Highlighting recent progress in the treatment of men with advanced prostate cancer.

Purpose Of Review: This review is designed to highlight recent research efforts to optimize treatment strategies in men with advanced prostate cancer.

Recent Findings: Recent research analyses have suggested an overall survival advantage to treating some men with newly identified metastatic prostate cancer with a "triplet" of androgen deprivation therapy, docetaxel, and an androgen receptor axis-targeted agent (ARAT), but further work remains to refine which men need this aggressive of a treatment approach. Randomized trials have led to the approval of poly(ADP-ribose) polymerase inhibitor/ARAT agent combinations for some men with metastatic castration resistant prostate cancer, but the applicability of this approach to the growing number of men receiving combinations of systemic therapy in the castration-sensitive setting is unclear.

Genomic amplifications identified by circulating tumor DNA analysis guide prognosis in metastatic castration-resistant prostate cancer.

Purpose: Analysis of circulating tumor DNA (ctDNA) in patients with metastatic prostate cancer (mPC) provides an opportunity to identify and monitor genomic alterations during a patient's treatment course. We evaluated whether the presence of specific gene amplifications (GAs) and plasma copy number (PCN) alterations are associated with disease features.

Methods: This is a single-institution retrospective study of patients with mPC who underwent ctDNA profiling using Guardant360 (Guardant Health Inc.

A phase I study of the ceramide nanoliposome in patients with advanced solid tumors.

Purpose: Ceramide is a sphingolipid metabolite that deactivates multiple oncogenic signaling pathways and promotes cell death. In-vivo data demonstrate single-agent anti-cancer activity and enhanced efficacy with combination strategies. This phase I dose-escalation trial evaluated Ceramide nanoLiposomes (CNL) in patients with advanced solid tumors and no standard treatment option.

First-in-human phase Ib trial of M9241 (NHS-IL12) plus avelumab in patients with advanced solid tumors, including dose expansion in patients with advanced urothelial carcinoma.

Background: In preclinical studies, combining M9241 (a novel immunocytokine containing interleukin (IL)-12 heterodimers) with avelumab (anti-programmed death ligand 1 antibody) resulted in additive or synergistic antitumor effects. We report dose-escalation and dose-expansion results from the phase Ib JAVELIN IL-12 trial investigating M9241 plus avelumab.

Methods: In the dose-escalation part of JAVELIN IL-12 (NCT02994953), eligible patients had locally advanced or metastatic solid tumors; in the dose-expansion part, eligible patients had locally advanced or metastatic urothelial carcinoma (UC) that had progressed with first-line therapy.

Treatments and challenges in advanced prostate cancer.

Purpose Of Review: This review is designed to highlight recent research examining treatment progress in advanced prostate cancer while identifying ongoing challenges to clinical outcomes.

Recent Findings: Recent randomized trials suggest an overall survival advantage to treating some men with newly identified metastatic prostate cancer with a "triplet" of androgen deprivation therapy, docetaxel, and an androgen receptor axis-targeted agent. Questions remain about which men are best served by these combinations.

Elevated serum CEA is associated with liver metastasis and distinctive circulating tumor DNA alterations in patients with castration-resistant prostate cancer.

Background: Elevated serum carcinoembryonic antigen (CEA) is used to identify "treatment emergent" forms of castration-resistant prostate cancer (CRPC) such as aggressive variant prostate cancer (AVPC). However, its individual utility as a prognostic marker and the genetic alterations associated with its expression have not been extensively studied in CRPC.

Methods: This study retrospectively analyzed clinical outcomes and circulating tumor DNA profiles in 163 patients with CRPC and elevated or normal serum CEA.

Recent advances in the treatment of advanced prostate cancer: maximizing existing therapies while searching for novel solutions.

Purpose Of Review: Present highlights from recent research examining treatment of advanced prostate cancer.

Recent Findings: Data are emerging that combining androgen deprivation, docetaxel, and additional androgen-receptor-targeted therapies in treatment naïve metastatic prostate cancer may be an effective strategy to improve outcomes. Genomically targeted therapies and radiopharmaceuticals continue to be evaluated in the treatment of advanced castration-resistant prostate cancer.

Phase II Clinical and Translational Study of Everolimus ± Paclitaxel as First-Line Therapy in Cisplatin-Ineligible Advanced Urothelial Carcinoma.

Background: Treatment options have been historically limited for cisplatin-ineligible patients with advanced urothelial carcinoma (UC). Given the need for alternatives to platinum-based chemotherapy, including non-chemotherapy regimens for patients with both impaired renal function and borderline functional status, in 2010 (prior to the immune checkpoint blockade era in metastatic UC), we initiated a phase II trial to test the activity of everolimus or everolimus plus paclitaxel in the cisplatin-ineligible setting.

Methods: This was an open-label phase II trial conducted within the US-based Hoosier Cancer Research Network (ClinicalTrials.

Spectrum of Alterations in Cell-Free DNA of Patients with Advanced Urothelial Carcinoma.

Detecting genomic alterations (GAs) in advanced urothelial carcinoma (aUC) can expand treatment options by identifying candidates for targeted therapies. Erdafitinib is FDA-approved for patients with platinum-refractory aUC with activating mutation or fusion in . We explored the prevalence and spectrum of GAs identified with plasma cfDNA NGS testing (Guardant360) in 997 patients with aUC.

Highlighting recent treatment advances in metastatic prostate cancer: expanding the treatment arsenal.

Purpose Of Review: Present highlights from recent research examining the treatment of advanced prostate cancer.

Recent Findings: Although debate remains about the optimal sequencing of docetaxel and novel androgen directed therapies in addition to androgen deprivation therapy (ADT) in the treatment of men with new metastatic prostate cancer, the novel LHRH antagonist relugolix seems poised to become an appealing option in a choice of initial ADT. Novel radioisotopes, genomically selected therapies, and immune therapy combinations show progress in opening up new treatment options for men with castration-resistant prostate cancer.

Avelumab as second-line therapy for metastatic, platinum-treated urothelial carcinoma in the phase Ib JAVELIN Solid Tumor study: 2-year updated efficacy and safety analysis.

Background: Anti-programmed cell death ligand 1 (PD-L1)/programmed cell death 1 antibodies have shown clinical activity in platinum-treated metastatic urothelial carcinoma, resulting in regulatory approval of several agents, including avelumab (anti-PD-L1). We report ≥2-year follow-up data for avelumab treatment and exploratory subgroup analyses in patients with urothelial carcinoma.

Methods: Patients with previously treated advanced/metastatic urothelial carcinoma, pooled from two cohorts of the phase Ib JAVELIN Solid Tumor trial, received avelumab 10 mg/kg every 2 weeks until disease progression, unacceptable toxicity or withdrawal.

Recent progress in treating advanced prostate cancer.

Purpose Of Review: Summarize recent advances in the treatment of advanced prostate cancer.

Recent Findings: Recent randomized data suggest a survival advantage to early use of novel androgen receptor inhibitors in combination with androgen deprivation therapy both in the setting of hormone-sensitive metastatic prostate cancer and nonmetastatic castration-resistant disease. While ongoing analyses examine optimal sequencing of existing agents for treatment of advanced prostate cancer, additional research focuses on expanding treatment options through development of novel genomically targeted therapies, antibody-drug conjugates, and immune therapy combinations.

Cabozantinib use in metastatic renal cell carcinoma patients in clinical practice: Evaluation of dosing patterns, tolerability, and outcomes compared to clinical trials.

Introduction: Despite first-line approval in metastatic renal cell carcinoma (mRCC), the tyrosine kinase inhibitor cabozantinib is associated with frequent treatment-limiting side effects. Dose reductions in published trials of the drug and in clinical practice are commonplace. We analyzed our institution's real-world experience with cabozantinib dosing in patients with mRCC to assess strategies to improve tolerability and patient outcomes.

Optimization of therapies for men with advanced prostate cancer: a review of recent developments with a look toward the future.

Purpose Of Review: Summarizes the rapid progress being made in treatment of advanced prostate cancer.

Recent Findings: Debate remains regarding the optimal sequencing of therapies in metastatic castration-sensitive prostate cancer with attention focused on the use of abiraterone versus docetaxel. Randomized trials now show a potential advantage to next-generation antiandrogens in the setting of nonmetastatic castration-resistant prostate cancer.

Circulating tumor DNA alterations in patients with metastatic castration-resistant prostate cancer.

Background: Because cell-free DNA (cfDNA) analysis facilitates the noninvasive genomic profiling of metastatic castration-resistant prostate cancer (mCRPC), the authors evaluated the association between cfDNA alterations and outcomes and evolution with therapy.

Methods: Patients with mCRPC underwent cfDNA genomic profiling using Guardant360, which examines major cancer-associated genes. Clinical factors, therapy information, failure-free survival, and overall survival (OS) were obtained for select patients.

Immune-related adverse events are linked with improved progression-free survival in patients receiving anti-PD-1/PD-L1 therapy.

Background: Immune-related adverse events (irAEs) are commonly encountered, when using programmed death-1/programmed death-ligand-1 (anti-PD-1/PD-L1) therapy and are often managed with corticosteroids. The effect of irAEs, particularly when steroids are required, on patient survival is not well established.

Methods: In this retrospective analysis, data for 157 patients with various tumor types treated with anti-PD-1/PD-L1 therapy were obtained.

Utility of cell-free nucleic acid and circulating tumor cell analyses in prostate cancer.

Prostate cancer is characterized by bone metastases and difficulty of objectively measuring disease burden. In this context, cell-free circulating tumor DNA (ctDNA) and circulating tumor cell (CTC) quantitation and genomic profiling afford the ability to noninvasively and serially monitor the tumor. Recent data suggest that ctDNA and CTC quantitation are prognostic for survival.

Recent advances in the management of metastatic prostate cancer: optimizing use of existing therapies, while searching for novel interventions.

Purpose Of Review: Summarizes recent advances in the treatment of metastatic castration-sensitive and castration-resistant prostate cancer.

Recent Findings: New randomized data suggest a survival advantage to early abiraterone in castration-sensitive metastatic prostate cancer. Prospective and retrospective studies are examining sequencing of existing cytotoxic and androgen-receptor-targeted therapies in both castration-sensitive and castration-resistant disease.

High frequency of rare structural chromosome abnormalities at relapse of cytogenetically normal acute myeloid leukemia with FLT3 internal tandem duplication.

FLT3 internal tandem duplication (ITD) mutations are present in acute myeloid leukemia (AML) in 30% of patients with acute myeloid leukemia (AML), most commonly in those with a normal karyotype, and are associated with short relapse-free survival. Both in vitro and in vivo studies of FLT3-ITD cell lines have demonstrated reactive oxygen species-mediated DNA double-strand breaks and associated error-prone DNA repair as a mechanism of genomic instability, and we hypothesized that genomic instability might be manifested by cytogenetic changes at relapse of FLT3-ITD AML. We retrospectively reviewed charts of patients with cytogenetically normal (CN) FLT3-ITD AML treated at the University of Maryland Greenebaum Cancer Center, with attention to metaphase analysis results at relapse.

Ten-day decitabine as initial therapy for newly diagnosed patients with acute myeloid leukemia unfit for intensive chemotherapy.

We retrospectively reviewed outcomes in 45 previously untreated patients with acute myeloid leukemia (AML) considered unfit for chemotherapy who were treated with 10-day courses of decitabine 20 mg/m(2) daily outside of a clinical trial, with no cut-offs for organ function or performance status (PS). Nineteen had Eastern Cooperative Group performance status (ECOG PS) ≥ 2, and 39 had ≥ 2 comorbidities. Fourteen patients (31%) achieved complete remission (CR) and five (11%) CR with incomplete count recovery, for an overall response rate of 42%, after a median of 2 (range, 1-4) courses.