PMCC PMCC

Search tips
Search criteria

Advanced
Results 1-12 (12)
 

Clipboard (0)
None

Select a Filter Below

Journals
Year of Publication
Document Types
1.  Denosumab and Bone Metastasis–Free Survival in Men With Nonmetastatic Castration-Resistant Prostate Cancer: Exploratory Analyses by Baseline Prostate-Specific Antigen Doubling Time 
Journal of Clinical Oncology  2013;31(30):3800-3806.
Purpose
Denosumab, an anti–RANK ligand monoclonal antibody, significantly increases bone metastasis–free survival (BMFS; hazard ratio [HR], 0.85; P = .028) and delays time to first bone metastasis in men with nonmetastatic castration-resistant prostate cancer (CRPC) and baseline prostate-specific antigen (PSA) ≥ 8.0 ng/mL and/or PSA doubling time (PSADT) ≤ 10.0 months. To identify men at greatest risk for bone metastasis or death, we evaluated relationships between PSA and PSADT with BMFS in the placebo group and the efficacy and safety of denosumab in men with PSADT ≤ 10, ≤ 6, and ≤ 4 months.
Patients and Methods
A total of 1,432 men with nonmetastatic CRPC were randomly assigned 1:1 to monthly subcutaneous denosumab 120 mg or placebo. Enrollment began February 2006; primary analysis cutoff was July 2010, when approximately 660 men were anticipated to have developed bone metastases or died.
Results
In the placebo group, shorter BMFS was observed as PSADT decreased below 8 months. In analyses by shorter baseline PSADT, denosumab consistently increased BMFS by a median of 6.0, 7.2, and 7.5 months among men with PSADT ≤ 10 (HR, 0.84; P = .042), ≤ 6 (HR, 0.77; P = .006), and ≤ 4 months (HR, 0.71; P = .004), respectively. Denosumab also consistently increased time to bone metastasis by PSADT subset. No difference in survival was observed between treatment groups for the overall study population or PSADT subsets.
Conclusion
Patients with shorter PSADT are at greater risk for bone metastasis or death. Denosumab consistently improves BMFS in men with shorter PSADT and seems to have the greatest treatment effects in men at high risk for progression.
doi:10.1200/JCO.2012.44.6716
PMCID: PMC3795889  PMID: 24043751
2.  New and Emerging Therapies for Bone Metastases in Genitourinary Cancers 
European urology  2012;63(2):309-320.
Bone metastases are a common feature of advanced genitourinary malignancies and a prominent cause of morbidity and mortality. Clinical manifestations can include pain, hypercalcemia, pathologic fractures, and spinal cord compression. Optimal systemic therapy for the skeletal component of these cancers often features a combination of disease-specific therapy and bone-targeted therapy. Some agents such as the radiopharmaceutical radium-223 blur the line between those two categories. Osteoclast inhibition is a validated strategy in the management of selected patients with bone metastases and can best be accomplished with one of two agents. Zoledronic acid is the most potent available bisphosphonate and is approved for the prevention of skeletal events due to solid tumors metastatic to bone. Denosumab is a fully human monoclonal antibody that binds and inactivates receptor activator of nuclear factor-kappa-B ligand and is approved for the same indication. Radiopharmaceuticals represent a distinct strategy. Beta-emitters such as strontium-89 and samarium-153 can be effective for the palliation of pain due to bone metastases, but their use is often limited by bone marrow suppression. The alpha-emitting radiopharmaceutical radium-223 has recently been shown to improve overall survival and prevent skeletal events in selected men with castration-resistant prostate cancer metastatic to bone. Multiple ongoing clinical trials are designed to examine the potential for therapeutic inhibition of additional targets such as Src and hepatocyte growth factor (MET). This review discusses the incidence, pathophysiology, and management of bone metastases in the most prevalent genitourinary malignancies.
doi:10.1016/j.eururo.2012.10.007
PMCID: PMC3661203  PMID: 23201471
3.  Targeting CDC25C, PLK1 and CHEK1 to overcome Docetaxel resistance induced by loss of LZTS1 in prostate cancer 
Oncotarget  2014;5(3):667-678.
Docetaxel is used as a standard treatment in patients with metastatic castration-resistant prostate cancer. However, a large subset of patients develops resistance. Understanding resistance mechanisms, which are largely unknown, will allow identification of predictive biomarkers and therapeutic targets. We established resistant IGR-CaP1 prostate cancer cell lines for different doses of Docetaxel. We investigated gene expression profiles by microarray analyses in these cell lines and generated a signature of 99 highly differentially expressed genes potentially implicated in chemoresistance. We focused on the role of the cell cycle regulator LZTS1, which was under-expressed in the Docetaxel-resistant cell lines, its inhibition resulting from the promoter methylation. Knockdown of LZTS1 in parental cells with siRNA showed that LZTS1 plays a role in the acquisition of the resistant phenotype. Furthermore, we observed that targeting CDC25C, a partner of LZTS1, with the NSC663284 inhibitor specifically killed the Docetaxel-resistant cells. To further investigate the role of CDC25C, we used inhibitors of the mitotic kinases that regulate CDC25C. Inhibition of CHEK1 and PLK1 induced growth arrest and cell death in the resistant cells. Our findings identify an important role of LZTS1 through its regulation of CDC25C in Docetaxel resistance in prostate cancer and suggest that CDC25C, or the mitotic kinases CHEK1 and PLK1, could be efficient therapeutic targets to overcome Docetaxel resistance
PMCID: PMC3996665  PMID: 24525428
Prostate cancer; chemoresistance; LZTS1; Cdc25c; PLK1; CHEK1
4.  Randomized Phase 3 Trial of Abiraterone Acetate in Men with Metastatic Castration-Resistant Prostate Cancer and No Prior Chemotherapy 
The New England journal of medicine  2012;368(2):138-148.
Background
Abiraterone acetate, an androgen biosynthesis inhibitor, improves overall survival (OS) in metastatic castration-resistant prostate cancer (mCRPC) post-chemotherapy. Many mCRPC patients never receive chemotherapy and thus cannot benefit from abiraterone acetate; we evaluated this agent in mCRPC patients who had not received chemotherapy.
Methods
In this double-blind study, 1088 patients were randomized 1:1 to abiraterone acetate (1000 mg) plus prednisone (5 mg twice daily) or placebo plus prednisone. Co-primary end points were radiographic progression-free survival (rPFS) and OS. Secondary end points measured clinically relevant landmarks of mCRPC progression. Patient-reported outcomes included pain progression and quality of life.
Results
The study was unblinded after a planned interim analysis (IA) at 43% of OS events. Treatment with abiraterone acetate-prednisone resulted in a 57% reduction in the risk of radiographic progression or death (hazard ratio [HR], 0.43; 95% confidence interval [CI]: 0.35 to 0.52; P<0.001; 13% OS events IA) and an estimated 25% decrease in the risk of death (HR, 0.75; 95% CI: 0.61 to 0.93; P=0.009; 43% OS events IA). Secondary end points supported superiority of abiraterone acetate-prednisone: time to cytotoxic chemotherapy initiation, opiate use for cancer-related pain, prostate-specific antigen progression (all P<0.001) and performance status deterioration (P=0.005). Self-reported time to pain progression and patient functional status degradation favored abiraterone acetate-prednisone (P=0.05 and P=0.003). Grade 3/4 mineralocorticoid-related adverse events and liver function test abnormalities were more common with abiraterone acetate-prednisone.
Conclusions
Abiraterone acetate produces OS and rPFS benefits, as well as significant delays in clinical deterioration and initiation of chemotherapy, in mCRPC.
doi:10.1056/NEJMoa1209096
PMCID: PMC3683570  PMID: 23228172
Abiraterone acetate; prednisone; metastatic castration-resistant prostate cancer; androgen; CYP17
5.  Detection of Previously Unidentified Metastatic Disease as a Leading Cause of Screening Failure in a Phase III Trial of Zibotentan Versus Placebo in Patients with Nonmetastatic, Castration Resistant Prostate Cancer 
The Journal of urology  2012;188(1):103-109.
Purpose
Understanding the extent of disease in asymptomatic patients with castration resistant prostate cancer is important when making treatment decisions and designing clinical trials. The ENTHUSE M0 (ENdoTHelin A USE) trial (NCT00626548) was a large phase III study comparing the endothelin A receptor antagonist zibotentan with placebo in patients with nonmetastatic, castration resistant prostate cancer. The study was stopped prematurely after early efficacy review indicated that it was unlikely to meet its co-primary objectives of improved overall and progression-free survival vs placebo. Screening failed in an unexpectedly high number of patients. We investigated this screening failure rate to promote better classification of patients thought to have nonmetastatic castration resistant prostate cancer and inform the design of future clinical trials in this setting.
Materials and Methods
The number of patients enrolled in and subsequently excluded from study was analyzed by geographic region and by the specialty of the investigating clinician (oncology or urology) who enrolled the study patients.
Results
Of 2,577 patients enrolled in a total of 350 hospital based centers in 39 countries screening failed in 1,155 (45%). The most common reason for screening failure was the detection of metastatic disease in 32% of all screened patients and in 71% of those in whom screening failed. The leading reasons for failed screening did not differ between investigator specialties overall or by geographic region.
Conclusions
The high frequency of asymptomatic metastasis in men thought to have nonmetastatic, castration resistant prostate cancer highlights the importance of periodic staging assessments for the condition. Optimal treatment modalities may differ for metastatic and nonmetastatic disease.
doi:10.1016/j.juro.2012.03.008
PMCID: PMC3473078  PMID: 22583636
prostate; prostatic neoplasms; neoplasm metastasis; mass screening; ZD4054
6.  Denosumab and Bone Metastasis-Free Survival in Men With Castration-Resistant Prostate Cancer: Results of a Global Phase 3, Randomised, Placebo-Controlled Trial 
Lancet  2011;379(9810):39-46.
Background
Bone metastases are a major cause of morbidity and mortality in men with prostate cancer. Preclinical studies suggest that osteoclast inhibition may prevent bone metastases. This phase 3 study evaluated denosumab, a fully human anti-RANKL monoclonal antibody, to prevent bone metastasis or death from any cause in men with non-metastatic castration-resistant prostate cancer (CRPC).
Methods
Men with non-metastatic CRPC at high risk for bone metastasis (PSA ≥8.0 ng/mL and/or PSA doubling time ≤10.0 months) were enrolled in 319 centers from 30 countries. Patients were randomised 1:1 in blinded fashion using an interactive voice response system to receive monthly subcutaneous denosumab 120 mg or placebo. The primary endpoint was bone metastasis-free survival, a composite endpoint determined by time to first occurrence of bone metastasis (symptomatic or asymptomatic) or death.
Results
1432 patients were randomised, 716 to receive denosumab and 716 to receive placebo. Denosumab significantly increased bone metastasis-free survival by a median of 4.2 months over placebo (hazard ratio 0.85 [0.73–0.98]; P=0.028). Denosumab also significantly delayed time to first bone metastasis (hazard ratio 0.84 [0.71–0.98]; P=0.032). Overall survival was similar between groups (hazard ratio 1.01 [0.85–1.20]; P=0.91). Rates of adverse events (AEs) and serious AEs were generally similar between groups, except for osteonecrosis of jaw (ONJ) and hypocalcemia. Yearly cumulative incidence of ONJ for denosumab was: 1%, 3%, 4% in years 1, 2, 3, respectively; overall, less than 5% (n=33). Hypocalcemia occurred in under 2% (n=12) of denosumab and under 1% (n=2) of placebo patients. The blinded treatment phase has been completed.
Conclusion
In men with CRPC, denosumab significantly prolonged bone metastasis-free survival and delayed time to bone metastasis. This is the first large randomised study to demonstrate that targeting the bone microenvironment prevents bone metastasis in men with prostate cancer.
doi:10.1016/S0140-6736(11)61226-9
PMCID: PMC3671878  PMID: 22093187
urology/prostate disease; denosumab; prostate cancer; prevention; bone metastasis; survival; hormone refractory; castration-resistant
7.  Abiraterone and Increased Survival in Metastatic Prostate Cancer 
The New England journal of medicine  2011;364(21):1995-2005.
BACKGROUND
Biosynthesis of extragonadal androgen may contribute to the progression of castration-resistant prostate cancer. We evaluated whether abiraterone acetate, an inhibitor of androgen biosynthesis, prolongs overall survival among patients with metastatic castration-resistant prostate cancer who have received chemotherapy.
METHODS
We randomly assigned, in a 2:1 ratio, 1195 patients who had previously received docetaxel to receive 5 mg of prednisone twice daily with either 1000 mg of abiraterone acetate (797 patients) or placebo (398 patients). The primary end point was overall survival. The secondary end points included time to prostate-specific antigen (PSA) progression (elevation in the PSA level according to prespecified criteria), progression-free survival according to radiologic findings based on prespecified criteria, and the PSA response rate.
RESULTS
After a median follow-up of 12.8 months, overall survival was longer in the abiraterone acetate–prednisone group than in the placebo–prednisone group (14.8 months vs. 10.9 months; hazard ratio, 0.65; 95% confidence interval, 0.54 to 0.77; P<0.001). Data were unblinded at the interim analysis, since these results exceeded the preplanned criteria for study termination. All secondary end points, including time to PSA progression (10.2 vs. 6.6 months; P<0.001), progression-free survival (5.6 months vs. 3.6 months; P<0.001), and PSA response rate (29% vs. 6%, P<0.001), favored the treatment group. Mineralocorticoid-related adverse events, including fluid retention, hypertension, and hypokalemia, were more frequently reported in the abiraterone acetate–prednisone group than in the placebo–prednisone group.
CONCLUSIONS
The inhibition of androgen biosynthesis by abiraterone acetate prolonged overall survival among patients with metastatic castration-resistant prostate cancer who previously received chemotherapy. (Funded by Cougar Biotechnology; COU-AA-301 ClinicalTrials.gov number, NCT00638690.)
doi:10.1056/NEJMoa1014618
PMCID: PMC3471149  PMID: 21612468
8.  Once-daily Dasatinib: Expansion of Phase II Study Evaluating Safety and Efficacy of Dasatinib in Patients With Metastatic Castration-resistant Prostate Cancer 
Urology  2011;77(5):1166-1171.
OBJECTIVES
To determine the activity and tolerability of 100-mg once-daily (QD) dasatinib in patients with metastatic castration-resistance prostate cancer (CRPC). Dasatinib, an oral Src family kinase inhibitor, has demonstrated both preclinical and clinical activity with twice-daily dosing in patients with metastatic CRPC.
METHODS
Chemotherapy-naive men with metastatic CRPC and increasing prostate-specific antigen levels were treated with dasatinib 100 mg QD. The primary measurement was a composite lack of disease progression, according to the Prostate Cancer Working Group 2 criteria, determined every 12 weeks during the study. The other analyses included changes in the prostate-specific antigen level, bone lesions, soft tissue disease, and bone turnover markers (urine N-telopeptide and bone alkaline phosphatase).
RESULTS
The present trial was designed before the publication of the recent Prostate Cancer Working Group 2 criteria; however, the analyses are presented to conform to the updated guidelines. A total of 48 patients received dasatinib. A lack of disease progression was observed in 21 patients (44%) at week 12 and in 8 (17%) at week 24. Urine N-telopeptide was reduced by ≥40% from baseline in 22 (51%) of 43 patients, and bone alkaline phosphatase was decreased in 26 (59%) of 44 patients. Dasatinib was well-tolerated, with only 6 patients (13%) with drug-related grade 3–4 adverse events and 3 (6%) with grade 3 adverse events. The most common treatment-related adverse events (≥20%) were fatigue, nausea, diarrhea, headache, and anorexia.
CONCLUSIONS
Dasatinib 100 mg QD has a favorable safety profile and maintains a similar degree of activity as the previously reported twice-daily dosing schedules. These data support additional study of dasatinib 100 mg QD for metastatic CRPC.
doi:10.1016/j.urology.2011.01.006
PMCID: PMC3394099  PMID: 21539969
9.  The IGR-CaP1 Xenograft Model Recapitulates Mixed Osteolytic/Blastic Bone Lesions Observed in Metastatic Prostate Cancer12 
Neoplasia (New York, N.Y.)  2012;14(5):376-387.
Bone metastases have a devastating impact on quality of life and bone pain in patients with prostate cancer and decrease survival. Animal models are important tools in investigating the pathogenesis of the disease and in developing treatment strategies for bone metastases, but few animal models recapitulate spontaneous clinical bone metastatic spread. In the present study, IGR-CaP1, a new cell line derived from primary prostate cancer, was stably transduced with a luciferase-expressing viral vector to monitor tumor growth in mice using bioluminescence imaging. The IGR-CaP1 tumors grew when subcutaneously injected or when orthotopically implanted, reconstituted the prostate adenocarcinoma with glandular acini-like structures, and could disseminate to the liver and lung. Bone lesions were detected using bioluminescence imaging after direct intratibial or intracardiac injections. Anatomic bone structure assessed using high-resolution computed tomographic scans showed both lytic and osteoblastic lesions. Technetium Tc 99m methylene diphosphonate micro single-photon emission computed tomography confirmed the mixed nature of the lesions and the intensive bone remodeling. We also identified an expression signature for responsiveness of IGR-CaP1 cells to the bone microenvironment, namely expression of CXCR4, MMP-9, Runx2, osteopontin, osteoprotegerin, ADAMTS14, FGFBP2, and HBB. The IGR-CaP1 cell line is a unique model derived from a primary tumor, which can reconstitute human prostate adenocarcinoma in animals and generate experimental bone metastases, providing a novel means for understanding the mechanisms of bone metastasis progression and allowing preclinical testing of new therapies.
PMCID: PMC3384425  PMID: 22745584
10.  Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study 
Lancet  2011;377(9768):813-822.
Summary
Background
Bone metastases are a major burden in men with advanced prostate cancer. We compared denosumab, a human monoclonal antibody against RANKL, with zoledronic acid for prevention of skeletal-related events in men with bone metastases from castration-resistant prostate cancer.
Methods
In this phase 3 study, men with castration-resistant prostate cancer and no previous exposure to intravenous bisphosphonate were enrolled from 342 centres in 39 countries. An interactive voice response system was used to assign patients (1:1 ratio), according to a computer-generated randomisation sequence, to receive 120 mg subcutaneous denosumab plus intravenous placebo, or 4 mg intravenous zoledronic acid plus subcutaneous placebo, every 4 weeks until the primary analysis cutoff date. Randomisation was stratified by previous skeletal-related event, prostate-specific antigen concentration, and chemotherapy for prostate cancer within 6 weeks before randomisation. Supplemental calcium and vitamin D were strongly recommended. Patients, study staff, and investigators were masked to treatment assignment. The primary endpoint was time to first on-study skeletal-related event (pathological fracture, radiation therapy, surgery to bone, or spinal cord compression), and was assessed for non-inferiority. The same outcome was further assessed for superiority as a secondary endpoint. Efficacy analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00321620, and has been completed.
Findings
1904 patients were randomised, of whom 950 assigned to denosumab and 951 assigned to receive zoledronic acid were eligible for the efficacy analysis. Median duration on study at primary analysis cutoff date was 12·2 months (IQR 5·9–18·5) for patients on denosumab and 11·2 months (IQR 5·6–17·4) for those on zoledronic acid. Median time to first on-study skeletal-related event was 20·7 months (95% CI 18·8–24·9) with denosumab compared with 17·1 months (15·0–19·4) with zoledronic acid (hazard ratio 0·82, 95% CI 0·71–0·95; p=0·0002 for non-inferiority; p=0·008 for superiority). Adverse events were recorded in 916 patients (97%) on denosumab and 918 patients (97%) on zoledronic acid, and serious adverse events were recorded in 594 patients (63%) on denosumab and 568 patients (60%) on zoledronic acid. More events of hypocalcaemia occurred in the denosumab group (121 [13%]) than in the zoledronic acid group (55 [6%]; p<0·0001). Osteonecrosis of the jaw occurred infrequently (22 [2%] vs 12 [1%]; p=0·09).
Interpretation
Denosumab was better than zoledronic acid for prevention of skeletal-related events, and potentially represents a novel treatment option in men with bone metastases from castration-resistant prostate cancer.
Funding
Amgen.
doi:10.1016/S0140-6736(10)62344-6
PMCID: PMC3090685  PMID: 21353695
11.  Biological characterization of two xenografts derived from human CUPs (carcinomas of unknown primary) 
BMC Cancer  2007;7:225.
Background
Carcinomas of unknown primary site (CUP) are epithelial malignancies revealed by metastatic lesions in the absence of any detectable primary tumor. Although they often adopt an aggressive clinical pattern, their basic biology remains poorly understood. Laboratory research on their biology have been hampered so far by the absence of cell lines representative of CUPs.
Methods
We attempted xenografts of CUP clinical specimens in immunodeficient mice and subsequent in vitro culture of transplanted malignant cells. Whenever possible, malignant xenografted or cultured cells were characterized by microsatellite genotyping, immunohistology, electron microscopy, multifish chromosome analysis and search of TP 53 gene mutations.
Results
Successful xenografts were achieved in 2 cases out of 4. One of them (Capi1) was lost after 3 passages whereas the other one (Capi3) has been adapted to in vitro culture and is currently available to the scientific community with reliable identification based on microsatellite genotyping. Both Capi1 and Capi3 have histological characteristics of adenocarcinomas and display intense expression of EMA, CEA and cytokeratin 7. Multifish chromosome analysis demonstrated a translocation involving chromosomes 4 and 21 in both specimens. Distinct rare missense mutations of the TP53 gene were detected in Capi1 (codon 312) and Capi3 (codon 181); the codon 181 mutation is consistent with a previously reported similar finding in a small series of CUP specimens. Finally, intense membrane expression of c-kit was recorded in Capi3.
Conclusion
Our data suggest that xenografted tumors can be obtained from a substantial fraction of CUP clinical specimens. The hypothesis of a preferential association of CUPs with TP 53 mutations of codon 181 deserves further investigations. The Capi3 cell line will be a useful tool for assessment of novel c-kit inhibitors.
doi:10.1186/1471-2407-7-225
PMCID: PMC2241840  PMID: 18088404
12.  Enzalutamide in European and North American men participating in the AFFIRM trial 
Bju International  2014;115(1):41-49.
Objective
To explore any differences in efficacy and safety outcomes between European (EU) (n = 684) and North American (NA) (n = 395) patients in the AFFIRM trial (NCT00974311).
Patients and Methods
Phase III, double-blind, placebo-controlled, multinational AFFIRM trial in men with metastatic castration-resistant prostate cancer (mCRPC) after docetaxel. Participants were randomly assigned in a 2:1 ratio to receive oral enzalutamide 160 mg/day or placebo. The primary end point was overall survival (OS) in a post hoc analysis.
Results
Enzalutamide significantly improved OS compared with placebo in both EU and NA patients. The median OS in EU patients was longer than NA patients in both treatment groups. However, the relative treatment effect, expressed as hazard ratio and 95% confidence interval, was similar in both regions: 0.64 (0.50, 0.82) for EU and 0.63 (0.47, 0.83) for NA. Significant improvements in other end points further confirmed the benefit of enzalutamide over placebo in patients from both regions. The tolerability profile of enzalutamide was comparable between EU and NA patients, with fatigue and nausea the most common adverse events. Four EU patients (4/461 enzalutamide-treated, 0.87%) and one NA patient (1/263 enzalutamide-treated, 0.38%) had seizures. The difference in median OS was related in part to the timing of development of mCRPC and baseline demographics on study entry.
Conclusion
This post hoc exploratory analysis of the AFFIRM trial showed a consistent OS benefit for enzalutamide in men with mCRPC who had previously progressed on docetaxel in both NA- and EU-treated patients, although the median OS was higher in EU relative to NA patients. Efficacy benefits were consistent across end points, with a comparable safety profile in both regions.
doi:10.1111/bju.12898
PMCID: PMC4312486  PMID: 25123978
androgen receptor inhibitor; enzalutamide; metastatic castration-resistant prostate cancer

Results 1-12 (12)