Luteinizing hormone-releasing hormone (LHRH) agonists are believed to have higher cardiovascular risk relative to gonadotropin-releasing hormone (GnRH) antagonists. However, previous studies have not ...consistently demonstrated this. We used real-world clinical practice data to evaluate differences in major adverse cardiovascular events (MACE) risk between LHRH agonists compared to a GnRH antagonist following androgen deprivation therapy (ADT) initiation.
We performed a retrospective analysis of data in the Decision Resources Group (now Clarivate) Real World Evidence repository, which represents >300 million US patients from 1991 to 2020 across all US regions. Patients with prostate cancer who received at least 1 injection of ADT were included. The risks of MACE and all-cause mortality as independent endpoints were evaluated, Kaplan-Meier curves were constructed, and associations between MACE and all available confounding risk factors were evaluated by Cox regression analysis using Statistical Package for the Social Sciences.
A total of 45,059 men with prostate cancer treated with ADT were analyzed. Overall, the risks of MACE and all-cause mortality were slightly lower in the first year after ADT initiation compared to subsequent years. MACE risk was higher for the GnRH antagonist compared to LHRH agonists (HR=1.62; 95% CI 1.21-2.18,
= .001). The risk of all-cause mortality was also higher for the GnRH antagonist vs LHRH agonists (HR=1.87; 95% CI 1.39-2.51,
< .001).
The adjusted incidence of MACE was higher for men treated with the GnRH antagonist compared to the LHRH agonists. The demographic and risk factors with the greatest impact on MACE risk were higher age, baseline metastasis, oncology (vs urology) setting, personal MACE history, antagonist (vs agonist), tobacco history, White (vs Black) race, and lower BMI.
Abstract Background IsoPSA is a serum-based assay that predicts prostate cancer (PCa) risk by partitioning isoforms of prostate-specific antigen (PSA) with an aqueous two-phase reagent. Objectives To ...determine the diagnostic accuracy of IsoPSA in identifying the presence or absence of PCa and the presence of high-grade disease in a contemporary biopsy cohort. Design, setting, and participants Multicenter prospective study of 261 men scheduled for prostate biopsy at five academic and community centers in the USA enrolled between August 2015 and December 2016. Intervention Performance of the IsoPSA assay. Outcome measurements and statistical analysis Discrimination power was evaluated using receiver operating characteristic (ROC) analysis. The outcome of the IsoPSA assay was transformed into risk probability using logistic regression. Decision curve analysis (DCA) was used to compare the net benefit of IsoPSA against other clinical protocols. Results and limitations The overall prevalence was 53% for any PCa and 34% for high-grade PCa. The area under the ROC curve was 0.79 for any cancer versus none and 0.81 for high-grade PCa versus low-grade PCa/benign histology. In this preliminary study, DCA revealed a superior net benefit of IsoPSA against no biopsy, all biopsy, and the modified Prostate Cancer Prevention Trial Risk Calculator 2.0. At a cutoff selected to recommend biopsy, IsoPSA demonstrated a 48% reduction in false-positive biopsies; at a cutoff selected to identity men at low risk of high-grade disease, there was a 45% reduction in the false-positive rate. Conclusion The structure-based IsoPSA assay outperformed concentration-based PSA measurement, and provided a net benefit against other protocols. Once validated, clinical use of IsoPSA could significantly reduce unnecessary biopsies while identifying patients needing treatment. Patient summary The IsoPSA assay outperformed prostate-specific antigen in predicting the overall risk of prostate cancer and the risk of clinically significant cancer in a preliminary study. The IsoPSA assay could assist in determining the need for prostate biopsy for patients.
We present long-term outcomes from 2 randomized studies STAMP (with abiraterone, NCT01487863) and STRIDE (with enzalutamide, NCT01981122) that were performed to study the impact of sequential or ...concurrent administration of androgen receptor-targeting agents (ARTAs) on sipuleucel-T immune response and overall survival (OS) in metastatic castration-resistant prostate cancer (mCRPC).
Sipuleucel-T was administered per current prescribing information. Results from STRIDE are presented together with updated STAMP results. Survival status of patients was updated using demographic information to query the National Death Index (NDI). Kaplan-Meier methodology was used to analyze survival.
Updated data reduced patient censoring in each study compared with the original analyses; the 95% confidence intervals (CIs) for OS are now estimable. Updated median OS (95% CI) is 33.3 (24.1-40.7) months for STAMP and 32.5 (26.0-45.1) months for STRIDE. There was no notable impact on median OS HR, 0.727 (0.458-1.155); P = 0.177, reference = STRIDE. OS with sequential administration was similar to concurrent administration NDI update: HR, 0.963 (0.639-1.453); P = 0.845, reference = concurrent arm. Sipuleucel-T potency, measured as antigen-presenting cell (APC) activation, was higher in subsequent infusions compared with the first infusion. Humoral responses (IgG + IgM antibody titers) to PA2024 and prostatic acid phosphatase were significantly elevated versus baseline. No new safety signals were observed.
Median OS was consistent regardless of whether the agents were administered sequentially or concurrently, including after NDI update. Results suggest that sipuleucel-T induces an immunologic prime-boost effect after initial sipuleucel-T exposure, even when combined with ARTAs.
Introduction
The treatment landscape for metastatic castration-resistant prostate cancer (mCRPC) continues to evolve. Sipuleucel-T was the first immunotherapy approved by the US Food and Drug ...Administration (FDA) to treat asymptomatic or minimally symptomatic mCRPC. The androgen receptor-targeting agents (ARTAs) abiraterone acetate and enzalutamide were initially approved to treat mCRPC. Looking at chemotherapy-naïve men with mCRPC, we compared survival outcomes between the sipuleucel-T + ARTA cohort (men who received either sipuleucel-T or an ARTA in the first line, and then the other in the second line within 6 months) and the ARTA monotherapy cohort (men who only received ARTA monotherapy).
Methods
This retrospective cohort analysis used longitudinal, adjudicated claims data from the US Medicare Fee-for-Service 100% research identifiable dataset that includes both urologic and oncologic practice settings. Eligible men started their first mCRPC treatment with either sipuleucel-T or ARTA in either 2014 or 2015 and had continuous Medicare Parts A, B, and D eligibility for the subsequent 3 years. A multivariable Cox proportional hazards regression model was used to analyze overall survival (OS), both overall and by index year, and to control for differences.
Results
The sipuleucel-T + ARTA and ARTA monotherapy cohorts comprised 773 and 4642 men, respectively, with different characteristics at treatment start. The most commonly used ARTAs were enzalutamide in the former and abiraterone in the latter cohort. Median OS was 30.4 and 14.3 months in the sipuleucel-T + ARTA and ARTA monotherapy cohorts, respectively, with the sipuleucel-T + ARTA cohort having a 28.3% lower risk of death than the ARTA monotherapy cohort (hazard ratio 0.717; 95% CI 0.648, 0.793;
p
< 0.01).
Conclusions
This real-world study of mCRPC treatment indicates that men receiving sipuleucel-T and ARTAs had a longer median OS than patients receiving treatment with an ARTA alone, suggesting that leveraging mechanisms of action can be beneficial in treating patients with mCRPC.
Plain Language Summary
The treatment landscape for metastatic castration-resistant prostate cancer (mCRPC) continues to evolve. There are multiple treatments for mCRPC, including sipuleucel-T, the first US Food and Drug Administration (FDA)-approved immunotherapy, and the androgen receptor-targeting agents (ARTAs) abiraterone acetate and enzalutamide. Although sipuleucel-T uses a unique mechanism of action that may be useful in developing a treatment strategy for mCRPC, an optimal treatment algorithm for prostate cancer remains undefined. Therefore, survival was compared in men with mCRPC who received sipuleucel-T and an ARTA in the first 6 months of treatment with those who received only ARTA monotherapy. A retrospective longitudinal study was conducted using the US Medicare Fee-for-Service 100% research identifiable dataset linked to the National Death Index. Eligible men started their first mCRPC treatment with either sipuleucel-T or ARTA in either 2014 or 2015 and had continuous Medicare eligibility for the subsequent 3 years. Men who received treatment with both sipuleucel-T and an ARTA had a longer median survival (30.4 months) than men who received an ARTA without sipuleucel-T (14.3 months). This represents a 28% reduced risk of death with sipuleucel-T. This real-world study of mCRPC treatment indicates that men receiving sipuleucel T and an ARTA survive longer than men who only receive an ARTA, suggesting that changing the mechanism of action can be beneficial in treating patients with mCRPC.
Background
The single-arm, open-label, multicenter, phase II Apa-RP study evaluates the biochemical recurrence (confirmed prostate-specific antigen PSA > 0.2 ng/mL)-free rate in patients with ...high-risk localized prostate cancer (HR-LPC) after radical prostatectomy following adjuvant apalutamide and androgen-deprivation therapy. In this substudy, relugolix, an oral gonadotropin-releasing hormone antagonist, was evaluated in combination with apalutamide.
Objective
The aim of this study was to evaluate whether the approved standard maintenance dose of relugolix in combination with apalutamide sustains castrate testosterone levels (< 50 ng/dL).
Patients and Methods
Twelve patients with HR-LPC who met all the main study criteria were included in the substudy. Patients received relugolix monotherapy for 2 weeks (loading dose 360 mg at Day − 14 then 120 mg/day daily until Day − 1), then daily relugolix (120 mg) with apalutamide (240 mg) from Day 1 to Day 28. Endpoints were rate of maintained castration (testosterone < 50 ng/dL) through Day 28 (primary) and safety (secondary).
Results
All 12 patients received relugolix and apalutamide and achieved castrate testosterone levels after 2-week relugolix monotherapy (median testosterone 348.5 ng/dL and 8.7 ng/dL at Days − 14 and − 1). All 11 patients who had testosterone measured at Day 28 maintained castrate testosterone (median 10.0 ng/dL) without relugolix dose adjustment. Treatment-emergent adverse events (TEAEs) occurred in nine patients during relugolix monotherapy and in eight patients during relugolix + apalutamide coadministration. Hot flush was the most common TEAE reported, in six and four patients, respectively.
Conclusions
Relugolix administered at approved standard doses concurrently with apalutamide was effective in maintaining castrate testosterone levels in HR-LPC without new safety signals.
Trial Registration Number and Date
NCT04523207, 21 August 2020.
Graphical abstract
Plain Language Summary
The Apa-RP study evaluates the combination of apalutamide with drugs that lower male sex hormones for reducing the risk of prostate cancer recurrence. Patients in this study had their prostate gland surgically removed and were at high risk for disease recurrence. Relugolix, a newly approved oral drug for advanced prostate cancer, lowers blood testosterone (the primary male sex hormone) and, in combination with apalutamide, may reduce the risk of prostate cancer recurrence. The Apa-RP substudy goal was to test whether relugolix lowers blood testosterone and maintains these low levels when administered with apalutamide. Researchers looked at the testosterone levels of 12 patients with early prostate cancer who received standard doses of relugolix alone for 2 weeks followed by apalutamide and relugolix for an additional 28 days. Testosterone was measured before and after 2 weeks of relugolix treatment, and then again 28 days after apalutamide was added. All 12 substudy patients achieved low testosterone levels (< 50 ng/dL) after 2 weeks of relugolix treatment. Testosterone was measured at Day 28 of relugolix + apalutamide treatment in 11 patients, all of whom maintained low testosterone without adjustment of their relugolix dose. Adverse effects were consistent with those previously reported for each drug when administered alone. All 12 patients completed the substudy and moved onto the main study, the longer-term results of which will be reported in the future. In summary, relugolix administered at the same time as apalutamide was effective in maintaining low testosterone levels in patients with prostate cancer, without any new safety concerns.
Half of patients with muscle-invasive bladder cancer worldwide may not receive curative-intent therapy. Elderly or frail patients are most affected by this unmet need. TAR-200 is a novel, ...intravesical drug delivery system that provides sustained, local release of gemcitabine into the bladder over a 21-day dosing cycle. The phase 1 TAR-200-103 study evaluated the safety, tolerability, and preliminary efficacy of TAR-200 in patients with muscle-invasive bladder cancer who either refused or were unfit for curative-intent therapy.
Eligible patients had cT2-cT3bN0M0 urothelial carcinoma of the bladder. TAR-200 was inserted for 4 consecutive 21-day cycles over 84 days. The primary end points were safety and tolerability at 84 days. Secondary end points included rates of clinical complete response and partial response as determined by cystoscopy, biopsy, and imaging; duration of response; and overall survival.
Median age of the 35 enrolled patients was 84 years, and most were male (24/35, 68.6%). Treatment-emergent adverse events related to TAR-200 occurred in 15 patients. Two patients experienced treatment-emergent adverse events leading to removal of TAR-200. At 3 months, complete response and partial response rates were 31.4% (11/35) and 8.6% (3/35), respectively, yielding an overall response rate of 40.0% (14/35; 95% CI 23.9-57.9). Median overall survival and duration of response were 27.3 months (95% CI 10.1-not estimable) and 14 months (95% CI 10.6-22.7), respectively. Progression-free rate at 12 months was 70.5%.
TAR-200 was generally safe, well tolerated, and had beneficial preliminary efficacy in this elderly and frail cohort with limited treatment options.
Various renal cell carcinomas (RCC) are derived from different segments of the renal tubular origin, which determines their morphological and immunohistochemical phenotype and their molecular ...signaling pathway as a therapeutic target. Most of these tumors utilize the mammalian target of rapamycin (mTOR) pathway to activate pathways involving metabolic and nutritional supplies.
Overexpressed mTOR signals are reported in more than 90% of the most common types of RCC. Many new renal tumor entities have been reported in recent years.
Among them, somatic mutations in tuberous sclerosis complex (TSC) result in loss of its normal inhibitory control over mTOR, thus promoting mTOR-associated proliferative activities in several new renal neoplastic entities including RCC with fibromyomatous stroma (RCCFMS), eosinophilic vacuolated tumor, eosinophilic solid & cystic RCC, and low-grade oncocytic tumor.
This short review provides a comprehensive correlation of tumor morphology and immunohistochemical phenotype with renal tubular differentiation and their shared mTOR. These essential pieces of knowledge are vital in the diagnosis and clinical management of renal cell neoplasms.
Background
Paneth cell-like granules (PCLG) in clear cell renal cell carcinomas (RCC) have previously been reported but were not found to express neuroendocrine markers. This study was to investigate ...if the eosinophilic granules (so called PCLG) were enlarged lysosomes.
Methods
A retrospective review of 72 different renal tumors was conducted which included 42 clear cell RCC, 16 papillary RCC, 6 chromophobe RCC, 5 clear cell papillary RCC, 2 urothelial carcinomas and 1 unclassified RCC. All tumors were evaluated for the eosinophilic granules on hematoxylin and eosin-stained sections. In addition, PAS-D staining, immunohistochemical stains, and electron microscopy were performed.
Results
The eosinophilic granules were found in 19% (8 out of 42) clear cell RCC, but not in the other renal tumor types. The granules stained positively for PAS-D and were also positive for lysosomal protein markers CD68 and lysozyme. Electron microscopy revealed that the eosinophilic granules were smooth ball-shaped structures in the cytoplasm, ranging in size from 0.8 to 1.4 µm. The overall findings indicate that the eosinophilic granules were best correlated with lysosomes.
Conclusions
The eosinophilic granules in clear cell RCC are expanded lysosomes, and this may be used as a unique feature for confirming the pathologic diagnosis of clear cell RCC. The findings further support the view that clear cell RCC have phagocytic capacity due to their containing abundant lysosomes in the cytoplasm.
Associate Editor
Ash Tewari
Editorial Board
Ralph Clayman, USA
Inderbir Gill, USA
Roger Kirby, UK
Mani Menon, USA
OBJECTIVES
To detail the technique and evaluate in a preliminary study the ...effectiveness of posterior reconstruction of Denonvilliers’ musculofascial plate (PRDMP) in enhancing early continence after robotic and laparoscopic radical prostatectomy (RP).
PATIENTS AND METHODS
Thirty‐two consecutive patients having robotic or laparoscopic RP with PRDMP (group 1). Thirty previous patients not having PRDMP were compared as historical controls (group 2). Continence, as measured by patient self‐reporting of the number of pads used/24 h, was assessed at 3 days and 6 weeks after catheter removal, by telephone interview. ‘Continent’ was defined as the use of none or one pads, ‘moderate incontinence’ as two pads, and ‘severe incontinence’ as more than two pads. Intraoperative transrectal ultrasonography (TRUS) was used to measure the membranous urethral length before and after PRDMP.
RESULTS
At 3 days after catheter removal, more patients in group 1 were continent than in group 2 (34% vs 3%, P = 0.007). At 6 weeks continence was again better in group 1 (56% vs 17%, P = 0.006). The mean length of the membranous urethra on TRUS measured before RP, after RP but before the musculofascial suture, and afterward, was 15.6, 12 and 14 mm, respectively. Thus, reconstruction restored the length of the transected membranous urethra by a mean of 2 mm.
CONCLUSIONS
PRDMP during robotic and laparoscopic RP leads to improved maintenance of membranous urethral length and significantly higher early continence rates.
Introduction
Since sipuleucel-T approval in 2010, the treatment landscape for metastatic castration-resistant prostate cancer (mCRPC) now includes the androgen-receptor signaling pathway inhibitors ...(ASPIs) abiraterone acetate or enzalutamide. In 2013 and 2014, these oral agents were approved for use in men with metastatic prostate cancer who had minimal to no symptoms. We compared overall survival (OS) in men who received their first mCRPC treatment using the Medicare Fee-for-Service 100% administrative claims research dataset with patient-level linkage to the National Death Index.
Methods
This retrospective cohort analysis (January 2013 to December 2017) included men who were chemo-naïve at treatment start in 2014 and who had continuous Medicare Parts A, B, and D eligibility during the 3-year observation period. We compared: first-line sipuleucel-T vs. first-line ASPIs and any-line sipuleucel-T vs. any-line ASPIs (without sipuleucel-T). We used a multivariable regression model to help control for potentially confounding factors while assessing survival outcomes.
Results
The model included 6044 eligible men (average age 75–78 years) with similar disease severity; > 80% were white. Median OS, presented as sipuleucel-T vs. ASPI, was 35.2 vs. 20.7 months (
n
, 906 vs. 5092; any-line cohort) and 34.9 vs. 21.0 months (
n
, 647 vs. 4810; first-line cohort). Model outcomes indicated sipuleucel-T was associated with significantly prolonged OS compared with ASPIs: adjusted hazard ratio, 0.59 (95% CI 0.527–0.651) and 0.56 (0.494–0.627) for the any-line and first-line cohorts, respectively.
Conclusion
This analysis suggests use of sipuleucel-T at any time was associated with improved OS compared with ASPI use alone. Of note, these analyses are intended as descriptive rather than definitive as this dataset contains limited data on key clinical factors. While selection bias is a risk in secondary claims data, this research provides important insight into real-world treatment outcomes.
PDF