Search

To describe prostate-specific antigen (PSA) response and treatment adherence, overall and stratified by race, for patients with non-metastatic castration-resistant prostate cancer (nmCRPC) treated with apalutamide.Electronic medical records representing 63 urology practices from the United States were used to conduct this study. Patients with ≥2 apalutamide prescription fills and ≥12 months of prior prostate cancer management were identified. Patients were followed from apalutamide initiation until a switch to another antineoplastic treatment, death, or end of data availability (October 4, 2019). PSA response (≥50% decline from baseline PSA) and apalutamide adherence rates are described for the overall nmCRPC population treated and also stratified by race (Black and non-Black cohorts).Overall, 193 patients with nmCRPC were initiated on apalutamide. Thirty-three patients were Black (17.1%), 138 were non-Black (71.5%), and the remaining had an unknown racial background. The mean baseline PSA level for the overall, Black, and non-Black cohorts, was 7.0 ng/mL, 10.5 ng/mL, and 5.6 ng/mL, respectively. At 12 months of follow-up, PSA response was 86.0%, 93.1%, and 85.9% for the overall, Black, and non-Black cohorts, respectively. During a mean follow-up period of 333 days, 352 days, and 326 days, adherence was 93.6%, 90.1%, and 94.5% for the overall, Black and non-Black cohorts, respectively.This real-world study of patients with nmCRPC initiated on apalutamide showed that PSA response was robust and consistent with clinical trial data. Moreover, both Black and non-Black patients demonstrated high treatment adherence.

Background Advanced prostate cancer (PC) patients, especially those with metastatic prostate cancer (mPC), often require complex management pathways. Despite the publication of clinical practice guidelines by leading urological and oncological organizations that provide a substantial and comprehensive framework, there are numerous clinical scenarios that are not always addressed, especially as new treatments become available, new imaging modalities are developed, and advances in genetic testing continue. Methods A 14-member expert review panel comprised of urologists and medical oncologists were chosen to provide guidance on addressing specific topics and issues regarding metastatic castration-resistant prostate cancer (mCRPC) patients. Panel members were chosen based upon their experience and expertise in the management of PC patients. Four academic members (two urologists and two medical oncologists) of the panel served as group leaders; the remaining eight panel members were from Large Urology Group Practice Association (LUGPA) practices with proven experience in leading their advanced PC clinics. The panel members were assigned to four separate working groups, each assigned a specific mCRPC topic to review and discuss with the entire panel. Results This article describes the practical recommendations of an expert panel on the management of mCRPC patients. The target reading audience for this publication is all providers (urologists, medical oncologists, radiation oncologists, or advanced practice providers) who evaluate and manage advanced PC patients, regardless of their practice setting. Conclusion The panel has provided recommendations for managing mCRPC with regard to specific issues: (a) biomarker monitoring and the role of genetic and molecular testing; (b) rationale, current strategies, and optimal sequencing of the various approved therapies, including hormonal therapy, cytotoxic chemotherapy, radiopharmaceuticals and immunotherapy; (c) adverse event management and monitoring; and (d) imaging advanced PC patients. These recommendations seek to complement national guidelines, not replace them, and a discussion of where the panel agreed or disagreed with national guidelines is included.

Data from guided wave propagation in structures, produced by piezoelectric elements, can offer valuable information regarding the possible existence of flaws. Numerical models can be used to complement the attained data for refining the potential for flaw characterization. Unfortunately, evaluation of these models remains computationally expensive, especially for small defects, due to the short wavelength required for detection and, the in turn fine discretization in time and space. This renders real–time simulation infeasible, rendering GW–approaches less attractive for inverse problem formulations, where the forward problem needs to be solved several times. We propose an accelerated computation method, which exploits the properties of guided waves interacting with defects, where an extra band of waves is created, whose phase is differentiated, depending on the location of the flaw (e.g. notch) within the medium. To expedite the actual simulation for the inverse problem, the system is parametrized in terms of the location of the flaw and, in an offline phase, is repeatedly solved to produce snapshots of the system’s response. The snapshots are used to create a physics–informed interpolation of the solution of the wave propagation problem for different flaw locations. The gained information is then used in an inverse setting for localising the defect using an evolution strategy as a means to stochastic, derivative-free numerical optimization. The method is demonstrated in simulations of a 2D slice of a thin plate., Structural Health Monitoring 2021: Enabling Next Generation SHM for Cyber-Physical Systems, ISBN:978-1-60595-687-9

INTRODUCTION AND OBJECTIVE:Real-world evidence on apalutamide (APA), recently approved to treat patients with non-metastatic castration-resistant prostate cancer (nmCRPC), is limited in the United ...

Background: The relative cardiovascular safety of gonadotropin-releasing hormone (GnRH) antagonists compared with GnRH agonists in men with prostate cancer and known atherosclerotic cardiovascular disease remains controversial. Methods: In this international, multicenter, prospective, randomized, open-label trial, men with prostate cancer and concomitant atherosclerotic cardiovascular disease were randomly assigned 1:1 to receive the GnRH antagonist degarelix or the GnRH agonist leuprolide for 12 months. The primary outcome was the time to first adjudicated major adverse cardiovascular event (composite of death, myocardial infarction, or stroke) through 12 months. Results: Because of slower-than-projected enrollment and fewer-than-projected primary outcome events, enrollment was stopped before the 900 planned participants were accrued. From May 3, 2016, to April 16, 2020, a total of 545 patients from 113 sites across 12 countries were randomly selected. Baseline characteristics were balanced between study groups. The median age was 73 years, 49.8% had localized prostate cancer; 26.3% had locally advanced disease, and 20.4% had metastatic disease. A major adverse cardiovascular event occurred in 15 (5.5%) patients assigned to degarelix and 11 (4.1%) patients assigned to leuprolide (hazard ratio, 1.28 [95% CI, 0.59–2.79]; P =0.53). Conclusions: PRONOUNCE (A Trial Comparing Cardiovascular Safety of Degarelix Versus Leuprolide in Patients With Advanced Prostate Cancer and Cardiovascular Disease) is the first, international, randomized clinical trial to prospectively compare the cardiovascular safety of a GnRH antagonist and a GnRH agonist in patients with prostate cancer. The study was terminated prematurely because of the smaller than planned number of participants and events, and no difference in major adverse cardiovascular events at 1 year between patients assigned to degarelix or leuprolide was observed. The relative cardiovascular safety of GnRH antagonists and agonists remains unresolved. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02663908.

Background: Upregulation of the glucocorticoid receptor (GR) is a potential mechanism of resistance to enzalutamide and other androgen receptor (AR) modulators in prostate cancer. Preclinical studies have demonstrated that GR activation can bypass enzalutamide-mediated AR inhibition and support prostate cancer cell growth. Overexpression of GR is associated with poor outcomes in castration-resistant prostate cancer patients (CRPC) treated with enzalutamide. ORIC-101 is a potent and selective orally bioavailable, small molecule antagonist of GR. Mechanistically, ORIC-101 inhibits GR transcriptional activity and blocks the pro-survival signals mediated by the activated nuclear hormone receptor. Methods: A modified interval 3+3 (i3+3) design was used to assess safety, pharmacokinetics (PK), and pharmacodynamics (PD) to select the Recommended Phase 2 Dose (RP2D) of ORIC-101 in combination with enzalutamide in patients with metastatic CRPC progressing on enzalutamide 160 mg, dosed once daily (NCT04033328). ORIC-101, at doses ranging from 80 to 240 mg once daily, given in a continuous dosing regimen, was added to enzalutamide at the time of disease progression. Plasma PK and PD biomarkers were assessed on multiple days and times before and after dosing. PD modulation in blood-derived peripheral blood mononuclear cells (PBMCs) was assessed by RT-qPCR for GR target genes. Antitumor activity was assessed by Prostate Cancer Clinical Trials Working Group 3 (PCWG3) and RECIST 1.1. Results: 10 patients were treated in 3 cohorts in the dose escalation portion of the study. ORIC-101 exposure increased with dose and no drug-drug interaction (DDI) was observed that necessitated reduction from the standard enzalutamide dose of 160 mg. No dose limiting toxicities were observed at any dose level. Based upon plasma exposure and PD modulation, the RP2D was established as 240 mg ORIC-101 plus 160 mg enzalutamide, both dosed once daily continuously in 28-day cycles. All adverse events (AEs) were Grade 1 or 2 with the most common (>15%), treatment-related AEs being fatigue (40%), nausea (30%), constipation (20%), decreased appetite (20%), high aspartate aminotransferase (20%), high alkaline phosphatase (20%), and headache (20%). There were no Grade ≥3 treatment-related AEs. Biomarker data demonstrated ORIC-101 induced reduction in GR target gene expression in PBMCs, indicating PD modulation across dose levels of ORIC-101. Data will be updated at the time of the presentation. Conclusions: Preliminary evidence suggests that ORIC-101 effectively modulates GR and has an acceptable tolerability profile when combined with enzalutamide. Dose expansion is ongoing at the RP2D. Citation Format: Wassim Abida, Neeraj Agarwal, Andrew W. Hahn, Neal Shore, Paul Sieber, Tanya Dorff, Mathew Rettig, Mathew Smith, Paul Monk, Rongda Xu, Ann Johnson, Anneleen Daemen, Edna Chow Maneval, Pratik S. Multani, Rupal Patel, Michael J. Morris. Initial results from a phase 1b study of ORIC-101, a glucocorticoid receptor antagonist, in combination with enzalutamide in patients with metastatic prostate cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P041.

BACKGROUND Patients with prostate cancer and their providers face uncertainty as they consider adjuvant radiotherapy (ART) or salvage radiotherapy (SRT) after undergoing radical prostatectomy. The authors prospectively evaluated the impact of the Decipher test, which predicts metastasis risk after radical prostatectomy, on decision making for ART and SRT. METHODS A total of 150 patients who were considering ART and 115 who were considering SRT were enrolled. Providers submitted a management recommendation before processing the Decipher test and again at the time of receipt of the test results. Patients completed validated surveys on prostate cancer (PCa)-specific decisional effectiveness and PCa-related anxiety. RESULTS Before the Decipher test, observation was recommended for 89% of patients considering ART and 58% of patients considering SRT. After Decipher testing, 18% (95% confidence interval [95% CI], 12%-25%) of treatment recommendations changed in the ART arm, including 31% among high-risk patients; and 32% (95% CI, 24%-42%) of management recommendations changed in the salvage arm, including 56% among high-risk patients. Decisional Conflict Scale (DCS) scores were better after viewing Decipher test results (ART arm: median DCS before Decipher, 25 and after Decipher, 19 [P

Purpose The optimal management of men with prostate cancer at high risk of recurrence postradical prostatectomy is controversial. The clinical utility of the Decipher test was evaluated prospectively on postoperative treatment decisions and patient-reported outcomes. Methods and Materials In the study, 246 eligible men across 19 centers were enrolled. Patients were dichotomized into those considering adjuvant or salvage radiation therapy (ART or SRT). Participating providers submitted a management recommendation before and after receiving the Decipher test results. Treatment received within 12 months and a validated survey on prostate cancer–related anxiety were collected longitudinally. Results Pre-Decipher, treatment was recommended for 12% and 40% for the ART and SRT arms, respectively. Post-Decipher, 17% and 30% of treatment recommendations changed in the ART and SRT arms, respectively. Post-Decipher treatment recommendation was administered 78% and 76% of the time in the ART and SRT arms, respectively. Multivariable analysis confirmed that the Decipher score was an independent predictor for change in management for both adjuvant and salvage patients. The number needed to test to change management for one patient was 4. Cancer-specific anxiety decreased among Decipher risk categories in both arms. Conclusions Use of Decipher postradical prostatectomy test was associated with postoperative treatment decisions. Overall, high Decipher risk was associated with an increase in treatment intensity whereas low risk scores were associated with a decrease in therapy administered independent of clinical and pathologic risk factors.

Background The objective of this study was to evaluate differences in tolerability in patients with metastatic castration-resistant prostate cancer treated with enzalutamide (ENZA) or abiraterone acetate plus prednisone (AA+P). Patients and Methods This was a phase IV, prospective, open-label, multicenter, real-world study. Patients were prescribed ENZA or AA+P at the treating physician’s discretion. Computerized tests of 4 cognitive domains (Cogstate), patient-reported outcomes (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 [EORTC QLQ-30], Functional Assessment of Chronic Illness Therapy-Fatigue [FACIT-Fatigue], Functional Assessment of Cancer Therapy-Cognitive Function [FACT-Cog]), and patient/caregiver surveys were assessed at baseline and 2 months. Safety data were collected. Results Of 100 treated patients, 92 were evaluable (46/arm). Baseline characteristics were similar, with mild cognitive impairment observed in ∼20% of patients. The FACIT-Fatigue demonstrated a statistically significant worsening from baseline of −4.00 (95% confidence interval, −6.61 to −1.39) for ENZA compared with AA+P, −0.01 (95% confidence interval, −2.40 to 2.38). Overall, more adverse events (AEs) and more AEs of fatigue were reported with ENZA versus AA+P (52% vs. 36% and 26% vs. 8%, respectively). Grade 3/4 AEs were similar (4% vs. 6%). Unique neuropsychiatric AEs reported with ENZA included amnesia, cognitive disorders, memory impairment, and confusional state; those for AA+P included cerebrovascular accident, presyncope, and spinal cord compression. Clinically meaningful cognitive decline was seen in 4 patients on ENZA versus 1 patient on AA+P. However, the overall mean changes from baseline for the Cogstate tests, the EORTC QLQ-C30, and the FACT-Cog assessment were similar and showed no meaningful change. Caregiver survey responses noted more fatigue with ENZA and more moodiness with AA+P compared with patient responses. Conclusions Although baseline values were similar, more fatigue and neurocognitive differences were observed with ENZA compared with AA+P.

5009 Background: Preclinical and phase 1 results suggest PI3K/mTOR pathway inhibition may enhance androgen receptor inhibition. We report the results of a double-blind, placebo-controlled, randomized Phase 1b/2 study of ENZ±LY (a dual PI3K/mTOR inhibitor) in pts with mCRPC who progressed on abiraterone. Methods: Phase 1b pts received single-agent LY 200 mg twice daily (BID) for 1 wk prior to starting LY+ENZ. Phase 2 pts were randomized 1:1 to 160 mg daily ENZ with PL or 200 mg BID LY on a 28-d cycle. The primary objective was progression-free survival (PFS: serological, radiographic [rPFS], or death) by PCWG2 criteria. Secondary objectives were rPFS, safety, decline in PSA, and PK. Exploratory biomarker analyses included outcomes by presence of androgen receptor variant 7 (AR-V7). 92 primary PFS events were needed for the study to have at least 80% power at one-sided alpha=0.20. Results: LY+ENZ was tolerable during Phase 1b with 1 dose limiting toxicity observed in 13 enrolled pts. Mean LY exposures remained in an efficacious range despite a 30% average decrease when combined with ENZ. In Phase 2, 129 pts were randomized to LY+ENZ (N=65) and PL+ENZ (N=64) (Table). Median PCWG2-PFS was 3.7 mos (LY+ENZ) vs 2.9 mos (PL+ENZ) (HR 0.66, 95% CI 0.43, 0.99; p-value 0.0208). Conclusions: Combination LY+ENZ had a clinically manageable safety profile. The primary end-point of PCWG2-PFS was met and is supported by a clinically meaningful delay in rPFS in AR-V7 negative pts. The biomarker data provide important insights to inform future development strategies. Clinical trial information: NCT02407054. [Table: see text]

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.

Objective To offer recommendations on identification of disease progression, treatment management strategies, and suggestions on timing of initiating and discontinuing specific castration-resistant prostate cancer (CRPC) treatments. Materials and Methods The Prostate Cancer Radiographic Assessments for Detection of Advanced Recurrence II Working Group convened to provide guidance on sequencing, combination, or layering of approved treatments for metastatic CRPC based on available data and clinical experience. Results A consensus was developed to address important questions on management of patients with metastatic CRPC. Conclusion In the absence of large-scale clinical trials, the Working Group recommends that patients may best be managed with a layered approach of approved therapies with unique or complimentary mechanisms of action.

BACKGROUND Patients with prostate cancer and their providers face uncertainty as they consider adjuvant radiotherapy (ART) or salvage radiotherapy (SRT) after undergoing radical prostatectomy. The authors prospectively evaluated the impact of the Decipher test, which predicts metastasis risk after radical prostatectomy, on decision making for ART and SRT. METHODS A total of 150 patients who were considering ART and 115 who were considering SRT were enrolled. Providers submitted a management recommendation before processing the Decipher test and again at the time of receipt of the test results. Patients completed validated surveys on prostate cancer (PCa)‐specific decisional effectiveness and PCa‐related anxiety. RESULTS Before the Decipher test, observation was recommended for 89% of patients considering ART and 58% of patients considering SRT. After Decipher testing, 18% (95% confidence interval [95% CI], 12%‐25%) of treatment recommendations changed in the ART arm, including 31% among high‐risk patients; and 32% (95% CI, 24%‐42%) of management recommendations changed in the salvage arm, including 56% among high‐risk patients. Decisional Conflict Scale (DCS) scores were better after viewing Decipher test results (ART arm: median DCS before Decipher, 25 and after Decipher, 19 [P, Use of the Decipher test appears to result in a change in treatment decision making in a substantial percentage of men with prostate cancer who are considering adjuvant or salvage radiotherapy after radical prostatectomy. Decisional effectiveness improves for both patients and providers with use of the Decipher test.

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.

The authors assessed the use of distal third radius dual energy X-ray absorptiometry (DXA) concomitantly with central (hip and lumbar spine) DXA to identify men with osteopenia or osteoporosis receiving androgen deprivation therapy (ADT) for prostate cancer. Initial classification with central DXA demonstrated 60 (17%) normal, 187 (55%) osteopenic, and 96 (28%) osteoporotic patients. Sixteen of 60 (27%) normal patients were reclassified as osteopenic (14) or osteoporotic (2), and 20 of 187 (11%) osteopenic patients were reclassified as osteoporotic with the combination of central DXA plus distal third radius DXA. The difference in reclassification was statistically significant. The addition of distal third radius to central DXA scanning in men with bone loss associated with ADT identifies a statistically significant number of men being reclassified as having osteopenia or osteoporosis. Combined central and distal third radius DXA scanning should be considered routine in the evaluation of all men suspected of bone loss associated with ADT. This has specific significant clinical relevance because of the large number of men with nonevaluable central DXA studies. Fracture risk prediction and treatment recommendations based on this reclassification will need to be determined by follow-up studies.

Denosumab, a fully human monoclonal antibody against RANK ligand, increased bone mineral density (BMD) and reduced fracture risk vs placebo in a phase 3 trial in men with prostate cancer on androgen deprivation therapy (ADT). The present analysis of this study evaluated BMD changes after 36 months in responder subgroups and in individual patients for three key skeletal sites (lumbar spine (LS), femoral neck (FN) and total hip (TH)) and the distal radius. Men with nonmetastatic prostate cancer receiving ADT were treated with subcutaneous denosumab 60 mg (n=734) or placebo (n=734) every 6 months for up to 36 months in a phase 3, randomized, double-blind study. Patients were instructed to take supplemental calcium and vitamin D. For this BMD responder analysis, the primary outcome measure was the percentage change in BMD from baseline to month 36 at the LS, FN and TH as measured by dual-energy X-ray absorptiometry. BMD at the distal 1/3 radius at 36 months was measured in a substudy of 309 patients. 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%; FN, 48 vs 13%; TH, 48 vs 6%; distal 1/3 radius, 40 vs 7% (P

Androgen deprivation therapy is associated with fracture risk in men with prostate cancer. We assessed the effects of toremifene, a selective estrogen receptor modulator, on fracture incidence in men receiving androgen deprivation therapy during a 2-year period.In this double-blind, placebo controlled phase III study 646 men receiving androgen deprivation therapy for prostate cancer were assigned to toremifene (80 mg by mouth daily) and 638 were assigned to placebo. Subjects were followed for 2 years. The primary study end point was new vertebral fractures. Secondary end points included fragility fractures, bone mineral density and lipid changes.The 2-year incidence of new vertebral fractures was 4.9% in the placebo group vs 2.5% in the toremifene group, a significant relative risk reduction of 50% (95% CI -1.5 to 75.0, p = 0.05). Toremifene significantly increased bone mineral density at the lumbar spine, hip and femoral neck vs placebo (p0.0001 for all comparisons). There was a concomitant decrease in markers of bone turnover (p0.05 for all comparisons). Toremifene also significantly improved lipid profiles. Venous thromboembolic events occurred more frequently with toremifene than placebo with 7 subjects (1.1%) in the placebo group experiencing a venous thromboembolic event vs 17 (2.6%) in the toremifene group. Other adverse events were similar between the groups.Toremifene significantly decreased the incidence of new vertebral fractures in men receiving androgen deprivation therapy for prostate cancer. It also significantly improved bone mineral density, bone turnover markers and serum lipid profiles.

Purpose Zoledronic acid (ZA) or denosumab treatment reduces skeletal-related events; however, the safety of prolonged therapy has not been adequately studied. Here, we describe safety results of extended denosumab therapy in patients with bone metastases from the open-label extension phase of two phase 3 trials. Methods Patients with metastatic breast or prostate cancer received subcutaneous denosumab 120 mg Q4W or intravenous ZA 4 mg Q4W in a double-blinded fashion. Denosumab demonstrated superior efficacy in the blinded treatment phase; thus, patients were offered open-label denosumab for up to an additional 2 years. Results Cumulative median (Q1, Q3) denosumab exposure was 19.1 (9.2, 32.2) months in the breast cancer trial (n = 1019) and 12.0 (5.6, 21.3) months in the prostate cancer trial (n = 942); 295 patients received denosumab for >3 years. No new safety signals were identified during the open-label phase, or among patients who switched from ZA to denosumab. During the blinded treatment phase, exposure-adjusted subject incidences of osteonecrosis of the jaw (ONJ) were 49 (1.9 %) and 31 (1.2 %) in the denosumab and ZA groups, respectively. In total, 32 (6.9 %) and 25 (5.5 %) new cases of ONJ (not adjusted for exposure) were reported for patients continuing and switching to denosumab, respectively. The incidences of hypocalcemia were 4.3 and 3.1 %, in patients continuing and switching to denosumab, respectively. Conclusion These results describe the safety profile of denosumab after long-term exposure, or after switching to denosumab from ZA. No new safety signals were identified. Hypocalcemia rates were similar in the blinded treatment and open-label phases. ONJ rates increased with increasing exposure to antiresorptives, consistent with previous reports.

A randomized, double-blind, dose finding, placebo controlled, parallel group clinical study was done to determine the incidence of prostate cancer in men with high grade prostatic intraepithelial neoplasia treated with toremifene.A total of 514 patients with high grade prostatic intraepithelial neoplasia and no evidence of prostate cancer on screening biopsy were randomized to 20, 40 or 60 mg toremifene, or placebo daily for 12 months. Patients underwent re-biopsy at 6 and 12 months.The number of evaluable patients, that is those with 1 on study biopsy who were compliant, was 447. The cumulative risk of prostate cancer was decreased in patients on 20 mg toremifene compared with placebo (24.4% vs 31.2%, p0.05). The annualized rate of prevention was 6.8 cancers per 100 men treated. In patients with no biopsy evidence of cancer at baseline and 6 months, the 12-month incidence of prostate cancer was decreased by 48.2% with 20 mg toremifene compared with placebo (9.1% vs 17.4%, p0.05). The 20 mg dose was most effective but cumulative and 12-month incidences of prostate cancer were lower for each toremifene dose vs placebo with a cumulative risk of 29.2% and 28.1%, and a 12-month incidence of 14.3% and 13.0% for 40 and 60 mg, respectively. Gleason scores were similar across treatments. The overall incidence of drug related and serious adverse events did not differ between any of the toremifene groups and the placebo group.Toremifene decreased the incidence of prostate cancer by 1 year and had a tolerability profile comparable to that of placebo in a high risk population.

Overactive bladder (OAB) syndrome is characterized by urinary frequency and urgency with or without urge incontinence, and often accompanied by nocturia. The prevalence of OAB increases with aging; it is a particularly common condition among the elderly, affecting at least 25% of people agedor = 65 years.The goal of this study was to assess the efficacy and tolerability of solifenacin 5 and 10 mg once daily for treating elderly subjects with OAB.This was a retrospective analysis of pooled data from 4 studies. Data were analyzed from elderly subjects (agedor = 65 years) with OAB who were treated with solifenacin in four 12-week, double-blind, Phase III, international, multicenter, randomized, parallel-group, fixed-dose, placebo-controlled studies and from elderly subjects who received solifenacin in a 40-week, open-label, flexible-dose extension trial that enrolled subjects who completed 2 of the double-blind studies. Micturition data were collected from diaries completed during the 3 days before each study visit. Efficacy end points included mean change from baseline for the number of incontinence episodes/24 hours, urgency episodes/24 hours, number of micturitions/24 hours, and volume voided/micturition. The proportion of subjects who became continent or had no urgency episodes at end point was also evaluated.The mean age of the subjects in the 12-week, double-blind studies (N = 1045; 781 women, 264 men) was 71.9 years; mean age in the 40-week extension trial (N = 509; 359 women, 150 men) was 71.2 years. The majority of subjects (74.7% in the 12-week, double-blind studies and 70.5% in the 40-week extension trial) were female, and90% of the elderly subjects were white. The duration of OAB ranged from 0 to 66 months, and 43.7% had received previous medical therapy for OAB. The completion rate for elderly subjects was 85.5% for the 12-week, double-blind studies and 80.0% for the 40-week extension trial. Efficacy end points at week 12 of double-blind treatment demonstrated statistically significant improvements in the symptoms of OAB with solifenacin compared with placebo. Mean (SE) changes in number of incontinence episodes/24 hours were -1.5 (0.17) for the 5-mg dose and -1.9 (0.14) for the 10-mg dose compared with -1.0 (0.14) for placebo (P = 0.013 for the 5-mg dose and P0.001 for the 10-mg dose, vs placebo); mean (SE) changes in the number of urgency episodes/24 hours were -3.2 (0.27) for the 5-mg dose and -3.2 (0.19) for the 10-mg dose compared with -1.6 (0.18) for placebo (P0.001 for both doses vs placebo); mean (SE) changes in the number of micturitions/24 hours were -2.0 (0.17) for the 5-mg dose and -2.5 (0.13) for the 10-mg dose compared with -1.1 (0.13) for placebo (P0.001 for both doses vs placebo); mean (SE) changes in the volume voided/micturition were 30.2 (3.24) mL for the 5-mg dose and 46.2 (2.55) mL for the 10-mg dose, compared with 9.1 (2.39) mL for placebo (P0.001 for both doses vs placebo). The proportion of subjects with restoration of continence was 49.1% and 47.3% of the 5- and 10-mg treatment groups, respectively, compared with 28.9% of the placebo group (P0.001 for both doses vs placebo). The proportion of subjects with resolution of urgency was 34.6% and 24.9% for the 5- and 10-mg treatment groups, respectively, compared with 16.9% of the placebo group (P0.001 for the 5-mg dose and P0.01 for the 10-mg dose). Improvements in incontinence, urgency, and micturitions were maintained during the 40-week extension trial. The most common adverse events in both the double-blind and extension trials were dry mouth, constipation, and urinary tract infection. Most adverse events were mild to moderate in nature and did not result in treatment discontinuation.In these pooled analyses, solifenacin 5 and 10 mg once daily were efficacious and well tolerated in the treatment of these elderly subjects with OAB. Solifenacin therapy was also associated with a high level of persistence in a 40-week extension trial.

In this multicenter, open-label study of extended- and immediate-release oxybutynin chloride, community-dwelling participants were studied for up to 12 months to evaluate the long-term safety profile of extended-release oxybutynin. Quality-of-life assessments designed to measure the impact of incontinence and evaluate treatment outcome were used to study subjective improvement. A total of 904 women and 163 men (mean age 64 years, range 29-91 years) were enrolled. The majority of discontinuations were in the first 3 months (25.5%); of those who continued after 3 months, 62% remained on extended-release oxybutynin chloride for one year. The majority of discontinuations were for adverse events; dry mouth was the most frequently cited event leading to discontinuation (8.4%). Significant improvements were seen in QOL measures. Long-term therapy with extended-release oxybutynin chloride was generally well tolerated and effective, improving quality of life significantly in participants with overactive bladder over 3-12 months of therapy.

Background The 4Kscore combines measurement of four kallikreins in blood with clinical information as a measure of the probability of significant (Gleason ≥7) prostate cancer (PCa) before prostate biopsy. Objective To perform the first prospective evaluation of the 4Kscore in predicting Gleason ≥7 PCa in the USA. Design, setting, and participants Prospective enrollment of 1012 men scheduled for prostate biopsy, regardless of prostate-specific antigen level or clinical findings, was conducted at 26 US urology centers between October 2013 and April 2014. Intervention The 4Kscore. Outcome measurements and statistical analysis The primary outcome was Gleason ≥7 PCa on prostate biopsy. The area under the receiver operating characteristic curve, risk calibration, and decision curve analysis (DCA) were determined, along with comparisons of probability cutoffs for reducing the number of biopsies and their impact on delaying diagnosis. Results and limitations Gleason ≥7 PCa was found in 231 (23%) of the 1012 patients. The 4Kscore showed excellent calibration and demonstrated higher discrimination (AUC 0.82) and net benefit compared to a modified Prostate Cancer Prevention Trial Risk Calculator 2.0 model and standard of care (biopsy for all men) according to DCA. A possible reduction of 30–58% in the number biopsies was identified with delayed diagnosis in only 1.3–4.7% of Gleason ≥7 PCa cases, depending on the threshold used for biopsy. Pathological assessment was performed according to the standard of care at each site without centralized review. Conclusion The 4Kscore showed excellent diagnostic performance in detecting significant PCa. It is a useful tool in selecting men who have significant disease and are most likely to benefit from a prostate biopsy from men with no cancer or indolent cancer. Patient summary The 4Kscore provides each patient with an accurate and personalized measure of the risk of Gleason ≥7 cancer to aid in decision-making regarding the need for prostate biopsy.

Context: Myostatin is a negative regulator of muscle growth. Androgen deprivation (ADT) is associated with muscle loss and increased body fat, and currently available therapies have limited efficacy to treat this complication. The antimyostatin peptibody (AMG 745/Mu-S) markedly attenuated muscle loss and decreased fat accumulation in orchiectomized mice. Objective: The objective of the study was to evaluate the safety, pharmacokinetics, and muscle efficacy of AMG 745 in men undergoing ADT for nonmetastatic prostate cancer. Methods: This was a randomized, blinded, placebo-controlled, multiple-dose, phase 1 study of AMG 745 given for 28 days. The end point of percentage change from baseline in lean body mass (LBM) as assessed by dual x-ray absorptiometry was prespecified. Results: Rates of adverse events (AMG 745 vs placebo) were the following: diarrhea (13% vs 9%), fatigue (13% vs 4%), contusion (10% vs 0%), and injection site bruising (6% vs 4%). Exposure increased linearly from 0.3 mg/kg to 3 mg/kg. AMG 745 significantly increased LBM in the 3 mg/kg vs the placebo groups on day 29 by 2.2% (±0.8% SE, P = 0.008); in exploratory fat mass analysis, a decrease of −2.5% (±1.0% SE, P = 0.021) was observed. Pharmacodynamic changes in muscle and fat were maintained at follow-up, 1 month after day 29. Conclusion: Four weekly sc doses of AMG 745 were well tolerated and were associated with increased LBM and decreased fat in the men receiving ADT for nonmetastatic prostate cancer. Results support further investigation of AMG 745 in clinical settings with muscle loss and atrophy.

Daniel Lin*, Seattle, WA; Shawn McGee, Sartell, MN; Kimberly Rieger-Christ, Burlington, MA; Neal Shore, Myrtle Beach, SC; Christopher Pieczonka, Syracuse, NY; James Cochran, Dallas, TX; Raoul Concepcion, Nashville, TN; Igor Dumbadze, Cincinnati, OH; Kenneth Deck, Laguna Hills, CA; James Bailen, Jeffersonville, IN; Ralph Jonathan Henderson, Shreveport, LA; Paul Sieber, Lancaster, PA; Timothy Dean Langford, Little Rock, AR; Scott Asroff, Mt. Laurel, NJ; Todd Waldmann, Meridian, ID

OBJECTIVES To evaluate whether the increased number of rectal perforations associated with contemporary transrectal ultrasound-guided, 12-core prostate biopsy, with a periprostatic block, is associated with a greater rate of postprocedural complications. METHODS We prospectively studied 1000 patients undergoing contemporary transrectal ultrasound-guided prostate biopsy and compared the rates of complicated urinary tract infection and significant rectal bleeding with the rates in our previous report of complications using a then-standard, 6-core biopsy technique, without a periprostatic block. RESULTS Three patients developed complicated urinary tract infections, two of which were with ciprofloxacin-resistant organisms. This was not a significant different statistically from our earlier report. Seven patients had significant rectal bleeding requiring endoscopic intervention. This rate also was not significantly different statistically from our earlier report. CONCLUSIONS Our infection and rectal bleeding complications associated with contemporary transrectal ultrasound-guided prostate biopsy were low. We experienced a small, nonstatistically significant, increase in the complicated urinary tract infection rate and a small, nonstatistically significant, increase in the rectal bleeding rate in association with the transition from an eight-core, no periprostatic block, technique to the contemporary technique.

A number of targeted agents under investigation or in development have shown promise in the treatment or prevention of bone metastases. Among them is denosumab (XGEVA, Amgen Inc.), a fully human monoclonal antibody targeting the RANK ligand (RANKL) pathway that was approved on 18 November 2010 in the United States (Amgen XGEVA [denosumab] prescribing information, 2012). Denosumab has been proven superior to zoledronic acid in preserving skeletal function and integrity by preventing skeletal complications among patients with bone metastases from solid tumors. Denosumab has demonstrated prolongation of bone metastasis-free survival in men with castration-resistant prostate cancer and is being investigated for this outcome in women with early-stage breast cancer. Another study is prospectively evaluating a potential prolongation of overall survival with denosumab in patients with metastatic lung cancer. Also currently in development are numerous targeted agents that impact the function of the various growth factors released from the bone matrix that stimulate tumor growth, bone destruction, and lead to bone metastases.

Prostate cancer is often associated with metastases to bone and/or soft tissue. The progression to metastatic castrate-resistant prostate cancer is a seminal event in disease progression affecting treatment decisions. A multidisciplinary group was convened to review the currently available imaging guidelines for metastatic disease in prostate cancer and found no consensus on eligibility criteria, type of imaging modality, and the frequency of scanning for detecting metastatic disease. The aim of this review was to present the recommendations from the group to identify optimal strategies for early identification of metastases in patients with prostate cancer.

Purpose Prostate cancer (PCa) prevention remains an appealing strategy for the reduction of overtreatment and secondary adverse effects. We evaluated the efficacy of toremifene citrate 20 mg in PCa prevention among men with isolated high-grade prostatic intraepithelial neoplasia (HGPIN) on biopsy. Patients and Methods One thousand five hundred ninety men with HGPIN, or HGPIN and atypia, and no PCa on prostate biopsy were randomly assigned 1:1 to receive toremifene citrate 20 mg or placebo in a 3-year phase III, double-blind, multicenter trial. Men underwent annual biopsy until cancer detection or study end. Efficacy analysis was performed in 1,467 men who underwent at least one on-study biopsy. Baseline risk factors were evaluated to determine influence on cancer detection. Results Cancer was detected in 34.7% and 32.3% of men in the placebo and treatment groups, respectively, with no observed difference (P = .39, log-rank test) in PCa-free survival. The 3-year Kaplan-Meier PCa-free survival estimate was 54.9% (99% CI, 43.3% to 66.5%) in the placebo group and 59.5% (99% CI, 48.1% to 70.9%) in the treatment group. Exploration of baseline risk factors demonstrated no subset in which a risk reduction was observed. In the placebo group, 17.9%, 12.9%, and 13.6% of men at risk at the beginning of years 1, 2, and 3, respectively, were diagnosed with PCa. Conclusion Although toremifene 20 mg did not lower the PCa detection rate, men with isolated HGPIN have a high likelihood of eventual PCa diagnosis, demonstrating they are ideal candidates for inclusion in chemoprevention trials and require surveillance by periodic prostate biopsy.

Purpose: We assessed the use of combination bowel preparation before radical prostatectomy.Materials and Methods: We reviewed 533 radical prostatectomies performed from 1984 to 1994. All patients underwent preoperative combination bowel preparation. The incidence, management and sequelae of rectal injury were determined. The literature addressing the management of rectal injuries was reviewed.Results: Rectal injury occurred in 8 patients (1.5 percent). Injury was recognized intraoperatively and repaired primarily in 6 cases, and repair included colostomy in 2. Injury was recognized postoperatively as recto-urinary fistula in 2 cases and initial management was conservative. No fistula closed with conservative management. There were no pelvic abscesses and no deaths.Conclusions: Combination bowel preparation permits safe closure of rectal injury at radical prostatectomy without the necessity of routine colostomy. In the event of recto-urinary fistula, conservative management is not warranted.

200 Background: Gonadotropin-releasing hormone (GnRH) antagonists achieve rapid decrease in testosterone (T) without transient T surge seen with GnRH agonists and thus may avoid clinical flare symptomatology. TAK-385 is an investigational, oral, non-peptide GnRH antagonist highly selective for the human GnRH receptor (IC50 0.12 nM). We report IA2 results from a phase 2, randomized, open label, parallel group study of TAK-385 in pts with advanced prostate cancer (NCT02083185). Methods: Pts aged ≥ 18 yrs with histologically confirmed prostate cancer, baseline T > 150 ng/dL and prostate-specific antigen (PSA) > 2 ng/mL, who were candidates for first-line androgen deprivation therapy, were randomized to receive oral TAK-385, 80 or 120 mg, once daily (QD) or leuprorelin (LEU) 22.5 mg subcutaneously every 12 wks, for 48 wks. The primary endpoint was effective castration rate of TAK-385 (T < 50 ng/dL) from wk 5–24. Secondary endpoints included: safety, pharmacokinetics (PK), and PSA. Results: At data cut-off, 75 pts had received TAK-385 (39 at 80 mg, 36 at 120 mg QD); 20 pts received LEU. Median age was 73 yrs with TAK-385 and 68.5 yrs with LEU; median treatment duration was 35.1 wks and 37.8 wks. After 3 days/4 wks/24 wks of treatment, median T was 36.9/10.6/8.9 ng/dL with TAK385 vs 648.1/13.0/11.5 ng/dL with LEU. T < 50 ng/dL was sustained over 5–24 wks in 92% vs 95% of pts (TAK-385 vs LEU). After 24 wks, PSA was reduced by 97.3% to a median of 0.1 ng/mL with TAK-385 vs 92.4% to 0.2 ng/mL with LEU. All-grade adverse events occurred in 91% vs 95% of pts (TAK-385 vs LEU); the most common were hot flush (59/60%), fatigue (21/15%), elevated alanine aminotransferase (9/10%), nasopharyngitis (8/5%), and elevated aspartate aminotransferase (5/10%). Initial analysis of pooled phase 1/2 data showed similar PK in the phase 2 pts and in previously studied healthy men, with dose-proportional plasma trough levels over > 6 mos. Conclusions: At IA2, the efficacy of TAK-385 was consistent with the GnRH antagonist mechanism of action and the safety profile was good. TAK-385 rapidly reduced T and sustained castration ( < 50 ng/dL) over 24 wks. Further investigation of TAK-385, as an option to injectable GnRH therapies, is warranted. Clinical trial information: NCT02083185.

Matthew Smith*, Boston, MA; Fred Saad, Montreal, Canada; Neal Shore, Myrtle Beach, SC; Stephane Oudard, Paris, France; Kurt Miller, Berlin, Germany; Bertrand Tombal, Bruxelles, Belgium; Paul Sieber, Lancaster, PA; Karim Fizazi, Villejuif, France; Peter Van Veldhuizen, Kansas City, MO; Ronaldo Damiao, Rio de Janeiro, Brazil; Gavin Marx, Wahroonga, Australia; Juan Morote, Barcelona, Spain; Amy Feng, Roger Dansey, Carsten Goessl, Thousand Oaks, CA

Since 1989 we have used serum prostate specific antigen (PSA) levels as an indication for ultrasound guided systematic biopsies of the prostate. Realizing that the PSA level in part reflects prostatic glandular epithelial volume, we reviewed the accumulated data on our last 2,340 biopsies to determine if the quotient of PSA and prostatic volume, prostate specific antigen density, provided any further diagnostic information. There were evaluable data for 2,020 patients. Prostate specific antigen density levels are shown to have a strong correlation with the diagnosis of prostate cancer and provide a more reliable indication for ultrasound guided biopsy of the prostate than PSA alone.

Summary Background Bone metastases are a major cause of morbidity and mortality in men with prostate cancer. Preclinical studies suggest that osteoclast inhibition might prevent bone metastases. We assessed denosumab, a fully human anti-RANKL monoclonal antibody, for prevention of bone metastasis or death in non-metastatic castration-resistant prostate cancer. Methods In this phase 3, double-blind, randomised, placebo-controlled study, men with non-metastatic castration-resistant prostate cancer at high risk of bone metastasis (prostate-specific antigen [PSA] ≥8·0 μg/L or PSA doubling time ≤10·0 months, or both) were enrolled at 319 centres from 30 countries. Patients were randomly assigned (1:1) via an interactive voice response system to receive subcutaneous denosumab 120 mg or subcutaneous placebo every 4 weeks. Randomisation was stratified by PSA eligibility criteria and previous or ongoing chemotherapy for prostate cancer. Patients, investigators, and all people involved in study conduct were masked to treatment allocation. 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 from any cause. Efficacy analysis was by intention to treat. The masked treatment phase of the trial has been completed. This trial was registered at ClinicalTrials.gov, number NCT00286091. Findings 1432 patients were randomly assigned to treatment groups (716 denosumab, 716 placebo). Denosumab significantly increased bone-metastasis-free survival by a median of 4·2 months compared with placebo (median 29·5 [95% CI 25·4–33·3] vs 25·2 [22·2–29·5] months; hazard ratio [HR] 0·85, 95% CI 0·73–0·98, p=0·028). Denosumab also significantly delayed time to first bone metastasis (33·2 [95% CI 29·5–38·0] vs 29·5 [22·4–33·1] months; HR 0·84, 95% CI 0·71–0·98, p=0·032). Overall survival did not differ between groups (denosumab, 43·9 [95% CI 40·1–not estimable] months vs placebo, 44·8 [40·1–not estimable] months; HR 1·01, 95% CI 0·85–1·20, p=0·91). Rates of adverse events and serious adverse events were similar in both groups, except for osteonecrosis of the jaw and hypocalcaemia. 33 (5%) patients on denosumab developed osteonecrosis of the jaw versus none on placebo. Hypocalcaemia occurred in 12 (2%) patients on denosumab and two ( Interpretation This large randomised study shows that targeting of the bone microenvironment can delay bone metastasis in men with prostate cancer. Funding Amgen Inc.

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 prespecified 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) versus placebo (1468 patients, 734 in each group) on BTM values. BTMs were measured at baseline, month 1, and predose 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 versus ≥ 70 years), prior duration of ADT (≤ 6 months versus6 months), and baseline BTM (≤ median versus 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 0.0001). The median change in TRAP-5b levels at month 1 was -55% in the denosumab group and -3% in the placebo group (p 0.0001). The maximal median change in P1NP was -64% in the denosumab group and -11% in the placebo group, (p 0.0001). 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.

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.

We evaluated the effects of toremifene on bone mineral density, a surrogate for fracture risk, in men receiving androgen deprivation therapy for prostate cancer.In an ongoing, multicenter, phase 3 fracture prevention study 1,392 men 50 years or older with prostate cancer receiving androgen deprivation therapy were randomized to 80 mg toremifene per day or placebo. Bone mineral density of the lumbar spine, total hip and femoral neck was assessed using dual energy x-ray absorptiometry. In this planned interim analysis of the first 197 subjects we compared bone mineral density changes from baseline to month 12 between the placebo and toremifene groups.Compared with the placebo group men in the toremifene group had significant increases in bone mineral density at each evaluated skeletal site. Lumbar spine bone mineral density decreased 0.7% in the placebo group and increased 1.6% in the toremifene group (between group comparison p0.001). Total hip bone mineral density decreased 1.3% in the placebo group and increased 0.7% in the toremifene group (p = 0.001). Femoral neck bone mineral density decreased 1.3% in the placebo group and increased 0.2% in the toremifene group (p = 0.009). Between group differences in the change in bone mineral density from baseline to month 12 were 2.3%, 2.0% and 1.5% for the lumbar spine, total hip and femoral neck, respectively.Toremifene significantly increased hip and spine bone mineral density in men receiving androgen deprivation therapy for prostate cancer. The effect of toremifene on the fracture risk is being assessed in the ongoing randomized, controlled trial.

Purpose: We initiated a prospective study to verify or refute the complications of lymphocele formation and excessive blood loss associated with heparin prophylaxis in pelvic lymphadenectomy and radical prostatectomy.Materials and Methods: A prospective study was completed on 579 men undergoing pelvic lymphadenectomy usually in association with radical prostatectomy. Patients were assigned to group 1 (given preoperative and postoperative subcutaneous heparin) and group 2 (no heparin). All patients were evaluated 2 to 3 weeks after surgery with ultrasound for pelvic lymphocele.Results: There was no statistically significant difference in the number or size of pelvic lymphoceles or blood loss in group 1 versus group 2.Conclusions: The use of heparin prophylaxis to prevent thromboembolic complications in conjunction with pelvic lymphadenectomy and radical prostatectomy is not associated with increased blood loss or increased rate of lymphocele formation.

144 Background: The goal of medical androgen deprivation therapy (ADT) for advanced prostate cancer is to provide an equivalency to orchiectomy based upon older assays for serum testosterone (T). Literature shows that based on more modern assays, medical ADT does not always provide optimal total T suppression equivalent to orchiectomy. With the understanding that free, or unbound, T is the biologically and clinically relevant component, the therapeutic goal of ADT should be to decrease free T to levels similar to orchiectomy. Free T has not been well studied in a substantial number of orchiectomized men. The purpose of this study was to examine a subpopulation of orchiectomized men in a clinical trial to determine the level of serum-free T in advanced prostate cancer. Methods: Baseline data was utilized from a double blind, randomized, placebo controlled trial (G300203) to determine the capacity of toremifene 80 mg to prevent bone fractures in men on ADT. This study included 1,389 men from 150 sites in the U.S. and Mexico. Baseline characteristics, including whether men were on medical ADT or status post orchiectomy, were available. Free T levels were assayed at baseline by radioimmunoassay (RIA) (Diagnostic Products Corporation) and are reported for men who underwent orchiectomy. Results: A subpopulation of 114 men underwent orchiectomy. Median age was 76 (range 51 to 90). Median serum free T level was 0.92 pg/ml (min. 0.35 pg/ml and max. 33.95 pg/ml) with a mean level of 1.71 pg/ml ± 2.77. Conclusions: This study is believed to be the largest cohort in which free T levels have been reported in men who underwent orchiectomy. In this cohort, median serum free T is approximately 0.9 pg/ml. This value could be considered to be the optimal testosterone suppression of free T with orchiectomy and represents the goal of medical ADT. At the time this study was performed, RIA was considered to be the standard but has since been shown to underestimate free T levels by 20 to 60%. Currently, equilibrium dialysis coupled with LC-MS/MS is the gold standard, but the results from this analysis provide us with increased understanding of the optimal level of free T in treating advanced prostate cancer. Clinical trial information: NCT00129142.

Can tamoxifen or anastrozole prevent bicalutamide-induced gynecomastia and breast pain in prostate cancer?