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1.  Androgen Deprivation Therapy and Diabetes Control among Diabetic Men with Prostate Cancer 
European urology  2013;65(4):816-824.
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.
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.
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).
ADT is associated with worsening of diabetes control, with both increases in HbA1c levels and the need for additional diabetes medications.
PMCID: PMC3779484  PMID: 23453420
prostate cancer; androgen deprivation therapy; diabetes
2.  Sarcopenia During Androgen-Deprivation Therapy for Prostate Cancer 
Journal of Clinical Oncology  2012;30(26):3271-3276.
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).
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).
In men receiving ADT, LBM decreased significantly after 12, 24, and 36 months.
PMCID: PMC3434987  PMID: 22649143
3.  Bone Targeted Agents: Preventing skeletal complications in prostate cancer 
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.
PMCID: PMC3721069  PMID: 23084529
zoledronic acid; denosumab; prostate cancer; bone metastasis; skeletal-related events; Prostate cancer; skeletal complications; bone; side effects of therapy; ADT
4.  Bone Density Testing Among Prostate Cancer Survivors Treated with Androgen Deprivation Therapy 
Cancer  2012;119(4):863-870.
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.
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).
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.
PMCID: PMC3671351  PMID: 23065626
prostate cancer; caner survivorship; male osteoporosis; androgen deprivation therapy; side effects of treatment
5.  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.
PMCID: PMC3661203  PMID: 23201471
6.  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.
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.
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.
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.
PMCID: PMC3671875  PMID: 22014807
androgen deprivation therapy; osteoporosis; prostate cancer; selective estrogen receptor modulators; toremifene
7.  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.
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.
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.
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.
Abiraterone acetate produces OS and rPFS benefits, as well as significant delays in clinical deterioration and initiation of chemotherapy, in mCRPC.
PMCID: PMC3683570  PMID: 23228172
Abiraterone acetate; prednisone; metastatic castration-resistant prostate cancer; androgen; CYP17
8.  A dose-ranging study of cabozantinib in men with castration-resistant prostate cancer and bone metastases 
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).
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.
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.
PMCID: PMC3684567  PMID: 23553848
cabozantinib; prostate cancer; MET; VEGFR; bone metastasis
9.  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.
PMCID: PMC3508523  PMID: 23093251
androgen receptor; CTCs; prostate cancer; abiraterone acetate; castration resistance
10.  Responder Analysis of the Effects of Denosumab on Bone Mineral Density in Men Receiving Androgen Deprivation Therapy for Prostate Cancer 
Men with prostate cancer are at risk of experiencing accelerated bone loss and fractures as a result of androgen deprivation therapy (ADT).
We evaluated the effects of denosumab, a fully human monoclonal antibody against RANKL, on preservation of BMD at 3 key skeletal sites (lumbar spine [LS], femoral neck [FN], and total hip [TH]) and the distal radius at 36 months both by responder category and individual responses in a waterfall plot analysis.
Design, Setting, and Participants
This phase 3, randomized, double-blind study of men with non-metastatic prostate cancer receiving ADT investigated the effects of denosumab on bone mineral density (BMD) and fractures. Patients were treated for 36 months.
Subcutaneous denosumab 60 mg (n=734) or placebo (n=734) every 6 months for up to 36 months. Patients were instructed to take supplemental Calcium and vitamin D.
Primary outcome measure: The percentage change from baseline to month 36 in LS, FN, and TH BMD was measured by dual energy x-ray absorptiometry. BMD at the distal 1/3 radius at 36 months was measured in a sub-study of 309 patients.
Results and Limitations
At 36 months, significantly more patients in the denosumab arm had increases of >3% BMD from baseline at each site studied compared with placebo (LS, 78% vs 17%; TH, 48% vs 6%; FN, 48% vs 13%; distal 1/3 radius, 40% vs 7%). The percentage of denosumab patients with bone loss at all 3 key BMD sites at month 36 was 1%, as opposed to 42% in placebo arm. At 36 months 69% of denosumab-treated patients had BMD increases at all three sites (LS, TH or FN) compared with 8% of placebo-treated patients. Lower baseline BMD was associated with higher magnitude lumbar spine, femoral neck, and total hip BMD responses to denosumab.
In men with prostate cancer receiving ADT significantly higher BMD response rates were observed with denosumab vs. placebo.
Trial Registration
This study is registered with with the identifier NCT00089674.
PMCID: PMC3671885  PMID: 22641239
androgen deprivation; bone mineral density; bone loss; antiresorptive therapy; responder analysis
11.  Androgen-deprivation therapy for nonmetastatic prostate cancer is associated with an increased risk of peripheral arterial disease and venous thromboembolism 
European urology  2012;61(6):1119-1128.
Previous studies demonstrate that androgen deprivation therapy with gonodotropin-releasing hormone (GnRH) agonists and orchiectomy for prostate cancer is associated with cardiovascular disease. However, few studies have examined its effect on the peripheral vascular system.
To study the risk of peripheral arterial disease and venous thromboembolism associated with androgen deprivation therapy for prostate cancer.
Design, Settings and Participants
Population-based observational study of 182,757 U.S. men aged 66 years and older who were diagnosed with loco-regional prostate cancer from 1992 to 2007, of whom 47.8% received GnRH agonists and 2.2% orchiectomy.
We used Cox proportional hazards models with time-varying treatment variables to assess whether treatment with GnRH agonists or orchiectomy was associated with peripheral arterial disease and/or venous thromboembolism.
Results and limitations
Overall, 47.8% of men received a GnRH agonist during follow-up and 2.2% underwent orchiectomy. GnRH agonist use was associated with an increased risk of incident peripheral arterial disease (adjusted hazard ratio [HR], 1.15, 95% confidence interval [CI] 1.11–1.19) and incident venous thromboembolism (adjusted HR, 1.1, 95% CI 1.04–1.16). In addition, orchiectomy was associated with an increased risk of peripheral arterial disease (adjusted HR, 1.14, 95% CI 1.03–1.27) and venous thromboembolism (adjusted HR, 1.22, 95% CI 1.07–1.40). Limitations include the observational study design, inability to assess the use of oral anti-androgens as monotherapy or combined androgen deprivation.
Androgen deprivation therapy for loco-regional prostate cancer is associated with an increased risk of peripheral artery disease and venous thromboembolism. Additional research is needed to better understand the potential risks and benefits, so that these treatments can be targeted to patients where the benefits are most clear.
PMCID: PMC3719131  PMID: 22336376
Prostate cancer; androgen deprivation therapy; peripheral vascular disease; venous thromboembolism
12.  Gonadotropin-releasing hormone Blockers and Cardiovascular Disease Risk: Analyses of Prospective Clinical Trials of Degarelix 
The Journal of urology  2011;186(5):1835-1842.
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
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.
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.
PMCID: PMC3712275  PMID: 21944083
cardiovascular events; degarelix; long-term treatment; predictors; prostate cancer patients
13.  Targeting MET and VEGFR Signaling in Castration-Resistant Prostate Cancer 
Effective management of bone metastases in men with castration-resistant prostate cancer (CRPC) remains an important unmet medical need. MET and VEGFR are rational targets for intervention in CRPC. Clinical trials involving agents that inhibit one but not both pathways have reported modest activity and no improvement in overall survival. Cabozantinib is an oral multitargeted tyrosine kinase inhibitor (TKI) that inhibits both MET and VEGFR2. A phase II randomized discontinuation study involving subjects with CRPC demonstrated that cabozantinib therapy is associated with improvement in bone scans, bone turnover markers, and pain response, but with significant adverse events leading to dose reduction and treatment discontinuation. Lower doses of cabozantinib retain high levels of activity with less toxicity. Ongoing phase III clinical trials will define the role of cabozantinib in CRPC. We summarize the rationale for targeting MET and VEGFR pathways in CRPC and the clinical data available to date.
PMCID: PMC3683553  PMID: 23337762
MET; VEGFR; cabozantinib; prostate cancer; bone metastasis
14.  In-vivo imaging and spectroscopy of dynamic metabolism using simultaneous 13C and 1H MRI 
Hyperpolarized (HP) 13C-labeled pyruvate studies with Magnetic Resonance (MR) have been used to observe the kinetics of metabolism in-vivo. Kinetic modeling to measure metabolic rates in-vivo is currently limited because of nonspecific hyperpolarized signals mixing between vascular, extravascular, and intracellular compartments. In this work simultaneous acquisition of both 1H and 13C signals after contrast agent injection is used to resolve specific compartments to improve the accuracy of the modeling. We demonstrate a novel technique to provide contrast to the intracellular compartments by sequential injection of HP [1-13C] pyruvate followed by gadolinium-chelate to provide T1-shortening to extra-cellular compartments. A kinetic model that distinguishes the intracellular space and includes the T1-shortening effect of the gadolinium-chelate can then be used to directly measure the intracellular 13C kinetics.
PMCID: PMC3676651  PMID: 21775254
intracellular; magnetic resonance; metabolism; pyruvate; gadolinium
15.  Racial differences in bone mineral density and fractures in men receiving androgen deprivation therapy for prostate cancer 
The Journal of urology  2012;187(3):889-893.
Whether race influences bone loss and fracture risk during androgen deprivation therapy (ADT) for prostate cancer is unknown. Using data from a prospective, clinical trial, we compared bone mineral density (BMD) and fracture between African American and Caucasian men receiving ADT.
Materials and Methods
Subjects (n=516) were in the placebo group of a two-year randomized placebo controlled fracture prevention trial and were African American (n=68) or Caucasian (n=448). We compared baseline characteristics, changes in BMD, and rates of new fractures between races.
Compared to Caucasian men, African American men had higher baseline hip BMD (0.98 ± 0.15 g/m2 versus 0.91 ± 0.15 g/m2; P=0.001) and similar spine BMD (1.09 ± 0.22 versus 1.11 ± 0.22; P=0.51). There was no difference in prevalent vertebral fractures between African American and Caucasian men (7.4% versus 15.0%; P=0.13). Percentage change in hip BMD at two years was similar between African American and Caucasian men (−2.21 ± 0.59% versus −2.54 ± 0.26%; P=0.65). Changes in BMD of the lumbar spine were also similar between African American and Caucasian men (−1.74 ± 0.69 versus −1.30 ± 0.33%; P=0.64). No new vertebral fractures were reported in African American men versus two fractures in Caucasian men.
In a clinical trial, African American men receiving ADT for prostate cancer have higher hip BMD and tended to have fewer prevalent vertebral fractures than Caucasian men. Despite lower baseline risk of osteoporosis and fracture, African American men experience a decline in BMD that is similar to Caucasian men.
PMCID: PMC3671868  PMID: 22245322
prostate cancer; androgen deprivation therapy; bone mineral density; fracture; survivorship
16.  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.
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).
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.
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.
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.
PMCID: PMC3671878  PMID: 22093187
urology/prostate disease; denosumab; prostate cancer; prevention; bone metastasis; survival; hormone refractory; castration-resistant
17.  Phase II Study of Abiraterone Acetate Plus Prednisone in Chemotherapy-Naïve Metastatic Castration-Resistant Prostate Cancer Demonstrating Radiographic Flare Discordant With Serologic Measures of Response 
Abiraterone is an oral inhibitor of CYP17, essential for androgen biosynthesis. This multicenter study assessed its efficacy in patients with CRPC without prior exposure to chemotherapy or CYP17 targeted therapy, and assessed the frequency of interpretation of bone scans discordant with PSA and clinical response.
Patients and Methods
33 patients received abiraterone acetate 1000 mg daily with prednisone 5 mg twice daily in continuous 28-day cycles. Patients were evaluated monthly for efficacy and safety. Bone scan flare was defined as the combination, after 3 months of therapy, of an interpreting radiologist's report indicating “disease progression” in the context of a ≥50% decline in PSA, with scan improvement 3 months later.
A ≥ 50% PSA decline at week 12 was confirmed in 22/33 (67%) patients. PSA declines of ≥ 50% were seen in 26 (79%) patients. Undetectable PSA levels (≤ 0.1 ng/mL) occurred in 2 patients. Median time on therapy and time to PSA progression are 63 and 71 weeks, respectively. Twenty three patients were evaluable for bone scan flare. Progression was indicated in the radiologist's report in 12/23 (52 %), and 10/12 subsequently showed improvement. As prospectively defined, bone scan flare was observed in 10/23 (43.5%) evaluable patients or 10/33 (30%) enrolled patients. Adverse events were typically grade 1/2 and consistent with prior published abiraterone reports.
Clinical response to abiraterone acetate plus prednisone was frequent and durable in men with metastatic CRPC progressing on hormonal therapy with over half of patients on therapy > 1 year. Further investigation is needed to clarify the potential confounding effect of the frequently occurring bone scan flare phenomena on patient management and interpretation of clinical trial results.
PMCID: PMC3657705  PMID: 21632851
abiraterone acetate; castration-resistant prostate cancer; CRPC; hormone-resistant prostate cancer; therapy; efficacy
18.  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.
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.
PMCID: PMC3047388  PMID: 17940447
cardiovascular disease; diabetes; gonadotropin-releasing hormone agonists; obesity; osteoporosis; prostate cancer
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.
PMCID: PMC3047394  PMID: 17062721
20.  Randomized Controlled Trial of Annual Zoledronic Acid to Prevent Gonadotropin-Releasing Hormone Agonist–Induced Bone Loss in Men With Prostate Cancer 
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.
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.
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.
PMCID: PMC3047397  PMID: 17369566
22.  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
23.  Obesity and Sex Steroids during Gonadotropin-Releasing Hormone Agonist Treatment for Prostate Cancer 
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.
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.
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.
PMCID: PMC3047403  PMID: 17200361
24.  Prognostic Role of Serum Parathyroid Hormone Levels in Advanced Prostate Cancer Patients Undergoing Zoledronic Acid Administration 
The Oncologist  2012;17(5):645-652.
The prognostic role, in terms of the overall survival outcome, of serum parathyroid hormone evaluated at baseline and after 3 months of zoledronic acid or placebo treatment in hormone-refractory prostate cancer patients with bone metastases enrolled in a randomized clinical trial was assessed.
Secondary hyperparathyroidism is frequent in prostate cancer patients with bone metastases, and this condition is worsened by the administration of potent bisphosphonates. Serum parathyroid hormone (PTH) elevation can impair the efficacy of these drugs in terms of survival.
The prognostic role of elevated serum PTH levels at baseline and after 3 months of zoledronic acid administration was assessed prospectively in 643 bone metastatic prostate cancer patients enrolled in a prospective randomized, placebo-controlled study.
On multivariate analysis, after adjusting for major prognostic factors and bone turnover markers, elevated baseline serum PTH level was negatively associated with overall survival (hazard ratio [HR], 1.448; 95% confidence interval [CI], 1.045–2.006; p < .03) in zoledronic acid–treated patients but not in placebo-treated patients. In patients with normal baseline PTH levels, there was a trend but insignificant association between zoledronic acid administration and a better survival outcome than with placebo (HR, 0.81; 95% CI, 0.65–1.01; p = .065), whereas a trend in the opposite direction was observed in patients with elevated PTH levels (HR, 1.45; 95% CI, 0.87–2.39; p = .151); interaction test, p = .040. Elevated serum PTH level after 3 months of zoledronic acid treatment was not significantly associated with survival outcome.
Secondary hyperparathyroidism has a negative prognostic impact in metastatic prostate cancer patients undergoing zoledronic acid administration. Counteracting elevated PTH levels by adequate doses of vitamin D may improve the efficacy of this drug.
PMCID: PMC3360904  PMID: 22523198
Bone metastasis; Parathyroid hormone; Prostate cancer; Zoledronic acid
25.  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.
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.
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.
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.
PMCID: PMC3286170  PMID: 22302227

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