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.
Sipuleucel‐T is an established cellular immunotherapy for treating metastatic castration‐resistant prostate cancer. The postapproval prospective registry trial PROCEED provides data on contemporary survival for sipuleucel‐T–treated men in an era of new life‐prolonging agents as well as the safety and tolerability of this immunotherapy in a real‐world setting.
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.
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.
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.
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.
Abstract Objective To offer recommendations on identification of disease progression, treatment management strategies, and suggestions on timing of initiating and discontinuing specific CRPC ...treatments. Materials and Methods The RADAR II Prostate Cancer Radiographic Assessments for Detection of Advanced Recurrence Working Group convened to provide guidance on sequencing, combination, or layering of approved treatments for mCRPC based on available data and clinical experience. Results A consensus was developed to address important questions on mCRPC patient management. Conclusions 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.
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 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.
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.
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.
ClinicalTrials.gov identifier NCT02200614.
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.
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.
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.
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.
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.
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.
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%.
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.
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.
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.
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.
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.
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.
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).
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%).
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.
ClinicalTrials.gov identifier NCT01664923.
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.
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.
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.
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.
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.
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.
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.