Benjamin A. Gartrell

Managing bone metastases and reducing skeletal related events in prostate cancer

Advanced-stage prostate cancer is associated with skeletal complications related to metastatic disease and its treatment. On the one hand, metastatic disease to bone is commonly associated with skeletal-related events (SREs); on the other hand, treatment with androgen-deprivation therapy (ADT) leads to loss in bone mineral density (BMD) and increased risk of fracture. Despite osteoblastic appearance on radiography, bone metastases from prostate cancer are associated with increased osteoblast and osteoclast activity providing the rationale for treatment with osteoclast-targeted agents. The bisphosphonate zoledronic acid and the monoclonal antibody denosumab reduce the incidence of SREs in metastatic castration-resistant prostate cancer (mCRPC). A number of agents prevent loss of BMD associated with ADT, but only denosumab is approved to reduce fractures in patients with non-metastatic prostate cancer. Another recently approved agent—radium-223—improves survival and delays SREs in mCRPC. The inhibitors of androgen receptor signalling, abiraterone and enzalutamide, improve survival in mCRPC and delay SREs, although the latter is likely related to control of disease rather than a direct effect on bone. Finally, the tyrosine kinase inhibitor cabozantinib shows promising activity in bone metastases from mCRPC. This Review addresses the skeletal morbidity associated with prostate cancer and the therapeutic options that exist to treat it.

Metabolic complications with the use of mTOR inhibitors for cancer therapy.

BACKGROUND mTOR inhibitors are now approved by regulatory agencies for the treatment of a variety of malignancies. The risk of metabolic complications with these agents is not well characterized. METHODS PubMed was searched for articles published from 2001 until 2011. Eligible studies included prospective randomized trials evaluating temsirolimus, everolimus, and ridaforolimus in patients with all solid tumor malignancies. Sixteen eligible phase II clinical trials and 8 randomized controlled clinical trials were included in a systematic review and meta-analysis and the number of metabolic related AEs (hyperglycemia, hypercholesterolemia, and hypertriglyceridemia) was extracted. Incidence rates and incident rate ratios were calculated. FINDINGS Twenty-four trials, including 4261 patients, were included in the calculation of the incidence rate. The average incidence rate of all grade metabolic related events was 0.70 (95% CI, 0.47, 0.93). The average incidence rate of serious (grade 3 and 4) metabolic related adverse events was 0.11 (95% CI, 0.08, 0.15). The incidence rate ratio (IRR) of a metabolic adverse event with mTOR inhibitor therapy compared with control was 2.93 (95% CI, 2.33, 3.70) and of serious grade 3 and 4 metabolic adverse events was 4.58 (95% CI, 2.86, 7.34). The IRR of all grade hyperglycemia was 2.95 (95% CI, 2.14, 4.05) and of grade 3-4 hyperglycemia was 5.25 (95% CI, 3.07, 9.00). The IRR of all grade hypertriglyceridemia was 2.49 (95% CI, 1.76, 3.52) and of grade 3-4 hypertriglyceridemia was 2.01 (95% CI, 0.65, 6.27). The IRR of all grade hypercholesterolemia was 3.35 (95% CI, 2.17, 5.18) and of grade 3-4 hypercholesterolemia was 6.51 (95% CI, 1.48, 28.59). These findings suggest a statistically significant increase in the risk of hyperglycemia, hypercholesterolemia (all grades and grade 3 and 4), and all grade hypertriglyceridemia associated with mTOR therapy when compared with control. INTERPRETATION The risk of all grade and grade 3-4, hyperglycemia, hypercholesterolemia, and hypertriglyceridemia, are increase in patients treated with mTOR inhibitors compared with control.

Toxicities Following Treatment with Bisphosphonates and Receptor Activator of Nuclear Factor-κB Ligand Inhibitors in Patients with Advanced Prostate Cancer

CONTEXT Advanced prostate cancer (PCa) is associated with skeletal complications, both as a result of bone metastases and because of fractures associated with fragility due to androgen-deprivation therapy (ADT). Osteoclast inhibitors are commonly used to reduce skeletal complications but are associated with a number of potential adverse events. OBJECTIVE To review clinical trials of osteoclast inhibitors in advanced PCa, to discuss the adverse event profile of these agents, and to discuss strategies to address specific adverse events. EVIDENCE ACQUISITION PubMed was searched for reports of clinical trials of osteoclast inhibitors in advanced PCa. As zoledronic acid and denosumab are used most commonly in this disease, these trials were the focus. The literature was reviewed to identify key publications addressing the prevention and management of adverse events associated with these drugs. EVIDENCE SYNTHESIS The major findings of the trials and the adverse events are discussed. Prevention and management of common adverse events are addressed. CONCLUSIONS Zoledronic acid prevents loss of bone mineral density associated with ADT and delays skeletal-related events in metastatic castration-resistant PCa (mCRPC). Denosumab reduces the incidence of fragility fractures associated with ADT, delays the onset of bone metastases in nonmetastatic castration-resistant disease, and is superior to zoledronic acid in the prevention of skeletal complications in mCRPC. Adverse events associated with both agents include osteonecrosis of the jaw and hypocalcemia. Hypocalcemia is more common with denosumab. Zoledronic acid requires dose modifications for renal insufficiency, is contraindicated in severe renal insufficiency, and has been associated with deterioration of renal function. Appropriate patient selection with close attention to dental health, supplementation with calcium and vitamin D, and monitoring of laboratory values are effective strategies to minimize the impact of adverse events associated with osteoclast inhibitors in advanced PCa.

Metastatic Prostate Cancer and the Bone: Significance and Therapeutic Options.

CONTEXT Skeletal involvement is common in metastatic prostate cancer (PCa) and is associated with skeletal-related events (SREs). The interaction of PCa with the bone microenvironment contributes to self-perpetuating progression of cancer in bone. Bone-targeted agents (BTAs) are available for use in metastatic castration-resistant prostate cancer (mCRPC). OBJECTIVE To review the biology of bone metastases in PCa and to review the clinical trial data for BTAs in PCa. EVIDENCE ACQUISITION A literature search was conducted in October 2014. Keywords included clinical trial, prostate cancer, denosumab, bisphosphonates, zoledronic acid, radium-223, bone turnover markers, skeletal-related events, and symptomatic skeletal events. EVIDENCE SYNTHESIS The biology of bone metastases in PCa is summarized. Data supporting the use of BTAs in PCa are reviewed, and issues related to the combination and sequencing of available agents are discussed. CONCLUSIONS The osteoclast-targeted agents zoledronic acid and denosumab decrease SREs in mCRPC, and the α-emitting radiopharmaceutical agent radium-223 improves survival and decreases symptomatic skeletal events. Limited data are available to guide the sequence and combination of BTAs with disease-modifying agents, although data support the use of osteoclast-targeted drugs with chemotherapy, androgen-targeted agents, and radium-223. Zoledronic acid does not reduce SREs when started prior to castration resistance, although osteoclast-targeted agents do improve outcomes when used in patients with asymptomatic to minimally symptomatic chemotherapy-naive mCRPC. The optimal sequence of radium-223 with chemotherapy is uncertain, although data suggest the efficacy and tolerability of radium-223 is similar with either sequence. Clinical trials evaluating the combination of BTAs with other agents are under way. The optimization of sequence and combination strategies will guide the best use of available agents. PATIENT SUMMARY The literature pertaining to bone metastases in prostate cancer (PCa) was reviewed, and the current understanding of the biology of PCa having spread to bone and the agents available to reduce skeletal complications was discussed.

Trends in the use of cytoreductive nephrectomy in the United States.

BACKGROUND Two randomized trials published in 2001 established CyNx for patients with metastatic renal carcinoma (mRCC) as a treatment standard in the cytokine era. However, first-line systemic therapy for mRCC changed in 2005 with FDA approval of VEGFR TKIs. We evaluated the patterns of use of CyNx from 2000 to 2008. MATERIALS AND METHODS The National Cancer Database was queried for patients diagnosed with mRCC. Patients who underwent CyNx were identified and were further categorized by pre-VEGFR versus VEGFR TKI era, race, insurance status, and hospital. For these subcategories, prevalence ratios (PRs) were generated using the proportion of patients with mRCC undergoing CyNx versus those not undergoing CyNx. RESULTS Of the 47,417 patients (pts) identified with mRCC, the prevalence of cytoreductive nephrectomy increased 3% each year from 2000 to 2005 (P < .0001), then decreased 3% each year from 2005 to 2008 (P = .0048), with a significant difference between the eras (0.97 vs. 1.025; P < .0001). Black and Hispanic pts were less likely than Caucasian pts to undergo CyNx. Pts with Medicaid, Medicare, and no insurance were less likely than pts with private insurance to undergo CyNx. Pts diagnosed at community hospitals were significantly less likely than pts at teaching hospitals to undergo CyNx. CONCLUSION The use of CyNx has declined in the VEGFR-TKI era. In addition, racial and socioeconomic disparities exist in the use of CyNx. The results of pending randomized trials evaluating the role of CyNx in the VEGFR-TKI era are awaited to optimize use of this modality and address potential disparities.

Abiraterone in the management of castration-resistant prostate cancer prior to chemotherapy.

The treatment armamentarium for metastatic castration-resistant prostate cancer (mCRPC) has increased significantly over the past several years. Approved drugs associated with improved survival include androgen pathway-targeted agents (abiraterone acetate and enzalutamide), chemotherapeutics (docetaxel and cabazitaxel), an autologous vaccine (sipuleucel-T) and a radiopharmaceutical (radium-223). Abiraterone acetate, a prodrug of abiraterone, inhibits the CYP17A enzyme, a critical enzyme in androgen biosynthesis. Abiraterone has regulatory approval in mCRPC in both chemotherapy-naïve patients and in the post-docetaxel setting based on results from two randomized phase III studies. In the COU-AA-302 trial, abiraterone demonstrated significant improvement in the coprimary endpoints of radiographic progression-free survival and overall survival, as well as in a number of secondary endpoints including time until initiation of chemotherapy, time until opiate use for cancer-related pain, prostate-specific antigen progression-free survival and decline in performance status. Abiraterone is well-tolerated, although adverse events associated with this agent include abnormalities in liver function testing and mineralocorticoid-associated adverse events. This review evaluates the use of abiraterone in mCRPC prior to the use of chemotherapy.

Emerging drugs for urothelial carcinoma

Introduction: Advanced urothelial carcinoma is associated with a poor prognosis. In the metastatic setting, the response rate to first-line, cisplatin-containing chemotherapy is high, but survival is poor. Second-line treatment options are limited. Advanced age at diagnosis and the presence of comorbidities often preclude treatment with cisplatin-containing regimens. Areas covered: This review addresses the current therapy of urothelial carcinoma, the unmet needs in treatment and the status of drug development in this disease. The molecular targets identified and efforts to incorporate targeted agents into therapy will be addressed. Expert opinion: There have been no major advances in the treatment of urothelial carcinoma in three decades. Despite high response rates in the first-line setting, survival is limited. Major impediments to improved outcomes include poor durability of response to first-line chemotherapy and lack of second-line treatments. Better understanding in tumor biology has identified multiple targets in urothelial carcinoma; however, such discoveries have yet to lead to the incorporation of targeted agents into the routine treatment of urothelial carcinoma. Multiple ongoing clinical trials are investigating the use of targeted agents in urothelial carcinoma. Continued efforts are underway to better understand the molecular drivers of disease and such efforts are likely to identify additional therapeutic targets.

Notch pathway is activated via genetic and epigenetic alterations and is a therapeutic target in clear cell renal cancer

Clear cell renal cell carcinoma (CCRCC) is an incurable malignancy in advanced stages and needs newer therapeutic targets. Transcriptomic analysis of CCRCCs and matched microdissected renal tubular controls revealed overexpression of NOTCH ligands and receptors in tumor tissues. Examination of the TCGA RNA-seq data set also revealed widespread activation of NOTCH pathway in a large cohort of CCRCC samples. Samples with NOTCH pathway activation were also clinically distinct and were associated with better overall survival. Parallel DNA methylation and copy number analysis demonstrated that both genetic and epigenetic alterations led to NOTCH pathway activation in CCRCC. NOTCH ligand JAGGED1 was overexpressed and associated with loss of CpG methylation of H3K4me1-associated enhancer regions. JAGGED2 was also overexpressed and associated with gene amplification in distinct CCRCC samples. Transgenic expression of intracellular NOTCH1 in mice with tubule-specific deletion of VHL led to dysplastic hyperproliferation of tubular epithelial cells, confirming the procarcinogenic role of NOTCH in vivo. Alteration of cell cycle pathways was seen in murine renal tubular cells with NOTCH overexpression, and molecular similarity to human tumors was observed, demonstrating that human CCRCC recapitulates features and gene expression changes observed in mice with transgenic overexpression of the Notch intracellular domain. Treatment with the γ-secretase inhibitor LY3039478 led to inhibition of CCRCC cells in vitro and in vivo. In summary, these data reveal the mechanistic basis of NOTCH pathway activation in CCRCC and demonstrate this pathway to a potential therapeutic target.

Emerging personalized approaches for the management of advanced urothelial carcinoma

Urothelial carcinoma of the bladder comprises a spectrum of illnesses ranging from nonmuscle-invasive to muscle-invasive to advanced/metastatic disease. Each of these clinical states is characterized by a unique pathogenesis, prognosis and approach to treatment. However, given the heterogeneity of urothelial carcinoma, differences in biology and outcomes exist not only among these clinical states but also within each state. Personalized medicine, also commonly referred to as individualized or stratified medicine, offers the potential to optimize treatment for a given patient, based on the ability to accurately predict prognosis, response to treatment and tolerability of treatment. This review will discuss recent efforts, current challenges and future opportunities, for the personalized management of urothelial carcinoma.

Metabolic complications with the use of mTOR inhibitors for cancer therapy: A systematic review and meta-analysis.

398 Background: mTOR inhibitors are approved in several malignancies including renal cell carcinoma (RCC). The risk of metabolic complications with these agents is not well characterized. METHODS PubMed was searched for articles published from 2001 until 2011. Eligible studies included prospective randomized trials evaluating temsirolimus, everolimus, and ridaforolimus in patients with all solid tumor malignancies. 16 eligible phase II clinical trials and 8 randomized controlled clinical trials were included in a systematic review and meta-analysis and the number of metabolic related AEs including hyperglycemia, hypercholesterolemia, and hypertriglyceridemia were extracted. Incidence rates and incident rate ratios were calculated. RESULTS In total, 24 trials (including 4,261 patients) were included. The average incidence rate of any grade metabolic adverse events and grade 3-4 metabolic adverse events was 0.70 per patient and 0.11 (95% CI, 0.08, 0.15) per patient respectively. Analysis of the 3,317 patients across 8 RCTs revealed that the log incidence rate ratio (IRR) of any grade metabolic adverse events with mTOR inhibitor therapy compared with control was 1.08 (95% CI, 0.84, 1.31) using a random-effects model. The risk of grade 3-4 adverse events was also increased with an IRR of 1.52 (95% CI, 1.05, 1.99). The IRR of all grade hyperglycemia was 1.08 (95% CI, 0.76, 1.40) and of grade 3-4 hyperglycemia was 1.66 (95% CI, 1.12, 2.20). The IRR of all grade hypertriglyceridemia was 0.91 (95% CI, 0.56, 1.26) and of grade 3-4 hypertriglyceridemia was 0.70 (95% CI,- 0.43, 1.83). The IRR of all grade hypercholesterolemia was 1.21 (95% CI, 0.77, 1.65) and of grade 3-4 hypercholesterolemia was 1.21 (95% CI, 0.77, 1.65). These findings suggest a statistically significant increase in the risk of hyperglycemia, hypercholesterolemia (all grades and grade 3 and 4), and all grade hypertriglyceridemia associated with mTOR therapy when compared with control. CONCLUSIONS The risk of all grade and grade 3-4 metabolic adverse events are increased in patients treated with mTOR inhibitors compared with control. However, grade 3-4 metabolic adverse events remain relatively uncommon.