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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.  Toremifene Improves Lipid Profiles in Men Receiving Androgen-Deprivation Therapy for Prostate Cancer: Interim Analysis of a Multicenter Phase III Study 
Purpose
Androgen-deprivation therapy (ADT) is associated with greater risk of incident coronary heart disease and hospital admission for myocardial infarction; treatment-related increases in serum lipids may contribute to greater cardiovascular disease risk. We evaluated the effects of toremifene, a selective estrogen-receptor modulator, on fasting serum lipid levels in men receiving ADT for prostate cancer.
Patients and Methods
In an ongoing, multicenter, double-blind, placebo-controlled phase III fracture-prevention study, 1,389 men receiving ADT for prostate cancer were randomly assigned to receive toremifene (80 mg/d) or placebo. In this interim analysis of 188 patients, changes in fasting serum lipids from baseline to month 12 were compared between the placebo and toremifene groups.
Results
Changes in serum lipids differed significantly between the groups. Mean (± SE) total cholesterol decreased by 1.0% ± 1.7% from baseline to month 12 in the placebo group and decreased by 8.1% ± 1.4% in the toremifene group (P = .001 for between group comparison). Low-density lipoprotein (LDL) cholesterol increased by 0.8% ± 2.5% in the placebo group and decreased by 8.2% ± 2.5% in the toremifene group (P = .003). In contrast, high-density lipoprotein (HDL) cholesterol decreased by 4.9% ± 1.2% in the placebo group and increased by 0.5% ± 2.2% in the toremifene group (P = .018). Triglycerides increased by 6.9% ± 4.2% in the placebo group and decreased by 13.2% ± 3.6% in the toremifene group (P = .003).
Conclusion
Toremifene significantly decreased total cholesterol, LDL cholesterol, and triglycerides, and increased HDL cholesterol in men receiving ADT for prostate cancer.
doi:10.1200/JCO.2007.13.5517
PMCID: PMC3049948  PMID: 18398147
3.  Sarcopenia During Androgen-Deprivation Therapy for Prostate Cancer 
Journal of Clinical Oncology  2012;30(26):3271-3276.
Purpose
To characterize changes in lean body mass (LBM) in men with prostate cancer receiving androgen-deprivation therapy (ADT).
Patients and Methods
We prospectively evaluated LBM in a prespecified substudy of a randomized controlled trial of denosumab to prevent fractures in men receiving ADT for nonmetastatic prostate cancer. LBM was measured by total-body dual-energy x-ray absorptiometry at study baseline and at 12, 24, and 36 months. The analyses included 252 patients (132, denosumab; 120, placebo) with a baseline and at least one on-study LBM assessment. Patients were stratified by age (< 70 v ≥ 70 years) and by ADT duration (≤ 6 v > 6 months).
Results
Median ADT duration was 20.4 months at study baseline. Mean LBM decreased significantly from baseline, by 1.0% at month 12 (95% CI, 0.4% to 1.5%; P < .001; n = 248), by 2.1% at month 24 (95% CI, 1.5% to 2.7%; P < .001; n = 205), and by 2.4% at month 36 (95% CI, 1.6% to 3.2%; P < .001; n = 168). Men age ≥ 70 years (n = 127) had significantly greater changes in LBM at all measured time points than younger men. At 36 months, LBM decreased by 2.8% in men age ≥ 70 years and by 0.9% in younger men (P = .035). Men with ≤ 6 months of ADT at study entry (n = 36) had a greater rate of decrease in LBM compared with men who had received more than 6 months of ADT at study entry (3.7% v 2.0%; P = .0645).
Conclusion
In men receiving ADT, LBM decreased significantly after 12, 24, and 36 months.
doi:10.1200/JCO.2011.38.8850
PMCID: PMC3434987  PMID: 22649143
4.  Cabozantinib in Patients With Advanced Prostate Cancer: Results of a Phase II Randomized Discontinuation Trial 
Journal of Clinical Oncology  2012;31(4):412-419.
Purpose
Cabozantinib (XL184) is an orally bioavailable tyrosine kinase inhibitor with activity against MET and vascular endothelial growth factor receptor 2. We evaluated the activity of cabozantinib in patients with castration-resistant prostate cancer (CRPC) in a phase II randomized discontinuation trial with an expansion cohort.
Patients and Methods
Patients received 100 mg of cabozantinib daily. Those with stable disease per RECIST at 12 weeks were randomly assigned to cabozantinib or placebo. Primary end points were objective response rate at 12 weeks and progression-free survival (PFS) after random assignment.
Results
One hundred seventy-one men with CRPC were enrolled. Random assignment was halted early based on the observed activity of cabozantinib. Seventy-two percent of patients had regression in soft tissue lesions, whereas 68% of evaluable patients had improvement on bone scan, including complete resolution in 12%. The objective response rate at 12 weeks was 5%, with stable disease in 75% of patients. Thirty-one patients with stable disease at week 12 were randomly assigned. Median PFS was 23.9 weeks (95% CI, 10.7 to 62.4 weeks) with cabozantinib and 5.9 weeks (95% CI, 5.4 to 6.6 weeks) with placebo (hazard ratio, 0.12; P < .001). Serum total alkaline phosphatase and plasma cross-linked C-terminal telopeptide of type I collagen were reduced by ≥ 50% in 57% of evaluable patients. On retrospective review, bone pain improved in 67% of evaluable patients, with a decrease in narcotic use in 56%. The most common grade 3 adverse events were fatigue (16%), hypertension (12%), and hand-foot syndrome (8%).
Conclusion
Cabozantinib has clinical activity in men with CRPC, including reduction of soft tissue lesions, improvement in PFS, resolution of bone scans, and reductions in bone turnover markers, pain, and narcotic use.
doi:10.1200/JCO.2012.45.0494
PMCID: PMC4110249  PMID: 23169517
5.  Bone Targeted Agents: Preventing skeletal complications in prostate cancer 
Summary
Prostate cancer is both the most common malignancy and the most common cause of cancer death in men. In the United States, there were approximately 217,730 new prostate cancer diagnoses and more than 32,050 deaths in 2010 1. Skeletal complications occur at various points during the disease course, either due to bone metastases directly, or as an unintended consequence of androgen deprivation therapy (ADT). Up to 90% of men with metastatic castration resistant prostate cancer (CRPC) develop bone metastases2,3. Bone metastases are associated with pathologic fractures, spinal cord compression, and bone pain and can require narcotics or palliative radiation for pain relief. Additionally, ADT results in bone loss and fragility fractures.
This review describes the biology of bone metastases, skeletal morbidity in men with prostate cancer, and recent advances in bone targeted therapies to prevent skeletal complications of prostate cancer.
doi:10.1016/j.ucl.2012.07.009
PMCID: PMC3721069  PMID: 23084529
zoledronic acid; denosumab; prostate cancer; bone metastasis; skeletal-related events; Prostate cancer; skeletal complications; bone; side effects of therapy; ADT
6.  Gonadotropin-releasing hormone Blockers and Cardiovascular Disease Risk: Analyses of Prospective Clinical Trials of Degarelix 
The Journal of urology  2011;186(5):1835-1842.
Purpose
To investigate associations of baseline CVD risk profile, dosing regimen and treatment duration with incident CVD events during androgen deprivation therapy with degarelix in patients with PCa.
Materials and Methods
Data from 1704 subjects who participated in 9 clinical trials was pooled for the analysis. Subjects received treatment with either monthly (20-240 mg) or 3-monthly doses (240-480 mg) of degarelix for an average of 22 months (up to 66 months). Endpoints were ischemic heart disease, cerebrovascular disorders, arterial thrombotic/embolic events, and claudication
Results
First-time CVD events were reported in 92 subjects in the year prior to study entry and 168 subjects after degarelix treatment. Event rates were similar before and after degarelix treatment (5.5 vs. 6.1 per 100 person-years; P=0.45) in the total population and in the subset of men without baseline CVD (5.6 vs. 4.3 per 100 person-years; p=0.11). In contrast, event rates were higher after degarelix treatment (5.3 to 10.5 events per 100 person-years; p=0.0013) in the subset of men with CVD at baseline. In multivariate analysis, CVD at baseline was the strongest independent predictor of events during treatment followed by older age, abstinence to alcohol and obesity (all p<0.05). Dose and schedule of degarelix treatment were not independently associated with CVD events.
Conclusions
In men with PCa, observed rates of CVD events were similar before and after degarelix treatment. Events during degarelix treatment were largely confined to those with pre-existing CVD and further modulated by age and modifiable risk factors.
doi:10.1016/j.juro.2011.07.035
PMCID: PMC3712275  PMID: 21944083
cardiovascular events; degarelix; long-term treatment; predictors; prostate cancer patients
7.  Toremifene Decreases Vertebral Fractures in Men Younger Than 80 Years Receiving Androgen Deprivation Therapy for Prostate Cancer 
The Journal of urology  2011;186(6):2239-2244.
Purpose
Androgen deprivation therapy (ADT) is associated with increased fracture risk. In a recent Phase III trial, toremifene significantly decreased vertebral fractures in men receiving ADT. Similar to other selective estrogen receptor modulators, toremifene was associated with an increase in venous thromboembolic events (VTEs), with the greatest risk in men aged ≥80 years. This post hoc analysis evaluated the efficacy and safety of toremifene in men aged <80 years.
Materials and Methods
This analysis included 847 subjects aged <80 years; 430 received toremifene 80 mg by mouth daily and 417 received placebo for up to 24 months. The primary endpoint was new vertebral fractures. Secondary endpoints included fragility fractures, bone mineral density (BMD), and safety.
Results
Compared with placebo, toremifene decreased the relative risk of new vertebral fractures by 79.5% (95% CI, 29.8%–94.0%; P<0.005). New vertebral fracture incidence was 1.0% with toremifene and 4.8% with placebo (absolute risk reduction, 3.8%). Compared with placebo, toremifene significantly reduced the incidence of a nontraumatic fracture or >7% bone loss by 24 months (P<0.0001). Toremifene also significantly increased BMD at all measured sites (P<0.001 for all comparisons). The incidence of VTEs was similar in the toremifene and placebo groups (2.1% vs 1.0%, respectively; P=0.26). Rates of other adverse events were also similar between groups.
Conclusions
Toremifene significantly decreased new vertebral fractures in men aged <80 years receiving ADT for prostate cancer. The risk of VTEs was lower than in the overall study population, suggesting an improved benefit–risk profile in younger men.
doi:10.1016/j.juro.2011.07.090
PMCID: PMC3671875  PMID: 22014807
androgen deprivation therapy; osteoporosis; prostate cancer; selective estrogen receptor modulators; toremifene
8.  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
9.  Risk of Myocardial Infarction or Diabetes During Androgen Deprivation Therapy for Prostate Cancer: Does Comorbidity Influence Risk? 
European urology  2012;64(1):159-166.
Background
Androgen deprivation therapy for prostate cancer is associated with cardiovascular disease and diabetes. Some data suggest that men with certain conditions may be more susceptible to developing cardiovascular disease than others.
Objective
Assess whether the risk of myocardial infarction or diabetes during androgen deprivation therapy is modified by specific baseline comorbidities.
Design, Settings and Participants
Population-based observational study of 185,106 U.S. men aged ≥66 years diagnosed with local/regional prostate cancer from 1992 to 2007. We assessed comorbidities monthly over the follow-up period.
Outcome Measurement and Analysis
Cox proportional hazards models with time varying variables assessing incident diabetes or myocardial infarction.
Results and limitations
Overall, 49.9% received androgen deprivation therapy during follow-up. Among men with no comorbidities, androgen deprivation therapy was associated with an increase in the adjusted hazard of myocardial infarction (adjusted hazard ratio [AHR]=1.09, 95% confidence interval [CI]=1.02–1.16) and diabetes (AHR=1.33, 95% CI=1.27–1.39). Risk of myocardial infarction and diabetes were similarly increased among men with and without specific comorbid illnesses (all P for interactions >.10 with one exception). Previous myocardial infarction, congestive heart failure, peripheral arterial disease, stroke, hypertension, chronic obstructive pulmonary disease, and renal disease were associated with new myocardial infarction and diabetes, and obesity and rheumatologic disease were also associated with diabetes. Limitations include the observational study design, reliance on administrative data to ascertain outcomes, and lack of information on risk factors such as smoking and family history.
Conclusions
Traditional risk factors for myocardial infarction and diabetes were also associated with developing these conditions during androgen deprivation therapy but did not significantly modify the risk attributable to androgen deprivation therapy. Strategies to screen and prevent diabetes and cardiovascular disease in men with prostate cancer should be similar to those recommended for the general population.
doi:10.1016/j.eururo.2012.04.035
PMCID: PMC3683550  PMID: 22537796
prostate cancer; myocardial infarction; diabetes
10.  Changes in Biomarkers of Inflammation and Angiogenesis During Androgen Deprivation Therapy for Prostate Cancer 
The Oncologist  2012;17(2):212-219.
Inflammatory and angiogenic biomarkers were measured in androgen deprivation therapy–treated and control groups of men with prostate cancer. Significantly higher concentrations of some inflammatory biomarkers were found in the treatment group.
Introduction.
Angiogenesis and inflammation are both important to the pathogenesis of malignancies. Androgen deprivation therapy (ADT) for prostate cancer causes drastic hormonal changes that alter both disease and host factors. We measured inflammatory and angiogenic biomarkers in ADT-treated and control groups of men with prostate cancer.
Materials and Methods.
Baseline and 12-week plasma samples were collected from 37 ADT-naïve men with locally advanced or recurrent prostate cancer. Of those, 23 initiated ADT with a gonadotropin-releasing hormone (GnRH) agonist and 14 served as nontreatment controls. Samples were tested for a panel of angiogenic and inflammatory biomarkers.
Results.
The treatment group had significantly higher concentrations of the inflammatory biomarkers interleukin (IL)-1β, IL-6, IL-8, tumor necrosis factor (TNF)-α, and stromal cell–derived factor (SDF)-1α. None of the angiogenic biomarkers were significantly different between the groups at baseline. Among patients with a short prostate-specific antigen (PSA) doubling time (<6 months), the proangiogenic factor basic fibroblast growth factor (bFGF) was lower at baseline. In the treatment group, plasma placental growth factor (PlGF) increased and IL-6 decreased after 12 weeks of ADT. Moreover, the treatment group continued to have significantly higher concentrations of the inflammatory biomarkers IL-1β, IL-8, and SDF-1α as well as bFGF than controls.
Discussion.
These men were characterized by elevations in several traditional markers of aggressive disease and also by higher levels of several inflammatory biomarkers. Although ADT decreased IL-6 levels, IL-1β, IL-8, and SDF-1α remained significantly higher than in controls. The role of these biomarkers should be further explored.
doi:10.1634/theoncologist.2011-0321
PMCID: PMC3286170  PMID: 22302227
11.  Denosumab and Changes in Bone Turnover Markers During Androgen Deprivation Therapy for Prostate Cancer 
Androgen deprivation therapy (ADT) for prostate cancer increases fracture risk, decreases bone mineral density, and increases bone turnover markers (BTMs) including serum type 1 C-telopeptide (sCTX), tartrate-resistant alkaline phosphatase 5b (TRAP-5b), and procollagen-1 N-terminal telopeptide (P1NP). In a pre-specified exploratory analysis of a phase 3, multicenter, double-blind study, we evaluated the effects of denosumab (60 mg subcutaneously every 6 months for 3 years) vs. placebo (1468 patients, 734 in each group) on BTM values. BTMs were measured at baseline, month 1, and pre-dose at months 6, 12, 24, and 36 in the overall population. BTMs at month 1 are also reported for subgroups based on age (<70 years vs. ≥ 70 years), prior duration of ADT (≤6 months vs. >6 months), and baseline BTM (≤ median vs. >median BTM values). Treatment with denosumab provided a rapid and sustained decrease of BTM values compared with placebo. The median change in sCTX levels at month 1 was −90% in the denosumab group and −3% in the placebo group (p <.0001). The median change in TRAP-5b levels at month 1 was −55% in the denosumab group and −3% in the placebo group (p <.0001). The maximal median change in P1NP was −64% in the denosumab group and −11% in the placebo group, (p <.0001). Significantly greater decreases in BTM for denosumab were also seen in subgroup analyses based on age, prior ADT treatment, and baseline BTM values. Suppression of bone turnover markers was consistent with marked increases in bone mineral density reported previously.
doi:10.1002/jbmr.492
PMCID: PMC3222788  PMID: 21898590
(5) denosumab; androgen deprivation therapy; bone turnover markers; prostate cancer
12.  Androgen Deprivation Therapy and Diabetes Control among Diabetic Men with Prostate Cancer 
European urology  2013;65(4):816-824.
Background
Androgen deprivation therapy (ADT) for prostate cancer is associated with decreased insulin sensitivity and incident diabetes. Few data are available about the effects of ADT on diabetes control among men with diabetes. We examined care for over 7500 men with prostate cancer who had diabetes at the time of diagnosis to assess the effect of ADT on diabetes control, as measured by HbA1c levels and the intensification of diabetes drug therapy.
Methods
We compared hemoglobin A1c (HbA1c) levels and intensification of diabetes pharmacotherapy among 2237 pairs of propensity matched men with prostate cancer and diabetes who were or were not treated with ADT. We calculated the difference-in-difference of HbA1c levels at baseline and 1 and 2 years in the 2 groups, compared using a paired t test. We used a Cox proportional hazards model to estimate time to intensification of diabetes therapy.
Results
The mean (SE) HbA1c at baseline was 7.24 (0.05) for the ADT group and 7.24 (0.04) for the no-ADT group. HbA1c increased at 1 year for men treated with ADT to 7.38 (0.04) and decreased among men not treated with ADT to 7.14 (0.04), for a difference in differences of +0.24 (P=0.008). Results were similar at 2 years (P=.03). Receipt of ADT was also associated with an increased hazard of addition of diabetes medication (adjusted hazard ratio=1.20, 95% CI=1.09-1.32).
Conclusions
ADT is associated with worsening of diabetes control, with both increases in HbA1c levels and the need for additional diabetes medications.
doi:10.1016/j.eururo.2013.02.023
PMCID: PMC3779484  PMID: 23453420
prostate cancer; androgen deprivation therapy; diabetes
13.  Bone Density Testing Among Prostate Cancer Survivors Treated with Androgen Deprivation Therapy 
Cancer  2012;119(4):863-870.
Purpose
Androgen deprivation therapy (ADT) causes bone loss and fractures. Guidelines recommend bone density testing before and during ADT to characterize fracture risk. We assessed bone density testing among men receiving ADT for at least 1 year.
Materials and Methods
Using Surveillance, Epidemiology, and End Results-Medicare data, we identified 28,960 men aged >65 with local/regional prostate cancer diagnosed during 2001–2007 and followed through 2009 who received ≥1 year of continuous ADT. We documented bone density testing in the 18-month period beginning 6 months before ADT initiation. We used logistic regression to identify factors associated with bone density testing.
Results
Among men receiving ≥1 year of ADT, 10.2% had a bone density assessment from 6 months before starting ADT through 1 year after. Bone density testing increased over time (14.5% of men initiating ADT in 2007–2009 vs 6.0% in 2001–2002, OR=2.29, 95% CI=1.83–2.85). Less bone density testing was observed for men aged ≥85 (vs. 66–69, OR=0.76, 95% CI=0.65–0.89), black vs. white men (OR=0.72, 95% CI=0.61–0.86), and men in areas with lower educational attainment (P<.001). Men seeing a medical oncologist and/or a primary care provider in addition to a urologist had higher odds of testing than men seeing only a urologist (P<.001).
Conclusions
Few men receiving ADT for prostate cancer undergo bone density testing, particularly older men, black men, and those living in areas with low educational attainment. Visits with a medical oncologist were associated with increased odds of testing. Interventions are needed to increase bone density testing among men receiving long-term ADT.
doi:10.1002/cncr.27830
PMCID: PMC3671351  PMID: 23065626
prostate cancer; caner survivorship; male osteoporosis; androgen deprivation therapy; side effects of treatment
14.  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
15.  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
16.  A dose-ranging study of cabozantinib in men with castration-resistant prostate cancer and bone metastases 
Background
Cabozantinib is an oral MET/VEGFR2 inhibitor. A recent phase II study of cabozantinib (100mg daily) demonstrated improved bone scans in subjects with metastatic castration-resistant prostate cancer (mCRPC), but adverse events (AEs) caused frequent dose reductions. This study was designed to determine the efficacy and tolerability of cabozantinib at lower starting doses.
Patients and Methods
An adaptive design was used to determine the lowest active daily dose among 60mg, 40mg, and 20mg. The primary endpoint was week 6 bone scan response, defined as ≥ 30% decrease in bone scan lesion area. The secondary endpoint was change in circulating tumor cells (CTCs).
Results
Among 11 evaluable subjects enrolled at 40mg, there were 9 partial responses (PRs), 1 complete response, and 1 stable disease (SD). Of 10 subjects subsequently enrolled at 20mg, there were 1 PR, 5 SDs, and 4 with progressive disease. Among 13 subjects enrolled on the 40mg expansion cohort, there were 6 PRs and 7 SDs. No subjects required dose reduction or treatment interruption at 6 or 12 weeks; 3 subjects at dose level 0 discontinued due to AEs by 12 weeks. At 40mg, median treatment duration was 27 weeks. 58% of subjects with ≥ 5 CTCs/7.5mL at baseline converted to < 5.
Conclusions
Cabozantinib 40mg daily was associated with a high rate of bone scan response. Cabozantinib 40mg daily was associated with better tolerability than previously reported for cabozantinib 100mg daily. These observations informed the design of phase III studies of cabozantinib in mCRPC.
doi:10.1158/1078-0432.CCR-13-0319
PMCID: PMC3684567  PMID: 23553848
cabozantinib; prostate cancer; MET; VEGFR; bone metastasis
17.  Androgen deprivation therapy for prostate cancer: new concepts and concerns 
Purpose of review
The aim of this review is to summarize new concepts and concerns regarding treatment-related osteoporosis, diabetes, and cardiovascular disease in men receiving androgen deprivation therapy for prostate cancer.
Recent findings
Gonadotropin-releasing hormone agonists increase bone turnover, decrease bone mineral density, and increase fracture risk. Bisphosphonates, selective and estrogen receptor modulators significantly increase bone mineral density during androgen deprivation therapy. Ongoing randomized controlled trials will assess efficacy of denosumab, toremifene, and zoledronic acid to prevent fractures in this setting. Gonadotropin-releasing hormone agonists also increase fat mass, decrease insulin sensitivity, and increase serum lipoproteins. In contrast to the classical metabolic syndrome, however, the phenotype of men during androgen deprivation therapy is characterized by increased high-density lipoprotein cholesterol and preferential accumulation of subcutaneous fat. Gonadotropin-releasing hormone agonists are associated with greater risk of incident diabetes and cardiovascular disease in men with prostate cancer.
Summary
Androgen therapy increases risk of fractures, diabetes mellitus, and cardiovascular disease in men with prostate cancer. Current and planned studies will evaluate strategies to prevent these treatment-related adverse effects.
doi:10.1097/MED.0b013e32814db88c
PMCID: PMC3047388  PMID: 17940447
cardiovascular disease; diabetes; gonadotropin-releasing hormone agonists; obesity; osteoporosis; prostate cancer
18.  Obesity and Mortality in Men With Locally Advanced Prostate Cancer 
Cancer  2007;110(12):2691-2699.
BACKGROUND
Greater body mass index (BMI) is associated with shorter time to prostate-specific antigen (PSA) failure following radical prostatectomy and radiation therapy (RT). Whether BMI is associated with prostate cancer-specific mortality (PCSM) was investigated in a large randomized trial of men treated with RT and androgen deprivation therapy (ADT) for locally advanced prostate cancer.
METHODS
Between 1987 and 1992, 945 eligible men with locally advanced prostate cancer were enrolled in a phase 3 trial (RTOG 85-31) and randomized to RT and immediate goserelin or RT alone followed by goserelin at recurrence. Height and weight data were available at baseline for 788 (83%) subjects. Cox regression analyses were performed to evaluate the relations between BMI and all-cause mortality, PCSM, and nonprostate cancer mortality. Covariates included age, race, treatment arm, history of prostatectomy, nodal involvement, Gleason score, clinical stage, and BMI.
RESULTS
The 5-year PCSM rate for men with BMI <25 kg/m2 was 6.5%, compared with 13.1% and 12.2% in men with BMI ≥25 to <30 and BMI ≥30, respectively (Gray's P = .005). In multivariate analyses, greater BMI was significantly associated with higher PCSM (for BMI ≥25 to <30, hazard ratio [HR] 1.52, 95% confidence interval [CI], 1.02–2.27, P = .04; for BMI ≥30, HR 1.64, 95% CI, 1.01–2.66, P = .04). BMI was not associated with nonprostate cancer or all-cause mortality.
CONCLUSIONS
Greater baseline BMI is independently associated with higher PCSM in men with locally advanced prostate cancer. Further studies are warranted to evaluate the mechanism(s) for increased cancer-specific mortality and to assess whether weight loss after prostate cancer diagnosis alters disease course.
doi:10.1002/cncr.23093
PMCID: PMC3047389  PMID: 17999404
obesity; BMI; mortality; prostate cancer; hormonal therapy; radiation therapy
19.  Treatment-Related Osteoporosis in Men with Prostate Cancer 
The intended therapeutic effect of gonadotropin-releasing hormone (GnRH) agonists is hypogonadism, a major cause of acquired osteoporosis in men. Consistent with this observation, GnRH agonists increase bone turnover and decrease bone mineral density, a surrogate for fracture risk. Large claims-based analyses and other retrospective studies provide compelling evidence that GnRH agonists increase risk of clinical fractures. Estrogens play a central role in homeostasis of the normal male skeleton, and estrogen deficiency rather than testosterone deficiency seems to be primarily responsible for the adverse skeletal effects of GnRH agonists. In randomized controlled trials, bisphosphonates (pamidronate and zoledronic acid) and selective estrogen receptor modulators (raloxifene and toremifene) increased bone mineral density in GnRH agonist – treated men. Two ongoing large randomized placebo-controlled studies will prospectively define fracture outcomes in men with prostate cancer and assess the efficacy of novel pharmacologic interventions (AMG162, toremifene) during GnRH agonist treatment.
doi:10.1158/1078-0432.CCR-06-0846
PMCID: PMC3047394  PMID: 17062721
20.  Predictors of Skeletal Complications in Men with Hormone-Refractory Metastatic Prostate Cancer 
Urology  2007;70(2):315-319.
OBJECTIVES
Skeletal complications are a major cause of morbidity in men with hormone-refractory metastatic prostate cancer. These analyses were designed to identify the variables associated with a greater risk of skeletal complications.
METHODS
The 643 subjects in this report were participants in a randomized placebo-controlled trial to evaluate the effects of zoledronic acid on the incidence of skeletal-related events. All subjects had bone metastases and disease progression despite medical or surgical castration. The relationships between the baseline covariates and the time to the first skeletal-related event were assessed by Cox proportional hazard analyses. The serum bone-specific alkaline phosphatase (BAP) and urinary N-telopeptide level was assessed as a representative specific marker of osteoblastic and osteoclastic activity, respectively. The other covariates included in the model were age, cancer duration, Eastern Cooperative Oncology Group performance status, analgesic use, and prostate-specific antigen, hemoglobin, and lactate dehydrogenase levels.
RESULTS
Elevated BAP levels were consistently associated with a greater risk of adverse skeletal outcomes. Elevated BAP was significantly associated with a shorter time to the first skeletal-related event on multivariate analyses of the entire study population (relative risk 1.84, 95% confidence interval 1.40 to 2.43; P <0.001) and in subset analyses of the placebo and zoledronic acid groups. Elevated BAP levels were also consistently associated with adverse skeletal outcomes on multivariate analyses of the time to radiotherapy and pathologic fracture, the most common types of skeletal-related events in the study population. No other baseline variable was consistently associated with the risk of adverse skeletal outcomes.
CONCLUSIONS
The results of our study have shown that elevated serum BAP levels are associated with a greater risk of adverse skeletal outcomes in men with hormone-refractory prostate cancer and bone metastases.
doi:10.1016/j.urology.2007.03.071
PMCID: PMC3047396  PMID: 17826496
21.  Randomized Controlled Trial of Annual Zoledronic Acid to Prevent Gonadotropin-Releasing Hormone Agonist–Induced Bone Loss in Men With Prostate Cancer 
Purpose
Gonadotropin-releasing hormone (GnRH) agonists decrease bone mineral density (BMD) and increase fracture risk in men with prostate cancer. Annual zoledronic acid increases BMD in postmenopausal women, but its efficacy in hypogonadal men is not known.
Patients and Methods
In a 12-month study, 40 men with nonmetastatic prostate cancer who were receiving a GnRH agonist and had T scores more than −2.5 were randomly assigned to zoledronic acid (4 mg intravenously on day 1 only) or placebo. BMD of the posteroanterior lumbar spine and proximal femur were measured by dual-energy x-ray absorptiometry.
Results
Mean (± SE) BMD of the posteroanterior lumbar spine decreased by 3.1% ± 1.0% in men assigned to placebo and increased by 4.0% ± 1.0% in men assigned to zoledronic acid (P < .001). BMD of the total hip decreased by 1.9% ± 0.7% in men assigned to placebo and increased by 0.7% ± 0.5% in men assigned to zoledronic acid (P = .004). Similar between-group differences were observed for the femoral neck and trochanter. Serum N-telopeptide, a marker of osteoclast activity, decreased significantly after zoledronic acid treatment.
Conclusion
In men receiving a GnRH agonist, a single treatment with zoledronic acid significantly increased BMD and durably suppressed serum N-telopeptide levels for 12 months. Annual zoledronic acid may be a convenient and effective strategy to prevent bone loss in hypogonadal men.
doi:10.1200/JCO.2006.07.3361
PMCID: PMC3047397  PMID: 17369566
23.  Androgen Deprivation Therapy and Risk for Diabetes and Cardiovascular Disease in Prostate Cancer Survivors 
Current urology reports  2008;9(3):197-202.
Gonadotropin-releasing hormone (GnRH) agonists are the mainstay of treatment for recurrent and metastatic prostate cancer. GnRH agonists are also an important part of therapy for many men with localized or locally advanced prostate cancer. Although GnRH agonists improve survival in certain settings, they involve adverse effects including vasomotor flushing, obesity, and osteoporosis. This article describes the evidence that GnRH agonists increase risk for diabetes and cardiovascular disease and reviews the potential mechanisms for treatment-related morbidity.
PMCID: PMC3047401  PMID: 18765113
24.  Obesity and Sex Steroids during Gonadotropin-Releasing Hormone Agonist Treatment for Prostate Cancer 
Purpose
To evaluate effects of obesity on sex steroid levels during treatment with a gonadotropin-releasing hormone agonist in men with prostate cancer.
Experimental Design
Forty-nine hormone-naïve men with recurrent or locally advanced prostate cancer were included in the analyses. All subjects were treated with leuprolide 3-month depot for 48 weeks. Serum levels of estradiol, sex hormone – binding globulin, total testosterone, and free testosterone were assessed at baseline, 24 weeks, and 48 weeks. Subjects were categorized by body mass index (BMI) and percent body fat.
Results
Pretreatment serum sex hormone – binding globulin and total testosterone levels were significantly lower in overweight and obese men than in men with normal BMI. In the overall study population, mean serum testosterone concentrations decreased from 372 ±18 ng/dL at baseline to 13 ± 1ng/dL at week 48 (P < 0.001). Free testosterone decreased from 6.75 ± 0.33 ng/dL at baseline to 0.21 ± 0.02 ng/dL at week 48 (P < 0.001). During treatment with leuprolide, obese men had significantly higher total and free testosterone levels than men with normal BMI. Compared with normal men, total and free testosterone levels during treatment were 1.8-fold and 2.3-fold higher in obese men. Similar results were observed when subjects were categorized by body fat.
Conclusions
Despite lower pretreatment serum testosterone levels, obese men have higher total and free testosterone levels during leuprolide treatment than men with normal BMI. These differences may contribute to the association between obesity and increased prostate cancer mortality.
doi:10.1158/1078-0432.CCR-06-2086
PMCID: PMC3047403  PMID: 17200361
25.  Androgen receptor signaling in circulating tumor cells as a marker of hormonally responsive prostate cancer 
Cancer discovery  2012;2(11):995-1003.
Androgen deprivation therapy (ADT) is initially effective in treating metastatic prostate cancer, and secondary hormonal therapies are being tested to suppress androgen receptor (AR) reactivation in castration-resistant prostate cancer (CRPC). Despite variable responses to AR pathway inhibitors in CRPC, there are no reliable biomarkers to guide their application. Here, we used microfluidic capture of circulating tumors cells (CTCs) to measure AR signaling readouts before and after therapeutic interventions. Single cell immunofluorescence analysis revealed predominantly “AR-on” CTC signatures in untreated patients, compared to heterogeneous (“AR-on, AR-off, and AR-mixed”) CTC populations in patients with CRPC. Initiation of first line ADT induced a profound switch from “AR-on” to “AR-off” CTCs, whereas secondary hormonal therapy in CRPC resulted in variable responses. Presence of “AR-mixed” CTCs and increasing “AR-on” cells despite treatment with abiraterone acetate were associated with an adverse treatment outcome. Measuring treatment-induced signaling responses within CTCs may help guide therapy in prostate cancer.
doi:10.1158/2159-8290.CD-12-0222
PMCID: PMC3508523  PMID: 23093251
androgen receptor; CTCs; prostate cancer; abiraterone acetate; castration resistance

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