Extended Safety and Tolerability of Darolutamide for Nonmetastatic Castration-Resistant Prostate Cancer and Adverse Event Time Course in ARAMIS.

BACKGROUND: Patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) are usually asymptomatic and seek treatments that improve survival but have a low risk of adverse events. Darolutamide, a structurally distinct androgen receptor inhibitor (ARi), significantly reduced the risk of metastasis and death versus placebo in ARAMIS. We assessed the extended safety and tolerability of darolutamide and the time-course profile of treatment-emergent adverse events (TEAEs) related to ARis and androgen-suppressive treatment. PATIENTS AND METHODS: Patients with nmCRPC were randomized 2:1 to darolutamide (n = 955) or placebo (n = 554). After trial unblinding, patients could receive open-label darolutamide. Tolerability and TEAEs were assessed every 16 weeks. Time interval-specific new and cumulative event rates were determined during the first 24 months of the double-blind period. RESULTS: Darolutamide remained well tolerated during the double-blind and open-label periods, with 98.8% of patients receiving the full planned dose. The incidence of TEAEs of interest in the darolutamide group was low and ≤2% different from that in the placebo group, except for fatigue. When incidences were adjusted for exposure time, there were minimal differences between the darolutamide double-blind and double-blind plus open-label periods. The rate of initial onset and cumulative incidence of grade 3/4 TEAEs and serious TEAEs were similar for darolutamide and placebo groups over 24 months. CONCLUSION: Extended treatment with darolutamide was well tolerated and no new safety signals were observed. Most ARi-associated and androgen-suppressive treatment-related TEAEs occurred at low incidences with darolutamide, were similar to placebo, and showed minimal increase over time with continued treatment. TRIAL NUMBER: ClinicalTrials.gov identifier NCT02200614.

Impact of Late Dosing on Testosterone Suppression with 2 Different Leuprolide Acetate Formulations: In Situ Gel and Microsphere. An Analysis of United States Clinical Data.

PURPOSE: Nonadherence to dosing schedules for androgen deprivation therapy increases the risk of testosterone escape for patients with prostate cancer. Two approved formulations of leuprolide acetate, the most commonly prescribed androgen deprivation therapy in the United States, use different extended release delivery technologies: an in situ gel and microspheres. We evaluated the prevalence and impact of late dosing on testosterone suppression for gel and microsphere formulations of leuprolide acetate. MATERIALS AND METHODS: We retrospectively analyzed records of patients with prostate cancer treated with gel or microsphere delivery of leuprolide acetate. Analyses used 2 definitions of "month," "28-day" (late dosing after day 28, 84, 112 or 168) and "extended" (late dosing after day 32, 97, 128 and 194). Frequencies of late dosing and associated testosterone values were calculated. RESULTS: A total of 2,038 patients received gel and 8,360 received microsphere formulations of leuprolide acetate. More than 80% and 27% of injections were late for 28-day and extended month, respectively. For 28-day month late injections 10% (gel delivery) and 14% (microsphere delivery) of testosterone values were above 50 ng/dl, and 25% (gel) vs 33% (microsphere) were above 20 ng/dl. For extended month 18% (gel) vs 25% (microsphere) were above 50 ng/dl, and 34% (gel) vs 44% (microsphere) were above 20 ng/dl. Microsphere leuprolide acetate was 1.5 times more likely to have testosterone above 50/20 ng/dl vs gel. Least square mean testosterone was 34 ng/dl (gel) vs 46 ng/dl (microsphere) for 28-day month, and 48 ng/dl (gel) vs 76 ng/dl (microsphere) for extended month. CONCLUSIONS: Leuprolide acetate therapies were frequently administered late. Gel formulation demonstrated higher rates of testosterone 50 ng/dl or less and 20 ng/dl or less than microsphere formulation. Optimal testosterone suppression can impact prostate cancer progression and patient survival, and differences in extended release technology for androgen deprivation therapy appear relevant.

Optimizing the management of castration-resistant prostate cancer patients: A practical guide for clinicians.

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.

The Impact of Late Luteinizing Hormone-Releasing Hormone Agonist Dosing on Testosterone Suppression in Patients with Prostate Cancer: An Analysis of United States Clinical Data.

PURPOSE: We evaluated the timeliness of androgen deprivation therapy dosing, the impact of dosing nonadherence on testosterone, and the frequency of testosterone and prostate specific antigen testing in patients with prostate cancer. MATERIALS AND METHODS: We retrospectively analyzed the records of 22,860 patients with prostate cancer treated with luteinizing hormone-releasing hormone agonists. Analyses were done using 2 definitions of month, including a 28-day month (late dosing after day 28, 84, 112 or 168) and an extended month (late after day 32, 97, 128 or 194) for 1, 3, 4 and 6-month formulations, respectively. The prevalence of late dosing, associated testosterone values, and the frequency of testosterone and prostate specific antigen testing were assessed. Statistical significance was assessed with the unpaired t-test. RESULTS: Of the injections 84% and 27% were late for the 28-day and extended month analyses, respectively. For the 28-day month 60% and 29% of injections were late by more than 1 and more than 2 weeks, respectively. Of testosterone values 4% were greater than 50 ng/dl for early/on time injections using both definitions, and 15% and 27% were greater than 50 ng/dl when late, and for the 28-day month and the extended month, respectively. For early/on time vs late injections 22% vs 31% of testosterone values were greater than 20 ng/dl for the 28-day month and 21% vs 43% for the extended month. Mean testosterone was higher when late (49 ng/dl for 28-day month, 79 ng/dl for extended month) vs early/on time (both 21 ng/dl). Of the injections prostate specific antigen measurements were performed in 83% and testosterone assessment was done in only 13%. CONCLUSIONS: Luteinizing hormone-releasing hormone agonists were frequently (84%) administered later than the schedules used in pivotal trials. Nearly half of the late testosterone values for the extended month were greater than 20 ng/dl and mean testosterone was almost double the castration level. Elevated testosterone remained unidentified with infrequent testing.

Real-world outcomes of sipuleucel-T treatment in PROCEED, a prospective registry of men with metastatic castration-resistant prostate cancer.

BACKGROUND: The large registry, PROVENGE Registry for the Observation, Collection, and Evaluation of Experience Data (PROCEED)(NCT01306890), evaluated sipuleucel-T immunotherapy for asymptomatic/minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC). METHODS: PROCEED enrolled patients with mCRPC receiving 3 biweekly sipuleucel-T infusions. Assessments included overall survival (OS), serious adverse events (SAEs), cerebrovascular events (CVEs), and anticancer interventions (ACIs). Follow-up was for ≥3 years or until death or study withdrawal. RESULTS: In 2011-2017, 1976 patients were followed for 46.6 months (median). The median age was 72 years, and the baseline median prostate-specific antigen level was 15.0 ng/mL; 86.7% were white, and 11.6% were African American. Among the patients, 1902 had 1 or more sipuleucel-T infusions. The median OS was 30.7 months (95% confidence interval [CI], 28.6-32.2 months). Known prognostic factors were independently associated with OS in a multivariable analysis. Among the 1255 patients who died, 964 (76.8%) died of prostate cancer (PC) progression. The median time from the first infusion to PC death was 42.7 months (95% CI, 39.4-46.2 months). The incidence of sipuleucel-T-related SAEs was 3.9%. The incidence of CVEs was 2.8%, and the rate per 100 person-years was 1.2 (95% CI, 0.9-1.6). The CVE incidence among 11,972 patients with mCRPC from the Surveillance, Epidemiology, and End Results-Medicare database was 2.8%; the rate per 100 person-years was 1.5 (95% CI, 1.4-1.7). One or more ACIs (abiraterone, enzalutamide, docetaxel, cabazitaxel, or radium 223) were received by 77.1% of the patients after sipuleucel-T; 32.5% and 17.4% of the patients experienced 1- and 2-year treatment-free intervals, respectively. CONCLUSIONS: PROCEED provides contemporary survival data for sipuleucel-T-treated men in a real-world setting of new life-prolonging agents, which will be useful in discussing treatment options with patients and in powering future trials with sipuleucel-T. The safety and tolerability of sipuleucel-T in PROCEED were consistent with previous findings.

A Clinician's Guide to Next Generation Imaging in Patients With Advanced Prostate Cancer (RADAR III).

PURPOSE: The advanced prostate cancer therapeutic landscape has changed dramatically in the last several years, resulting in improved overall survival of patients with castration naïve and castration resistant disease. The evolution and development of novel next generation imaging techniques will affect diagnostic and therapeutic decision making. Clinicians must navigate when and which next generation imaging techniques to use and how to adjust treatment strategies based on the results, often in the absence of correlative therapeutic data. Therefore, guidance is needed based on best available information and current clinical experience. MATERIALS AND METHODS: The RADAR (Radiographic Assessments for Detection of Advanced Recurrence) III Group convened to offer guidance on the use of next generation imaging to stage prostate cancer based on available data and clinical experience. The group also discussed the potential impact of next generation imaging on treatment options based on earlier detection of disease. RESULTS: The group unanimously agreed that progression to metastatic disease is a seminal event for patient treatment. Next generation imaging techniques are able to detect previously undetectable metastases, which could redefine the phases of prostate cancer progression. Thus, earlier systemic or locally directed treatment may positively alter patient outcomes. CONCLUSIONS: The RADAR III Group recommends next generation imaging techniques in select patients in whom disease progression is suspected based on laboratory (biomarker) values, comorbidities and symptoms. Currently 18F-fluciclovine and 68Ga prostate specific membrane antigen positron emission tomography/computerized tomography are the next generation imaging agents with a favorable combination of availability, specificity and sensitivity. There is ongoing research of additional next generation imaging technologies, which may offer improved diagnostic accuracy and therapeutic options. As next generation imaging techniques evolve and presumably result in improved global accessibility, clinician ability to detect micrometastases may be enhanced for decision making and patient outcomes.

Germline testing for prostate cancer: community urology perspective.

In an attempt to better understand how community urology practices would begin to incorporate hereditary testing in prostate cancer patients, we developed an eight-question on line survey to identify current testing patterns, utilization of genetic counseling and barriers that practices face. Fifty-two large community urology practices participated. A total of 32/52 (63%) of the responders were already offering testing to select patients. The big hurdles practices were concerned when initiating testing were fear of medical/legal liability (22%), concerns over reimbursement and out of pocket patient expense (20%) and the complexity, time and difficulty to enter a complete family history/pedigree into the EHR (18%).

Correction to: Number-needed-to-treat analysis of clinical progression in patients with metastatic castration-resistant prostate cancer in the STRIVE and TERRAIN trials.

It has been highlighted that in the original article [1] there was a typesetting mistake in the Results - NNT in Strive section. This Correction article states the incorrect and correct sentence.

Number-needed-to-treat analysis of clinical progression in patients with metastatic castration-resistant prostate cancer in the STRIVE and TERRAIN trials.

BACKGROUND: This analysis estimated the number needed to treat with enzalutamide versus bicalutamide to achieve one additional patient with chemotherapy-naïve metastatic castration-resistant prostate cancer who would obtain clinical benefit regarding progression-free survival, radiographic progression-free survival, or no prostate-specific antigen progression at 1 and 2 years following treatment initiation. METHODS: Clinical event rates were obtained from the STRIVE (NCT01664923) and TERRAIN (NCT01288911) trials, and the number needed to treat was the inverse of the absolute rate difference between the event rates of enzalutamide and bicalutamide. The 95% Confidence Interval of the number needed to treat was derived from the 95% Confidence Interval of the event rate difference. RESULTS: Using STRIVE data (patients with metastatic disease: n = 128 enzalutamide; n = 129 bicalutamide) comparing enzalutamide with bicalutamide at 1 and 2 years, the numbers needed to treat to achieve one additional patient with chemotherapy-naïve metastatic castration-resistant prostate cancer with progression-free survival were 2.0 and 2.8, respectively; with radiographic progression-free survival, 2.6 and 3.0, respectively; and without prostate-specific antigen progression, 1.8 and 2.4, respectively. Using TERRAIN data (n = 184 enzalutamide; n = 191 bicalutamide) comparing enzalutamide with bicalutamide at 1 and 2 years, the numbers needed to treat to achieve one additional patient with progression-free survival were 4.3 and 3.7, respectively; with radiographic progression-free survival, 10.0 and 2.8, respectively; and without prostate-specific antigen progression, 2.1 and 3.2, respectively. CONCLUSIONS: The combined data from TERRAIN and STRIVE demonstrated that treating chemotherapy-naïve metastatic castration-resistant prostate cancer with enzalutamide leads to more patients without clinical progression at 1 and 2 years than with bicalutamide. TRIAL REGISTRATION: STRIVE (NCT01664923; registration date: August 10, 2012) and TERRAIN (NCT01288911; registration date: February 1, 2011).

Avoiding obsolescence in advanced prostate cancer management: a guide for urologists.

Prostate cancer is one of the most common cancers diagnosed in men in the USA and 20­30% of men treated for localised prostate cancer will fail therapy and develop advanced prostate cancer. More drugs have been approved for the treatment of advanced prostate cancer in the past 3 years than in the past three decades, and each drug has its own mechanism of action and, often, unique monitoring requirements. As the treatment landscape for men with advanced prostate cancer is undergoing significant expansion, the roles of both oncologists and urologists are shifting, and the decision for the urologist to treat vs refer requires early assessment to identify which patients are candidates for these novel treatments and the monitoring of patients for tolerability, response, and potential side-effects. Given these rapid changes, the authors of this review met in January 2013 and again in April 2013 to discuss the current challenges facing urologists in adopting these new treatments into their own practices. Here, we provide a brief overview of advanced prostate cancer medical therapies approved in the past decade, the necessary monitoring procedures and early detection methods needed to safely and effectively manage patients receiving these therapies, and our recommendations for applying these new therapies within different models of urology practice, such that urologists can remain an integral component of their patient's care once he has transitioned into advanced prostate cancer

Development and evaluation of the MiCheck® Prostate test for clinically significant prostate cancer.

BACKGROUND: There is a clinical need to identify patients with an elevated PSA who would benefit from prostate biopsy due to the presence of clinically significant prostate cancer (CSCaP). We have previously reported the development of the MiCheck® Test for clinically significant prostate cancer. Here, we report MiCheck's further development and incorporation of the Roche Cobas standard clinical chemistry analyzer. OBJECTIVES: To further develop and adapt the MiCheck® Prostate test so it can be performed using a standard clinical chemistry analyzer and characterize its performance using the MiCheck-01 clinical trial sample set. DESIGN, SETTINGS, AND PARTICIPANTS: About 358 patient samples from the MiCheck-01 US clinical trial were used for the development of the MiCheck® Prostate test. These consisted of 46 controls, 137 non-CaP, 62 non-CSCaP, and 113 CSCaP. METHODS: Serum analyte concentrations for cellular growth factors were determined using custom-made Luminex-based R&D Systems multi-analyte kits. Analytes that can also be measured using standard chemistry analyzers were examined for their ability to contribute to an algorithm with high sensitivity for the detection of clinically significant prostate cancer. Samples were then re-measured using a Roche Cobas analyzer for development of the final algorithm. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Logistic regression modeling with Monte Carlo cross-validation was used to identify Human Epidydimal Protein 4 (HE4) as an analyte able to significantly improve the algorithm specificity at 95% sensitivity. A final model was developed using analyte measurements from the Cobas analzyer. RESULTS: The MiCheck® logistic regression model was developed and consisted of PSA, %free PSA, DRE, and HE4. The model differentiated clinically significant cancer from no cancer or not-clinically significant cancer with AUC of 0.85, sensitivity of 95%, and specificity of 50%. Applying the MiCheck® test to all evaluable 358 patients from the MiCheck-01 study demonstrated that up to 50% of unnecessary biopsies could be avoided while delaying diagnosis of only 5.3% of Gleason Score (GS) ≥3+4 cancers, 1.8% of GS≥4+3 cancers and no cancers of GS 8 to 10. CONCLUSIONS: The MiCheck® Prostate test identifies clinically significant prostate cancer with high sensitivity and negative predictive value (NPV). It can be performed in a clinical laboratory using a Roche Cobas clinical chemistry analyzer. The MiCheck® Prostate test could assist in reducing unnecessary prostate biopsies with a marginal number of patients experiencing a delayed diagnosis.

Obesity, body composition, and prostate cancer.

BACKGROUND: Established risk factors for prostate cancer have not translated to effective prevention or adjuvant care strategies. Several epidemiologic studies suggest greater body adiposity may be a modifiable risk factor for high-grade (Gleason 7, Gleason 8-10) prostate cancer and prostate cancer mortality. However, BMI only approximates body adiposity, and may be confounded by centralized fat deposition or lean body mass in older men. Our objective was to use bioelectric impedance analysis (BIA) to measure body composition and determine the association between prostate cancer and total body fat mass (FM) fat-free mass (FFM), and percent body fat (%BF), and which body composition measure mediated the association between BMI or waist circumference (WC) with prostate cancer. METHODS: The study used a multi-centered recruitment protocol targeting men scheduled for prostate biopsy. Men without prostate cancer at biopsy served as controls (n = 1057). Prostate cancer cases were classified as having Gleason 6 (n = 402), Gleason 7 (n = 272), or Gleason 8-10 (n = 135) cancer. BIA and body size measures were ascertained by trained staff prior to diagnosis, and clinical and comorbidity status were determined by chart review. Analyses utilized multivariable linear and logistic regression. RESULTS: Body size and composition measures were not significantly associated with low-grade (Gleason 6) prostate cancer. In contrast, BMI, WC, FM, and FFM were associated with an increased risk of Gleason 7 and Gleason 8-10 prostate cancer. Furthermore, BMI and WC were no longer associated with Gleason 8-10 (OR(BMI) = 1.039 (1.000, 1.081), OR(WC) = 1.016 (0.999, 1.033), continuous scales) with control for total body FFM (OR(BMI) = 0.998 (0.946, 1.052), OR(WC) = 0.995 (0.974, 1.017)). Furthermore, increasing FFM remained significantly associated with Gleason 7 (OR(FFM) = 1.030 (1.008, 1.052)) and Gleason 8-10 (OR(FFM) = 1.044 (1.014, 1.074)) after controlling for FM. CONCLUSIONS: Our results suggest that associations between BMI and WC with high-grade prostate cancer are mediated through the measurement of total body FFM. It is unlikely that FFM causes prostate cancer, but instead provides a marker of testosterone or IGF1 activities involved with retaining lean mass as men age.

Enzalutamide versus bicalutamide in patients with nonmetastatic castration-resistant prostate cancer: a prespecified subgroup analysis of the STRIVE trial.

BACKGROUND: In the phase 2, randomized, double-blind STRIVE trial, enzalutamide significantly reduced the risk of prostate cancer progression or death versus bicalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC) and nonmetastatic CRPC (nmCRPC). The objective of this protocol-specified subgroup analysis of STRIVE was to investigate the benefit of enzalutamide versus bicalutamide specifically in patients with nmCRPC. METHODS: Patients (N = 139) were stratified by disease stage and randomized to enzalutamide 160 mg/day plus androgen deprivation therapy (ADT; n = 70) or bicalutamide 50 mg/day plus ADT (n = 69). RESULTS: Baseline characteristics of patients with nmCRPC were comparable between groups. At a median of 17 months follow-up, enzalutamide reduced the risk of progression or death by 76% versus bicalutamide in patients with nmCRPC (hazard ratio [HR], 0.24; 95% CI 0.14-0.42). Enzalutamide reduced risk of prostate-specific antigen progression by 82% versus bicalutamide in patients with nmCRPC (HR, 0.18; 95% CI 0.10-0.34). The most frequently reported adverse events by patients receiving enzalutamide were fatigue (36.2%), hot flush (20.3%), decreased appetite (17.4%), dizziness (17.4%), and nausea (17.4%). CONCLUSIONS: This STRIVE subgroup analysis of patients with nmCRPC illustrates the benefit of enzalutamide in reducing the risk of progression or death versus bicalutamide in patients with nmCRPC. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01664923.

Oxidative stress measured by urine F2-isoprostane level is associated with prostate cancer.

PURPOSE: Oxidative stress is implicated in prostate cancer by several lines of evidence. We studied the relationship between the level of F2-isoprostanes, a validated biomarker of oxidative stress, and prostate cancer and high grade prostatic intraepithelial neoplasia. MATERIALS AND METHODS: This case-control analysis within the Nashville Men's Health Study included men recruited at prostate biopsy. Body morphometrics, health history and urine were collected from more than 2,000 men before biopsy. F2-isoprostanes were measured by gas chromatography/mass spectrometry within an age matched sample of Nashville Men's Health Study participants that included 140 patients with high grade prostatic intraepithelial neoplasia, 160 biopsy negative controls and 200 prostate cancer cases. Multivariable linear and logistic regression was used to determine the associations between F2-isoprostane level, and high grade prostatic intraepithelial neoplasia and prostate cancer. RESULTS: Mean patient age was 66.9 years (SD 7.2) and 10.1% were nonwhite. Adjusted geometric mean F2-isoprostane levels were higher in patients with prostate cancer (1.82, 95% CI 1.66-2.00) or high grade prostatic intraepithelial neoplasia (1.82, 95% CI 1.68-1.96) than in controls (1.63, 95% CI 1.49-1.78, p <0.001), but were similar across Gleason scores (p = 0.511). The adjusted odds of high grade prostatic intraepithelial neoplasia and prostate cancer increased with increasing F2-isoprostane quartile (p-trend = 0.015 and 0.047, respectively) and the highest F2-isoprostane quartile was associated with significantly increased odds of prostate cancer (OR 2.44, 95% CI 1.17-5.09, p = 0.017). CONCLUSIONS: Pre-diagnosis urine F2-isoprostane level is increased in men with high grade prostatic intraepithelial neoplasia or prostate cancer, suggesting urinary F2-isoprostane provides a biomarker for the role for oxidative stress in prostate carcinogenesis. F2-isoprostanes may also serve to estimate the efficacy of interventions targeting oxidative stress mechanisms in prostate cancer prevention or treatment.

A comparison of prostate health index, total PSA, %free PSA, and proPSA in a contemporary US population-The MiCheck-01 prospective trial.

BACKGROUND: Increasing numbers of patients are presenting with aggressive prostate cancer (CaP); therefore, there exists a need to optimally identify these patients pre-biopsy. OBJECTIVES: To compare the accuracy of total prostate specific antigen (PSA), %free PSA, and prostate health index (PHI) to differentiate between patients without CaP, with non-aggressive (Gleason 3 + 3, non-AgCaP) and with aggressive (Gleason ≥ 3 + 4, AgCaP) in a contemporary US population. DESIGN, SETTINGS, AND PARTICIPANTS: Serum samples were collected from 332 US patients scheduled for biopsy due to an elevated age-adjusted PSA. Site and Central biopsy pathologic assessment were performed. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Testing of PSA, free PSA, proPSA, and PHI was performed along with central pathology review. Test performance using logistic regression analysis for differentiating CaP from non-CaP as well as non-AgCaP from AgCaP was evaluated. RESULTS AND LIMITATIONS: Central pathology review resulted in 32 upgrades including 14 Gleason 3 + 3 scores being upgraded to AgCaP with final distribution of 148 no-CaP, 64 non-AgCaP, and 120 AgCaP patients. Receiver operator curve (ROC) analysis of the different tests showed that PHI performed best at differentiating CaP from no-CaP subjects (area under the receiver operator curve 0.79). In contrast, the different tests were essentially equivalent in differentiating AgCaP vs. non-AgCaP. CONCLUSIONS: In this recent US study of prebiopsy patients we observed a high proportion of AgCaP patients consistent with previous studies in contemporary US populations. Central Gleason review is recommended for multi-institutional studies comparing biomarkers. PHI was superior to PSA, free PSA, %free PSA, and proPSA in detecting CaP in this population but was not superior at differentiating AgCaP from non-AgCaP.

Development and evaluation of the MiCheck test for aggressive prostate cancer.

BACKGROUND: A clinical need exists for a biomarker test to accurately delineate aggressive prostate cancer (AgCaP), and thus better assist clinicians and patients decision-making on whether to proceed to prostate biopsy. OBJECTIVES: To develop a blood test for AgCaP and compare to PSA, %free PSA, proPSA, and prostate health index (PHI) tests. DESIGN, SETTINGS AND PARTICIPANTS: Patient samples from the MiCheck-01 trial were used for development of the MiCheck test. METHODS: Serum analyte concentrations for cellular growth factors were determined using a custom-made Luminex-based R&D Systems multianalyte kit. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Bayesian model averaging and random forest approaches were used to identify clinical factors and growth factors able to distinguish between men with AgCaP (Gleason Score [GS] ≥3+4) from those with non-AgCaP (GS 3+3). Logistic regression and Monte Carlo cross-validation identified variable combinations in order to able to maximize differentiation of AgCaP from non-AgCaP. RESULTS: The MiCheck logistic regression model was developed and comprises the following variables: serum prostate-specific antigen (PSA), patient age, Digital Rectal Exam (DRE) status, Leptin, IL-7, vascular endothelial growth factor, and Glypican-1. The model differentiated AgCaP from non-AgCaP with an area under the curve of 0.83 and was superior to PSA, %free PSA and PHI in all patient groups, regardless of PSA range. Applying the MiCheck test to all evaluable biopsy patients from the MiCheck-01 study demonstrated that up to 30% of biopsies could be avoided while delaying diagnosis of only 6.8% of GS ≥3+4 cancers, 5% of GS ≥4+3 cancers and no cancers of GS 8 or higher. CONCLUSIONS: The MiCheck test outperforms PSA, %free PSA and PHI tests in differentiating AgCaP vs. non-AgCaP patients. The MiCheck test could result in a significant number of biopsies being avoided with a low number of patients experiencing a delayed diagnosis.

The Effect of Local Antibiogram-based Augmented Antibiotic Prophylaxis on Infection-related Complications Following Prostate Biopsy.

Given the number of prostate biopsies performed annually in the United States and associated infectious events as a result, we sought to determine if implementation of a standardized biopsy protocol utilizing antibiotic prophylaxis based on locally derived antibiograms would result in a decrease, relative to a contemporary control population, in the incidence of infection-related complications among community-based practices. A total of nine member groups of LUGPA participated in both a retrospective review and a prospective study of infection-related complications following prostate biopsy. Historic infectious complications, defined as chills/rigor, temperature higher than 101 °F, or documented positive blood or urine cultures, were self-reported by a retrospective review of patients undergoing prostate biopsy under the practice's current protocol in the year prior to the study. The prospective phase of the study required each group to develop a locally derived augmented prophylaxis regimen (>2 antibiotics) based on local antibiograms. After implementation, the practices enrolled patients undergoing prostate biopsy over an 8-week period. Monitoring for infection-related complication took place over the ensuing 3 weeks post-biopsy. Seven hundred fifty-nine patients over nine practices were enrolled into the study utilizing the augmented locally determined prophylaxis protocol. There was a 53% reduction in the incidence of infection-related complication, relative to the historical rate. By developing a standardized biopsy protocol with specific emphasis on incorporating an augmented antibiotic prophylactic regimen based upon local antibiograms, we were able to demonstrate in a prospective trial across nine geographically distinct community practices a significant reduction in the incidence of infection-related complications.

Prolonged PSA stabilization and overall survival following sipuleucel-T monotherapy in metastatic castration-resistant prostate cancer patients.

BACKGROUND: Sipuleucel-T is an autologous cellular immunotherapy that is FDA approved for the treatment of asymptomatic or minimally symptomatic metastatic castrate-resistant prostate cancer (mCRPC). The IMPACT registry trial demonstrated a 4.1 month survival benefit, but not a consistent PSA response or improvement in progression-free survival. Based upon several factors, including this lack of objective treatment response, sipuleucel-T has been under-utilized in this patient population, despite current NCCN recommendations. METHODS: In order to explore if delayed treatment response occurs in a subset of patients, we performed a single institutional retrospective analysis of mCRPC patients treated with sipuleucel-T and ongoing ADT alone. Within that group, we then identified a subset of sipuleucel-T-treated men with long-term disease control and no additional interventions. To independently confirm this finding, we evaluated a total of 336 patients from 4 large urology group practices treated with sipuleucel-T between 2010 and 2014 and identified 44 patients who met the same criteria and demonstrated evidence of PSA stabilization post sipuleucel-T treatment. RESULTS: For this subgroup of patients, 79% (95% CI: 64.5%, 88.1%) survived 36 months with a median time to subsequent therapy of 17.8 months (95% CI 10.3, 25.3). CONCLUSIONS: Although patient selection could account for some or all of these results, these data support the utilization of sipuleucel-T alone in select mCRPC patients that is associated with a delay in disease progression and a good overall prognosis.

Development of a reliable assay to measure glypican-1 in plasma and serum reveals circulating glypican-1 as a novel prostate cancer biomarker.

Prostate cancer is responsible for hundreds of thousands of annual deaths worldwide. The current gold standard in early detection of prostate cancer, the prostate specific antigen test, boasts a high sensitivity but low specificity, resulting in many unnecessary prostate biopsies. Thus, emphasis has been placed on identifying new biomarkers to improve prostate cancer detection. Glypican-1 has recently been proposed as one such biomarker, however further exploration into its predictive power has been hindered by a lack of available, dependable glypican-1 immunoassays. Previously, we identified human glypican-1 as the antigenic target of the MIL-38 monoclonal antibody. Additionally, we have now generated another monoclonal antibody, 3G5, that also recognizes human glypican-1. Here we report the development of a reliable, custom Luminex® assay that enables precise quantitation of circulating human glypican-1 in plasma and serum. Using this assay, we show for the first time that circulating glypican-1 levels can differentiate non-cancer (normal and benign prostatic hyperplasia) patients from prostate cancer patients, as well as benign prostatic hyperplasia patients alone from prostate cancer patients. Our findings strongly promote future investigation into the use of glypican-1 for early detection of prostate cancer.