The use of docetaxel prolongs survival for patients with castrate-resistant prostate cancer (CRPC). Inhibition of vascular endothelial growth factor (VEGF) with bevacizumab may further enhance the antitumor effect of docetaxel and estramustine in patients with CRPC., Methods: This cooperative group trial enrolled men with CRPC. Patients received oral estramustine 280 mg 3 times daily on Days 1 through 5 of every cycle plus 70 mg/m² docetaxel and 15 mg/kg bevacizumab on Day 2 every 3 weeks. Prostate-specific antigen (PSA) values were monitored every cycle, and imaging studies were obtained every 3 cycles. The primary endpoint was progression-free survival (PFS), and the secondary objectives were safety, PSA decline, measurable disease response, and overall survival., Results: Seventy-nine patients were enrolled; and 77 patients received a median of 8 cycles and were evaluable. A 50% PSA decline was observed in 58 patients (75%). Twenty-three of 39 patients with measurable disease had a partial response (59%). The median PFS was 8 months, and the overall median survival was 24 months. Neutropenia without fever (69%), fatigue (25%), and thrombosis/emboli (9%) were the most common severe toxicities. Twenty-four of 77 patients were removed from protocol treatment because of disease progression, 35 of 77 patients were removed because of a physician or patient decision, and 15 patients were removed secondary to toxicity., Conclusions: The combination of docetaxel, estramustine, and bevacizumab was tolerable but complicated by toxicity. Although the endpoint of PFS did not meet the desired level, encouraging antitumor activity and overall survival were observed. Further phase 3 evaluation of the role of bevacizumab in CRPC is ongoing., (Copyright © 2010 American Cancer Society.)

Prostate cancer relies on signaling through the androgen receptor (AR) for maintenance and progression; and androgen-deprivation therapy remains a cornerstone of treatment for advanced prostate cancer. An effective clinical classification of prostate cancer should account for the extent of the disease as well as the mechanisms that are driving the growth of the tumor. The previous terms hormone-sensitive and hormone-refractory described response to treatment. It has become clear that these terms do not reflect the mechanism of disease relapse; however over the last decade there has been a better understanding of androgen-receptor mediated signaling effects and incomplete suppression of androgens in prostate cancer. The Prostate Cancer Clinical Trials Working Group 2 (PCWG2) now recommends addressing the spectrum of clinical states based on castration status as this ligand-centered terminology can more accurately describe the patients' disease, and ultimately provides a useful framework for patient management and drug development. Optimized use of androgen-deprivation therapy, low molecular weight inhibitors of adrenal androgen biosynthesis, and new AR antagonists are promising new therapeutics that can further define the meaning of castrate state. As hormone resistance is redefined to include patients that are refractory to treatments that ablate adrenal and in situ tumoral androgens, a meaningful new clinical state in patients will be forged. We propose a model for incorporating these patients into the current PCWG2 conceptualization of the disease.

Purpose: An open-label, dose-escalating phase Ib/IIa trial was performed to establish a safety profile of ascending doses of cetuximab (IMC C225) in combination with doxorubicin administered weekly for 6 treatments in patients with metastatic castration-resistant prostate cancer. The secondary endpoint was to assess the efficacy of cetuximab in combination with doxorubicin as well as to determine the optimal biologic dose and the maximum tolerated dose., Patients and Methods: Patients in 8 groups received escalating doses of cetuximab 20-300 mg/m(2) plus doxorubicin 15 or 20 mg/m(2) given intravenously weekly for 6 consecutive weeks, followed by a 1-week observation period. A treatment response was defined as a > 50% decline in prostate-specific antigen (PSA) or regression of radiographically measurable disease., Results: Of the 36 treated patients, 25% had grade 2 neutropenia, 39% had leukopenia, and 44% had stomatitis at doxorubicin 20 mg/m(2). Erythematous skin exanthema was seen in 38% of the patients. There was no significant regression of bone or soft tissue disease, but stable disease was observed in 20 (65%) of the 31 patients with bone disease and 14 (61%) of the 23 patients with lymph node disease. Declines in PSA were modest in the 36 patients, with 1 (2.7%) with an 80% decline from baseline, 2 (5.6%) with > 50% to < 80% declines, and 14 (39%) with progression. Median survival was approximately 18 months., Conclusion: In a heavily pretreated population of men with metastatic castration-resistant prostate cancer, this study of cetuximab/doxorubicin was associated with minimal PSA declines posttherapy, though median survival was longer compared to historical control groups. Further studies with cetuximab combined with more contemporary chemotherapy for castration-resistant prostate cancer might be warranted.

Purpose: AT-101 binds and inhibits the antiapoptotic function of Bcl-2, Bcl-xL, Mcl-1, and Bcl-w and is a potent stimulator of proapoptotic proteins. In this multi-institution phase I/II trial, we evaluated the safety and efficacy of single-agent AT-101, in men with chemotherapy naïve, castrate-resistant prostate cancer (CRPC)., Experimental Design: Patients with progressive CRPC were to be treated with escalating doses of AT-101 on a continuous daily basis until the maximally tolerated dose was achieved. At the recommended phase 2 dose, an additional 21 patients were planned to assess for preliminary evidence of efficacy., Results: Twenty-three patients were enrolled. The phase I starting dose was 30 mg/day on a continuous basis; however, ongoing trials with AT-101 showed increased gastrointestinal toxicity with this daily schedule when given for repetitive cycles. As a result, the phase II starting dose was chosen to be 30 mg/day for 21 of 28 days. The most frequent observed adverse events (any grade) were diarrhea (43.5%), fatigue (34.8%), nausea (21.7%), anorexia (21.7%), and small intestinal obstruction (21.7%). Due to the high incidence of grade 3 small intestinal obstruction (n = 5; 21.7%), a reduction in dose to 20 mg/day for 21 of 28 days was mandated for all patients. Two patients had a confirmed > or =50% posttherapy prostate-specific antigen decline. No objective responses (Response Evaluation Criteria in Solid Tumors) were observed., Conclusion: AT-101 administered at 20 mg/day for 21 of 28 days was well-tolerated. Evidence of single-agent clinical activity was observed with prostate-specific antigen declines in some patients. Further investigation of AT-101 in prostate cancer is warranted and trials combining AT-101 with androgen deprivation, as well as with docetaxel chemotherapy are ongoing.

Microtubules are vital and dynamic cellular organelles and many agents have been developed that target them. The cytotoxic effects of taxanes and epothilones are mediated by stabilization of microtubule dynamics. Taxanes are one of the most effective cytotoxic agents, and have a broad spectrum of antitumor activity. However, their efficacy is limited by the development of resistance to these effects. Epothilones have a similar mechanism of action to taxanes, but a decreased propensity for drug resistance. Epothilones are macrolides, and have in vitro and in vivo activity in taxane-resistant or taxane-insensitive human cancer cell lines. Several epothilones are in clinical development: ixabepilone, patupilone, BMS-310705, KOS-862, KOS-1584, and ZK-EPO. Multiple dosing schedules of ixabepilone and patupilone have been studied. The toxicity profiles of epothilones are quite diverse and depend on the compound and the administration schedule. The epothilones have demonstrated a wide range of clinical activity, including important antitumor effects, in advanced prostate cancer. Epothilones are particularly useful in patients with prostate cancer who have previously been treated with taxanes or who have taxane-refractory tumors. In the setting of castrate metastatic prostate cancer, ixabepilone and patupilone showed encouraging clinical activity in the phase II setting and further studies are needed to determine if they provide additional clinical benefit to patients with advanced disease.

Purpose: Docetaxel/estramustine is a known active regimen in hormonerefractory prostate cancer (HRPC). A phase II study was conducted to assess the safety and efficacy of docetaxel/estramustine combined with exisulind, an apoptotic antineoplastic drug., Patients and Methods: Eighty men with chemotherapy-naive HRPC were enrolled in a multicenter, cooperative group study. The treatment regimen consisted of oral estramustine (280 mg 3 times daily for 5 days), docetaxel 70 mg/m2, oral exisulind (250 mg twice daily), oral dexamethasone (8 mg twice daily for 3 days), and oral warfarin (2 mg daily)., Results: Seventy-five eligible patients were treated with a median of 6 cycles of therapy. Fortyseven patients (62.7%; 95% CI, 50.7%-73.6%) had a > or = 50% decline in prostate-specific antigen levels. Forty-six patients had measurable disease with 6 partial responses (13%; 95% CI, 4.9%-26.3%). The main grade 3/4 toxicities were neutrophils (79%), fatigue (15%), and thrombosis/embolism (10%). The median time to first progression was 5.1 months (95% CI, 4.4-6.3 months) and the median survival time was 17.8 months (95% CI, 14.7-20.1 months)., Conclusion: The combination of estramustine/docetaxel/exisulind was associated with significant thomboembolic toxicity despite prophylactic warfarin. The contribution of exisulind to toxicity is uncertain. Prostate-specific antigen decline, response rates, and progression-free and overall survival are similar to those reported with docetaxel/estramustine.

Purpose: MLN2704 is an immunoconjugate designed to deliver the maytansinoid antimicrotubule agent drug maytansinoid-1 directly to prostate-specific membrane antigen (PSMA)-expressing cells via the PSMA-targeted monoclonal antibody MLN591. This novel immunoconjugate has shown cytotoxic anti-prostate cancer activity. This study investigated the safety profile, pharmacokinetics, immunogenicity, and preliminary antitumor activity of MLN2704., Patients and Methods: Patients with progressive, metastatic, castration-resistant prostate cancer received MLN2704 intravenously over 2.5 hours. Dose-limiting toxicity (DLT), maximum-tolerated dose (MTD), pharmacokinetics, immunogenicity, and antitumor activity were assessed., Results: Twenty-three patients received MLN2704 at doses of 18 to 343 mg/m(2). Eighteen of these patients received >or= three doses at 4-week intervals. Pharmacokinetics of conjugate levels were dose proportional. There was no correlation between clearance and body-surface area. MLN2704 was nonimmunogenic. Study drug-related grade 3 toxicities occurred in three (13%) of 23 patients, including uncomplicated febrile neutropenia (the only DLT) in one patient, reversible elevations in hepatic transaminases, leukopenia, and lymphopenia. No grade 4 toxicities were observed. The most frequent grade 1 or 2 toxicities included fatigue, nausea, and diarrhea. Neuropathy occurred in eight (35%) of 23 patients, including five of six patients treated at 343 mg/m(2). Two (22%) of the nine patients treated at 264 or 343 mg/m(2) had sustained a more than 50% decrease in prostate-specific antigen versus baseline, accompanied by measurable tumor regression in the patient treated at 264 mg/m(2)., Conclusion: Therapeutic doses of MLN2704 can be administered safely on a repetitive basis. An MTD was not defined. MLN2704 is being administered at more frequent intervals in ongoing trials to determine an optimal dosing schedule.

We have shown the immunogenicity and safety of synthetic carbohydrate vaccines when conjugated to the carrier keyhole limpet hemocyanin (KLH) and given with the adjuvant, QS-21, in patients with biochemically relapsed prostate cancer. To determine whether immune response could be further enhanced with stimulation by multiple antigens, a hexavalent vaccine was prepared using previously determined doses and administered in a Phase II setting to 30 high-risk patients. The hexavalent vaccine included GM2, Globo H, Lewis(y), glycosylated MUC-1-32mer and Tn and TF in a clustered formation, conjugated to KLH and mixed with QS-21. Eight vaccinations were administered over 13 months. All 30 patients had significant elevations in antibody titers to at least two of the six antigens; 22 patients had increased reactivity with FACS. These serologic responses were lower than that seen previously in patients treated with the respective monovalent vaccines. The reciprocal median combined IgM and IgG antibody titers with ELISA against MUC1, Tn, TF, globo H and GM2 for these 30 patients were 640, 80, 120, 40 and 0, compared to 1280, 640, 1280, 320 and 160 seen in patients receiving individual monovalent vaccines. This hexavalent vaccine of synthetic "self" antigens broke immunologic tolerance against two or more antigens in all 30 vaccinated patients, was safe, but antibody titers against several of the antigens were lower than those seen in individual monovalent trials. No impact on PSA slope was detected. We address the relevance of the multivalent approach for prostate cancer treatment.

Purpose: We defined the antitumor effects of bortezomib alone and in combination with prednisone in patients with progressive, castration resistant metastatic prostate cancer., Materials and Methods: A total of 30 men with progressive castration resistant disease were treated in 2 groups. Cohort 1 received 1.5 mg/m2 bortezomib intravenously twice weekly for 2 cycles (2 weeks on and 1 week off), followed by 1.6 mg/m2 weekly (4 weeks on and 2 weeks off). Prednisone (10 mg) was given orally throughout. Cohort 2 comprised patients with limited chemotherapy exposure who received a decreased dose of bortezomib (1.3 mg/m2) during the induction period with prednisone added only at disease progression. The primary end point was no evidence of disease progression at 12 weeks, defined as no increase in prostate specific antigen from baseline and no radiographic progression. Interleukin-6 was assessed to correlate with antitumor effects., Results: One of 24 evaluable patients (4%) achieved the primary end point. In cohort 1, 18 patients were treated, 13 were evaluable for response and 4 discontinued treatment due to toxicities, including 3 before attaining the point of being evaluable. No patient achieved the primary end point. In cohort 2, 12 patients were treated and 11 were evaluable for response. Toxicity was slightly mitigated compared with that in cohort 1. One patient achieved the primary end point. Interleukin-6 did not correlate with posttreatment prostate specific antigen changes in either cohort., Conclusions: Although interleukin-6 and other pathways regulated by nuclear factor-kappa B may be legitimate targets, treatment with bortezomib alone and with prednisone does not appear to have significant antitumor effects in patients with castration resistant metastatic prostate cancer.

Background: Estramustine phosphate is a mustard-oestradiol conjugate, and has hormonal and non-hormonal effects. In phase II trials of patients with cancer, response to microtubule inhibitors increases when these drugs are combined with estramustine. We aimed to assess whether combining estramustine with chemotherapy increases survival in patients with castration-refractory prostate cancer., Methods: We systematically searched for randomised clinical trials that compared chemotherapy regimens with and without estramustine in patients with histologically-proven prostate cancer and were published between 1966 and 2004. Data from these studies were verified centrally and updated individual patient data were analysed. The primary endpoint was overall survival. Secondary endpoints were prostate-specific antigen (PSA) response, time to PSA progression, and toxicity. A Cox regression model that was stratified by trial and adjusted for covariates at baseline was used., Findings: The initial search identified seven eligible trials that included 742 patients, from which data from five trials including 605 patients had been collected. Individual patient data from two trials (137 patients) were no longer available. The 605 patients had been accrued between Jan 1, 1993 and Dec 1, 2003 and randomly assigned to chemotherapy plus estramustine or to chemotherapy without estramustine. Chemotherapy (with or without estramustine) consisted of docetaxel, paclitaxel, ixabepilone, and vinblastine. Median follow-up was 2.8 years (range 0.0-3.4), and 510 deaths had occurred by the end of follow-up. Cox regression analysis stratified by trial showed that concentrations of serum haemoglobin (p<0.0001), use of chemotherapy plus estramustine (p=0.008), performance status (p=0.002), and serum PSA concentrations (p=0.04) were associated independently with overall survival. Overall survival was significantly better in patients assigned chemotherapy plus estramustine (adjusted hazard ratio [HR] 0.77 [95% CI 0.63-0.93], p=0.008). Estimated absolute increase in overall survival when estramustine was added to chemotherapy was 9.5% (SE 4.0) at 1 year after randomisation. We did not note a significant association between treatment effect on overall survival and age, concentration of serum haemoglobin, performance status, or serum PSA concentration. Patients who received chemotherapy plus estramustine had a better PSA response than those who received chemotherapy without estramustine (RR 0.53 [0.38-0.72], p<0.0001). Time to PSA progression was significantly longer in patients assigned chemotherapy plus estramustine than in those assigned chemotherapy without estramustine (HR 0.74 [0.58-0.94], p=0.01). Patients assigned chemotherapy and estramustine had more grade 3 or grade 4 thromboembolic events compared with those assigned chemotherapy without estramustine (12 of 271 vs 1 of 275)., Interpretation: In patients with castration-refractory prostate cancer, addition of estramustine to chemotherapy increases time to PSA progression and overall survival compared with chemotherapy without estramustine. However, this benefit should be balanced with the risk of increased thromboembolic events in patients who receive estramustine and chemotherapy in combination compared with chemotherapy without estramustine.

Background: This randomized, noncomparative, multicenter, clinical trial evaluated ixabepilone or mitoxantrone/prednisone (MP) as second-line chemotherapy for taxane-refractory, hormone-refractory, prostate cancer (HRPC)., Methods: Patients with HRPC that progressed during or within 60 days of cessation of taxane chemotherapy were randomly selected with equal probability to ixabepilone 35 mg/m(2) intravenously every 3 weeks, or mitoxantrone 14 mg/m(2) intravenously every 3 weeks and prednisone 5 mg orally twice daily. Treatment continued until progression or toxicity; crossover was allowed., Results: Forty-one patients were accrued to each arm of the study. The median number of cycles administered for each arm was 3. Median survival from protocol entry was 10.4 months with ixabepilone and 9.8 months with MP. Prostate-specific antigen (PSA) declines of >or=50% were observed in 17% of ixabepilone (95% CI, 7-32) and 20% of second-line MP patients (95% CI, 9-35). Partial responses were observed in 1 of 24 ixabepilone and in 2 of 21 MP patients with evaluable measurable disease. Median duration of second-line ixabepilone and MP treatment was 2.2 months and 2.3 months, respectively. For third-line crossover treatment, PSA declines of >or=50% were observed in 3 of 27 ixabepilone-treated and 4 of 15 MP-treated patients. Prior taxane response was associated with an increased likelihood of second-line ixabepilone or MP response. Low baseline lactate dehydrogenase and absence of visceral metastases independently predicted improved survival. The most common grade 3/4 toxicity associated with second-line treatment was neutropenia (54% of ixabepilone patients and 63% of MP patients)., Conclusions: Ixabepilone and MP had modest activity as second-line chemotherapy for docetaxel-refractory HRPC. The median survival for the entire cohort treated in this study was 9.8 months., ((c) 2007 American Cancer Society.)

Purpose: To define the maximum tolerated dose (MTD), toxicities, and pharmacokinetics of 17-allylamino-17-demethoxygeldanamycin (17-AAG) when administered using continuous and intermittent dosing schedules., Experimental Design: Patients with progressive solid tumor malignancies were treated with 17-AAG using an accelerated titration dose escalation schema. The starting dose and schedule were 5 mg/m(2) daily for 5 days with cycles repeated every 21 days. Dosing modifications based on safety, pharmacodynamic modeling, and clinical outcomes led to the evaluation of the following schedules: daily x 3 repeated every 14 days; twice weekly (days 1, 4, 8, and 11) for 2 weeks every 3 weeks; and twice weekly (days 1 and 4) without interruption. During cycle 1, blood was collected for pharmacokinetic and pharmacodynamic studies., Results: Fifty-four eligible patients were treated. The MTD was schedule dependent: 56 mg/m(2) on the daily x 5 schedule; 112 mg/m(2) on the daily x 3 schedule; and 220 mg/m(2) on the days 1, 4, 8, and 11 every-21-day schedule. Continuous twice-weekly dosing was deemed too toxic because of delayed hepatotoxicity. Hepatic toxicity was also dose limiting with the daily x 5 schedule. Other common toxicities encountered were fatigue, myalgias, and nausea. This latter adverse effect may have been attributable, in part, to the DMSO-based formulation. Concentrations of 17-AAG above those required for activity in preclinical models could be safely achieved in plasma. Induction of a heat shock response and down-regulation of Akt and Raf-1 were observed in biomarker studies., Conclusion: The MTD and toxicity profile of 17-AAG were schedule dependent. Intermittent dosing schedules were less toxic and are recommended for future phase II studies.

Background: Epothilones and taxanes interfere with microtubule function. Ixabepilone, which is an epothilone-B analog, has activity against taxane-resistant cell lines and as first-line therapy for men with hormone-refractory prostate carcinoma (HRPC). Clinical cross-resistance of ixabepilone and taxanes in HRPC is unknown., Methods: Records were evaluated retrospectively from patients with HRPC who were treated on a randomized Phase II trial of ixabepilone with or without estramustine and who subsequently received taxane chemotherapy. Posttherapy declines in prostate-specific antigen (PSA) levels and time to PSA progression were defined by consensus criteria. The median survival was evaluated by using the Kaplan-Meier method., Results: Forty-nine patients who received ixabepilone with estramustine (28 patients) or without estramustine (21 patients) subsequently received second-line taxane therapy. Second-line PSA declines > or = 50% were achieved by 51% of patients (95% confidence interval [95% CI], 33-66%). Second-line PSA declines > or = 50% were achieved by 61% of patients (95% CI, 42-78%) who achieved a first-line PSA decline > or = 50% with ixabepilone, compared with 33% of patients (95% CI, 13-59%) who did not (P = 0.08). Patients who discontinued first-line ixabepilone treatment for disease progression were less likely to achieve a PSA decline > or = 50% in response to second-line, taxane-based therapy compared with patients who discontinued for toxicity or patient preference (36% vs. 71%; P = 0.01)., Conclusions: Second-line taxane chemotherapy after ixabepilone resulted in a substantial frequency of PSA declines. Although patients with ixabepilone-refractory disease were less likely to respond to second-line taxane chemotherapy, 36% did achieve a PSA response. These findings were consistent with incomplete clinical cross-resistance between the taxanes and the epothilones., (Copyright 2005 American Cancer Society.)

Background: Histone deacetylase inhibitors are a novel class of therapeutic agents that inhibit deacetylate histones and other proteins involved in the regulation of gene expression and cell cycle progression. Phase I trials of intravenous and oral formulations of one such agent, vorinostat (suberoylanilide hydroxamic acid [SAHA]), have shown that it is safe and tolerable, that it inhibits histone deacetylation in peripheral blood mononuclear cells, and that it has a broad range of antitumor activity., Patients and Methods: Thirteen patients with mesothelioma were included in a phase I trial of oral SAHA. All but one had previously been treated with chemotherapy., Results: Four patients completed > or = 6 cycles of therapy; 2 patients demonstrated a partial response. The toxicities in this cohort of patients were similar to those observed in the entire phase I trial: primarily fatigue, dehydration, nausea, and vomiting., Conclusion: Given the dearth of treatment options for patients with advanced mesothelioma who have progressed after first-line chemotherapy, these results are encouraging. A placebo-controlled, randomized phase III study of oral SAHA is now open for patients with mesothelioma in whom treatment with pemetrexed has failed.

High-risk tumors exhibit a more aggressive natural history and have higher positive margin and recurrence rates after radical prostatectomy or radiotherapy alone, where unimodality therapy likely represents undertreatment. Hence, the therapeutic ratio (patients who actually realize a survival benefit from a therapeutic intervention) may, therefore, be greater in high-risk disease if its natural history can be altered by multimodality therapy. It is, thus, important to investigate therapies that optimize complete extirpation of all cancer cells and reduce the incidence of positive surgical margins and disease recurrence. Neoadjuvant therapy extends the logic of early adjuvant therapy further by applying systemic therapy earlier in the course of the disease before definitive locoregional therapy. In prostate cancer, outcomes have not been improved significantly when neoadjuvant hormone therapy is used before surgery; although outcomes are improved when androgen ablation is combined with radiotherapy, many patients remain at risk for systemic recurrence. With recent data confirming improved survival data with docetaxel chemotherapy in metastatic disease, future trials are now focusing on earlier combinations of chemohormonal or biologic therapies in high-risk patients.

Background: Prostate-specific membrane antigen (PSMA) is a transmembrane glycoprotein primarily expressed on benign and malignant prostatic epithelial cells. J591 is an IgG1 monoclonal antibody that targets the external domain of the PSMA. The relationship among dose, safety, pharmacokinetics, and antibody-dependent cellular cytotoxicity (ADCC) activation for unlabeled J591 has not been explored., Patients and Methods: Patients with progressive metastatic prostate cancer despite androgen deprivation were eligible. Each patient received 10, 25, 50, and 100 mg of J591. Two milligrams of antibody, conjugated with the chelate 1,4,7,10-tetraazacyclododecane-N, N',N'',N'''-tetraacetic acid, were labeled with 5 mCi indium-111 (111In) as a tracer. One group of patients received unlabeled J591 before the labeled antibody; the other received both together. Toxicities, pharmacokinetic properties, biodistribution, ADCC induction, immunogenicity, and clinical antitumor effects were assessed., Results: Fourteen patients were treated (seven in each group). Treatment was well tolerated. Biodistribution of 111In-labeled J591 was comparable in both groups. The mean T1/2 was .96, 1.9, 2.75, and 3.47 days for the 10, 25, 50, and 100 mg doses, respectively. Selective targeting of 111In-labeled J591 to tumor was seen. Hepatic saturation occurred by the 25-mg dose. ADCC activity was proportional to dose. One patient showed a >50% prostate-specific antigen decline., Conclusions: J591 is well tolerated in repetitive dose-escalating administrations. The rate of serum clearance decreases with increasing antibody mass. ADCC activation is proportional to antibody mass. The optimal dose is 25 mg for radioimmunotherapy and 100 mg for immunotherapy. Phase II studies using J591 as a radioconjugate are under way.

Purpose: First-line chemotherapy with docetaxel in patients with progressive castrate metastatic prostate cancer has been shown to improve overall survival compared with mitoxantrone-based therapies. The use and outcomes of chemotherapy after first-line antimicrotubule-based therapy have not been well described., Patients and Methods: Patients with progressive castrate metastatic prostate cancer enrolled on an antimicrotubule-based protocol for treatment were followed to determine their baseline characteristics and outcomes with second- or third-line systemic therapy., Results: Of 108 patients treated with antimicrotubule-based therapy, 81% received second-line therapy, and 40% received third-line therapies. Corresponding prostate-specific antigen (PSA) decreases > or = 50% were observed in 72%, 15%, and 22% of patients. Median survival times from the start of first-, second-, and third-line therapy were 21 months (95% confidence interval [CI], 18-25 months), 13 months (95% CI, 10-15 months) and 12 months (95% CI, 9-19 months). Significant prognostic indicators for survival in the second-line setting include pretreatment PSA level, alkaline phosphatase level, and performance status. Patients not fit to receive second-line therapy were more symptomatic with first-line therapy, as illustrated by a greater need for narcotic therapy (67% vs. 15%) and palliative radiation therapy after first-line therapy (57% vs. 10%) in lieu of second-line systemic therapy., Conclusion: Eighty percent of patients received second-line chemotherapy, with a median survival of 12 months from the start of second-line treatment. Although only 40% received third-line chemotherapy, median survival was similar to that of patients in the second-line setting. Our data show that patients who initiate chemotherapy with symptoms are more likely to require palliative radiation therapy rather than chemotherapy as second-line therapy. A sequential or continuous administration of therapy may optimize the care of this subset of symptomatic patients.

Purpose: Methods accurately categorizing the diverse biology of prostate cancer are needed. A positive baseline reverse transcriptase-PCR for prostate-specific antigen (RT-PCR PSA) in the androgen-independent setting is an independent prognostic marker of survival. The objectives of the current study were to examine the prognostic implication of baseline RT-PCR PSA positivity during treatment with an active chemotherapeutic agent and explore whether an RT-PCR PSA "response" provides prognostic information., Materials and Methods: In a combined analysis of a phase I and a randomized phase II trial of BMS-247550 (an epothilone B analogue), 104 patients with hormone-refractory prostate cancer had whole blood samples collected at baseline, then with each cycle of therapy. RT-PCR PSA was assessed and related to time to progression (TTP)., Results: From 100 evaluable patients, 368 samples were received, of which 90.8% were evaluable for RT-PCR PSA status. Baseline RT-PCR PSA status was significantly associated with TTP (hazard ratio, 2.22; 95% confidence interval, 1.40-3.52). Twenty-six of 38 patients positive at first assessment had at least one follow-up RT-PCR PSA that was negative ("response"). In univariate analysis, RT-PCR PSA response was not significantly associated with TTP, but in multivariate analysis, RT-PCR PSA response was of borderline statistical significance in predicting TTP (hazard ratio, 0.41; 95% confidence interval, 0.16-1.01)., Conclusion: These results provide further confirmation that baseline RT-PCR PSA is a statistically significant predictor of TTP in hormone-refractory prostate cancer. Moreover, this is the first report to suggest that RT-PCR PSA response during chemotherapy treatment may predict TTP.

Purpose: Standard imaging studies are limited as outcome measures for patients with metastatic prostate cancer. We tested the hypothesis that serial fluorodeoxyglucose positron emission tomography (FDG-PET) scans can serve as an outcome measure for patients with castrate metastatic prostate cancer treated with antimicrotubule chemotherapy., Experimental Design: FDG-PET scans were done at baseline, 4, and 12 weeks of treatment. The average maximum standardized uptake value (SUVmaxavg) was measured in up to five lesions and was tested as the quantitative outcome measure. Prostate-specific antigen (PSA) at 4 weeks and PSA, bone scan, and soft tissue imaging at 12 weeks were considered standard outcome measures. The change in SUVmaxavg that distinguished clinically assessed progression from nonprogression was sought., Results: Twenty-two PET scans were reviewed and compared with PSA at 4 weeks; 18 PETs were compared at 12 weeks with standard outcome measures. Applying the PSA Working Group Consensus Criteria guideline that a 25% PSA increase constitutes progression to the SUVmaxavg, PET correctly identified the clinical status of 20 of 22 patients (91%) at 4 weeks and 17 of 18 patients at 12 weeks (94%). The accuracy of PET could be further optimized if a >33% increase in PSA and SUVmaxavg were used to define progression., Conclusion: FDG-PET is promising as an outcome measure in prostate cancer. As a single modality, it can show treatment effects that are usually described by a combination of PSA, bone scintigraphy, and soft tissue imaging. Preliminarily, a >33% increase in SUVmaxavg or the appearance of a new lesion optimally dichotomizes patients as progressors or nonprogressors.

Purpose: To evaluate the antitumor activity and safety of the epothilone B analog, ixabepilone, with or without estramustine phosphate (EMP), in chemotherapy-naive patients with progressive castrate metastatic prostate cancer., Patients and Methods: Patients were randomly assigned to receive ixabepilone (35 mg/m(2)) by intravenous infusion every 3 weeks with or without EMP 280 mg orally three times daily on days 1 to 5., Results: Between December 2001 and October 2003, 92 patients were enrolled and randomly assigned to treatment with ixabepilone alone (45 patients) or in combination with EMP (47 patients). Grades 3 and 4 toxicities experienced by more than 5% of patients included neutropenia (22%), fatigue (9%), and neuropathy (13%) on the ixabepilone arm, and neutropenia (29%), febrile neutropenia (9%), fatigue (9%), neuropathy (7%), and thrombosis (6%) on the ixabepilone + EMP arm. Post-treatment declines in prostate-specific antigen of > or = 50% were achieved in 21 of 44 patients (48%; 95% CI, 33% to 64%) on the ixabepilone arm, and 31 of 45 patients (69%; 95% CI, 55% to 82%) on the ixabepilone + EMP arm. In patients with measurable disease, partial responses were observed in eight of 25 patients (32%; 95% CI, 14% to 50%) on the ixabepilone arm, and 11 of 23 (48%; 95% CI, 27% to 68%) on the ixabepilone + EMP arm. Time to prostate-specific antigen progression was 4.4 months (95% CI, 3.1 to 6.9 months) on the ixabepilone-alone arm and 5.2 months (95% CI, 4.5 to 6.8 months) on the combination arm., Conclusion: Ixabepilone, with or without estramustine phosphate, is well tolerated and has antitumor activity in patients with castrate metastatic prostate cancer.

Because patients with hormone-refractory prostate carcinoma are a very diverse group, management of these patients represents a unique challenge. Despite much research, to the authors' knowledge few studies published to date have provided definitive treatment answers. The Society of Urologic Oncology (SUO) convened a multidisciplinary panel of urologists, oncologists, and radiation oncologists to develop a treatment algorithm for patients with hormone-refractory prostate carcinoma. The resulting treatment outline was based on a review of the literature review and on the expert opinions of the panelists. The current article provided a logical progression of treatment choices that included hormonal manipulations, chemotherapeutic options, and adjunctive therapies. Future clinical trials and therapies were also discussed by the authors. Management strategies should be targeted toward the individual patient. Although significant progress has been made in understanding and treating hormone-refractory prostate carcinoma, earlier interventions would be ideal and better therapeutic approaches to prolong survival are necessary.

The purpose of the study was to determine whether 3D proton magnetic resonance spectroscopic imaging (MRSI) can predict treatment outcome in high risk patients with prostate cancer. Endorectal magnetic resonance imaging (MRI) and 1H-MRSI were performed in 16 patients with prostate cancer who were considered high risk because of clinical stage T3-4, Gleason score>/=8, and/or prostate-specific antigen (PSA) level>20 ng/mL. Patients were treated with chemotherapy/hormone therapy, underwent radical prostatectomy (RP) or radiation therapy, and were followed for PSA relapse (follow-up, 19-43 months). The ratio of choline plus creatine to citrate was used to localize peripheral zone cancer. An MRSI risk score on a scale of 0-3 was derived from the volume and degree of metabolic abnormality. Magnetic resonance spectroscopic imaging risk score, MRI tumor/node (TN) stage, clinical stage, Gleason score, and PSA were used as predictors of pathologic stage in patients treated with RP (n=10) and PSA relapse in all patients. Magnetic resonance imaging TN stage (P<0.01) and MRSI risk score (P<0.05) correlated with pathologic stage, but clinical stage did not (P=0.35). Magnetic resonance imaging TN stage was the only significant predictor of PSA relapse in the univariate analysis (P<0.05). Although the MRSI risk score did not reach significance (P=0.13), 6 patients with a score<0.9 were relapse-free, whereas 7 of 10 patients with a score>0.9 relapsed. Magnetic resonance imaging and MRSI risk assessments agreed in 15 of 16 patients. These preliminary results suggest that tumor metabolic assessment may indicate treatment outcome in high-risk patients with prostate cancer. Although MRSI did not provide added prognostic value to MRI in this small number of patients, MRSI might increase the confidence of the clinician in assessing risk on MRI by contributing supporting metabolic data.

Background: Preclinical and clinical data have suggested that high-dose calcitriol (1,25-dihydroxycholecalciferol) has activity against prostate carcinoma. Pulse-dosed calcitriol and dexamethasone may maximize tolerability and efficacy. The authors examined the toxicity of pulse-dosed calcitriol with zoledronate and with the addition of dexamethasone at the time of disease progression., Methods: Patients with progressive prostate carcinoma were eligible for the current study. In cohorts of 3-6 patients, calcitriol was administered for 3 consecutive days per week, starting at a dose of 4 microg per day. Doses were escalated to 30 microg per day. Intravenous zoledronate (4 mg) was administered monthly. Dexamethasone could be added to the regimen at disease progression. Toxicities, markers of bone turnover, plasma calcitriol levels, and clinical outcomes were recorded., Results: Thirty-one patients were treated in cohorts that were defined by the calcitriol dose administered (4, 6, 8, 10, 14, 20, 24, or 30 microg). Seven patients received dexamethasone. Three patients had their doses reduced due to calcium-related laboratory findings. Patients tolerated therapy well, even in the 30 microg cohort; therefore, a maximum tolerated dose was not defined. Peak plasma levels observed in the 24 microg and 30 microg cohorts ranged from 391 to 968 pg/mL. Minimal antitumor effects were observed., Conclusions: Calcitriol was well tolerated at doses up to and including 30 microg 3 times per week in combination with intravenous zoledronate 4 mg monthly, with or without dexamethasone, in patients with progressive prostate carcinoma. Peak plasma levels in the 24 microg and 30 microg cohorts were greater than the levels associated with antitumor effects preclinically. Due to the cumbersome dosing schedule and the lack of significant activity observed, Phase II trials of this regimen are not planned., (Copyright 2004 American Cancer Society.)

Purpose: We determined the feasibility of radical prostatectomy after neoadjuvant chemohormonal therapy in locally advanced (stage T3 or greater) and/or high risk tumors (Gleason 8 to 10 and/or serum prostate specific antigen (PSA) greater than 20 ng/ml)., Materials and Methods: Enrollment criteria included clinical stage T1 to 2 with any Gleason grade and PSA greater than 20 ng/ml, clinical stage T3 to 4 with any serum PSA or Gleason grade, or any clinical stage with biopsy Gleason grade of 8 to 10 and any serum PSA. All patients received neoadjuvant hormonal therapy during chemotherapy (4 cycles of paclitaxel and carboplatin and estramustine) followed by radical prostatectomy. Nerve sparing was decided on an individual basis and a nerve graft was offered to those who underwent unilateral or bilateral nerve resection. Perioperative morbidity, mortality and delayed complications were assessed., Results: A total of 36 patients were enrolled. After chemohormonal therapy clinical stage was less in 39% of patients and greater in 36%. Bilateral nerve sparing was performed in 3 patients and the remaining 33 underwent either unilateral or bilateral neurovascular bundle resection with nerve grafts performed in 17 (52%). Deep vein thrombosis (22%) was the most frequent complication of chemotherapy. Minor postoperative complications occurred in 6 patients. At a median followup of 29 months (range 5 to 51) after radical prostatectomy 32 (89%) were continent and 5 (15%) preoperatively potent men remained potent. The positive surgical margin rate was 22%. Of all subjects 45% remain free from biochemical recurrence., Conclusions: Neoadjuvant chemohormonal therapy followed by radical prostatectomy can be performed with low morbidity. Positive surgical margin rates are low. This approach yielded good local control of disease, however impact on tumor recurrence and survival is not known.

Background: The authors determined the safety and efficacy of estramustine, docetaxel, and carboplatin with granulocyte-colony-stimulating factor (G-CSF) support in patients with hormone-refractory prostate carcinoma., Methods: In the current multicenter, cooperative group study, patients with advanced prostate carcinoma whose disease progressed despite androgen deprivation therapy were treated with a combination of oral estramustine(240 mg three times per day for 5 days), 70 mg/m2 of docetaxel, and carboplatin at a dose of (area under the curve) 5. G-CSF was used to minimize the neutropenia associated with this regimen. Each cycle was repeated every 21 days., Results: Forty patients were treated with a median of 7 cycles of therapy. Of the 34 evaluable patients with elevated pretreatment prostate-specific antigen (PSA) levels, 23 (68%) had a > or = 50% decline in PSA and 20 (59%) had a > or = 75% decline. Twenty-one patients had measurable disease, with 1 complete response (5%) and 10 partial responses (47%), for an overall measurable response rate of 52% (95% confidence interval [95% CI], 30-74%). The most common Grade 3 or Grade 4 toxicities (according to the National Cancer Institute Common Toxicity Criteria) included neutropenia in 23% of patients, thrombocytopenia in 13%, and fatigue in 13%. Febrile neutropenia occurred in 1 patient (3%). The overall median time to disease progression was 8.1 months (95% CI, 6-10 months) and the overall survival period was 19 months (95% CI, 13-26 months)., Conclusions: The combination of estramustine, docetaxel, and carboplatin with G-CSF support was found to have significant clinical activity with an acceptable toxicity profile in patients with progressive hormone-refractory prostate carcinoma., (Copyright 2003 American Cancer Society.)

Background: The combination of paclitaxel, oral estramustine phosphate (EMP), and carboplatin (TEC) has shown antitumor activity in patients with castrate, metastatic prostate carcinoma. To improve the therapeutic efficacy and reduce the toxicity of TEC, the authors substituted intravenous (i.v.) EMP for oral EMP based on single-agent studies demonstrating an improved safety profile with i.v. EMP., Methods: Patients with progressive, castrate, metastatic prostate carcinoma were treated with up to 6 4-week cycles of i.v. EMP (500-1500 mg/m(2) per week), paclitaxel (100 mg/m(2) per week), and carboplatin (target area under the curve = 6 mg/mL every 4 weeks)., Results: Thirty patients were treated in 6 dose cohorts. Deep venous thrombosis occurred in 5 of 30 patients (17%). Other common Grade 3/4 (according to National Cancer Institute Common Toxicity Criteria) toxicities included hepatic toxicity (23%) and leukopenia (24%). Posttherapy prostate specific antigen declines > 50% were seen in 18 of 30 patients (60%), and declines > 80% were seen in 15 of 30 patients (50%). Eleven of 17 patients (65%) with measurable soft tissue disease achieved a partial response. Four of 27 patients (15%) with osseous metastases demonstrated improvement on bone scan., Conclusions: Intravenous EMP was administered safely with paclitaxel and carboplatin and produced clinical outcomes similar to the outcomes achieved with the TEC regimen. Substitution of i.v. EMP for the oral formulation was found to result in a lower incidence of severe nausea but increased hepatic toxicity., (Copyright 2003 American Cancer Society.)

Given their novel mechanisms of action and relatively favorable toxicity profiles, differentiation agents have been the focus of much investigation in the field of oncology. Among the most well studied of these agents in prostate cancer have been the retinoids, vitamin D, peroxisome-proliferator-activated receptor gamma (PPARgamma) ligands, and, most recently, the histone deacetylase (HDAC) inhibitors. While the clinical activity of these agents has been limited, several obstacles to the development of these novel drugs have become apparent. A lack of validated measures of outcome and uncertainty regarding the appropriate disease states in which to test these agents have led to difficulty in trial design. Furthermore, a better understanding of the biologic targets and genes manipulated by these therapies is required such that more potent and selective drugs may be developed. By overcoming these obstacles, the full potential of this therapeutic class may be realized.

Objectives: In designing a Phase II trial, the acceptable clinical activity region for a new therapy is often developed using data from historically treated patients. This region incorrectly ignores the variability of this estimate, because the efficacy of the prior treatment lies somewhere around the estimate. The size of this interval is dependent on the sample size used. This report illustrates the use of a published method that accounts for this uncertainty and aids in the decision to proceed to a definitive trial., Methods: A historical data set of low-risk patients with progressive castrate metastatic prostate cancer and a group of similar patients treated in a Phase II chemotherapy trial were used. The 1-year Kaplan-Meier estimate of survival was obtained for both. This approach uses the 75% upper confidence bound of the 1-year survival probability from the historical data set to define the lower limit of acceptable clinical activity. Use of this bound makes the approach more conservative, and hence the decision to proceed to a Phase III trial more difficult., Results: In the low-risk historical patients, the 1-year Kaplan-Meier estimate of survival was 66.4% (75% upper confidence bound 71.0%). In the Phase II patients, the 1-year Kaplan-Meier estimate of survival was 89.5% (95% lower confidence bound 78.2%)., Conclusions: A hypothesis test using the 75% upper confidence bound to define the lower limit of acceptable clinical activity demonstrates that the 1-year survival probability on Taxol/estramustine/carboplatin is greater than that of the historical population, and hence should be taken into a definitive trial. The design provides investigators increased confidence in making this decision.

Purpose: To develop a pretreatment prognostic model for survival of patients with progressive metastatic prostate cancer after castration using parameters that are measured during routine clinical management., Patients and Methods: Pretreatment clinical and biochemical determinants from 409 patients enrolled onto 19 consecutive therapeutic protocols from June 1989 through January 2000 were evaluated. The factors selected were age, Karnofsky performance status (KPS), hemoglobin (HGB), prostate-specific antigen (PSA), lactate dehydrogenase (LDH), alkaline phosphatase (ALK), and albumin. These factors were combined in an accelerated failure time regression model to produce a nomogram to predict median, 1-year, and 2-year survival. The nomogram was validated internally and externally using data from a multicenter randomized trial of suramin plus hydrocortisone versus hydrocortisone alone., Results: The median survival of the entire group was 15.8 months (range, 0.9 to 77.8 months); 87% have died. In multivariable analysis, KPS, HGB, ALK, albumin, and LDH were significantly associated with survival (P <.05), whereas age and PSA were not. All seven factors were included in the nomogram. When applied to the external validation data set, the nomogram achieved a concordance index of 0.67. Calibration plots suggested that the nomogram was well calibrated for all predictions., Conclusion: A nomogram derived from pretreatment parameters that are measured on a routine basis was constructed. It can be used to predict the median, 1-year, and 2-year survival of patients with progressive castrate metastatic disease with reasonable accuracy. The information is useful to assess prognosis, guide treatment selection, and design clinical trials.