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. Trials to refine use of prostate-specific membrane antigen (PSMA)-directed radiopharmaceuticals are ongoing, while novel treatment approaches targeting mechanisms driving advanced prostate cancer continue to be explored. SUMMARY: Ongoing research focuses on refining the best combination and sequence of treatments for men with advanced prostate cancer. Future questions remain about use of existing therapies, and novel treatment approaches need to be developed.

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. METHODS: The primary objective was to establish the maximum tolerated dose. Secondary objectives included determining the recommended phase II dose, the safety and tolerability, the pharmacokinetic profile and preliminary anti-tumor efficacy. RESULTS: 15 patients with heavily pretreated metastatic disease enrolled. Safety data were analyzed for all patients, while pharmacokinetic data were available for 14 patients. There were no grade 3 or higher treatment-related adverse events. The maximum tolerated dose was not reached and there were no dose-limiting toxicities. The most common grade 1 or 2 treatment-related adverse events included headache, fatigue, constipation, nausea and transaminitis. The maximum concentration and area under the curve increased with dose. Clearance was consistent between doses and was observed mainly through the liver without significant hepatotoxicity. The half-life ranged from 20 to 30 h and the volume of distribution was consistent with a lipophilic drug. CONCLUSIONS: CNL exhibited an encouraging safety profile and pharmacokinetic parameters, with some signals of efficacy including prolonged stable disease in 1 patient with refractory pancreatic cancer. Pre-clinical data indicate potential synergy between CNL and multiple systemic therapies including chemotherapy, targeted therapy, and immunotherapy. Future studies are planned investigating CNL in combination strategies. TRIAL REGISTRATION: This study is registered under ClinicalTrials.gov ID: NCT02834611.

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. Patients received M9241 at 4, 8, 12, or 16.8 µg/kg every 4 weeks (Q4W) plus avelumab 10 mg/kg every 2 weeks (Q2W, dose levels (DLs) 1-4) or M9241 16.8 µg/kg Q4W plus avelumab 800 mg once a week for 12 weeks followed by Q2W (DL5/dose expansion). Primary endpoints for the dose-escalation part were adverse events (AEs) and dose-limiting toxicities (DLTs), and those for the dose-expansion part were confirmed best overall response (BOR) per investigator (Response Evaluation Criteria in Solid Tumors V.1.1) and safety. The dose-expansion part followed a two-stage design; 16 patients were enrolled and treated in stage 1 (single-arm part). A futility analysis based on BOR was planned to determine whether stage 2 (randomized controlled part) would be initiated. RESULTS: At data cut-off, 36 patients had received M9241 plus avelumab in the dose-escalation part. All DLs were well tolerated; one DLT occurred at DL3 (grade 3 autoimmune hepatitis). The maximum-tolerated dose was not reached, and DL5 was declared the recommended phase II dose, considering an observed drug-drug interaction at DL4. Two patients with advanced bladder cancer (DL2 and DL4) had prolonged complete responses. In the dose-expansion part, no objective responses were recorded in the 16 patients with advanced UC; the study failed to meet the criterion (≥3 confirmed objective responses) to initiate stage 2. Any-grade treatment-related AEs occurred in 15 patients (93.8%), including grade ≥3 in 8 (50.0%); no treatment-related deaths occurred. Exposures for avelumab and M9241 concentrations were within expected ranges. CONCLUSIONS: M9241 plus avelumab was well tolerated at all DLs, including the dose-expansion part, with no new safety signals. However, the dose-expansion part did not meet the predefined efficacy criterion to proceed to stage 2.

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. Additional treatment success is being identified with prostate-specific membrane antigen positron emission tomography (PSMA)-radiopharmaceuticals, combinations involving targeted therapies, and novel manipulations of the androgen receptor axis. Challenges remain in selecting between available therapies, harnessing immune therapies, and treating tumors with emergent neuroendocrine differentiation. SUMMARY: An expanding number of therapeutics are becoming available for men with advanced prostate cancer improving outcomes but at the same time making treatment selection more demanding. Ongoing research will be required to continue to hone treatment paradigms.

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.). This test identifies single nucleotide variants (SNVs) and GAs of select genes by next-generation sequencing. A total of 155 men with mPC were studied. Patients were stratified by GA status. The Kaplan-Meier method and multivariate cox regression models were used to estimate overall survival (OS) or failure-free survival (FFS) from either the date of GA detection or the initiation of systemic therapy. The chi-square test was used to evaluate associations between clinical factors and GAs. Results: The presence of liver and/or lung metastases was associated with GAs of BRAF, CDK6, PI3KCA, and FGFR1. Survival analyses were completed on a subset of 83 patients with metastatic castration-resistant prostate cancer (mCRPC). Median OS was improved in patients with 1 GA compared to patients with ≥2 GAs, whether determined from the date of initial GA(s) detection (14.9 mo vs. 8.9 mo) or date of therapy initiation nearest to GA detection (16.7 mo vs. 9.0 mo). Patients without GAs had not reached median OS. Patients with androgen receptor (AR) GA only were also found to have better median OS compared to patients with AR GA plus at least one other additional GA (19.3 mo vs. 8.9 mo). Patients with PIK3CA GA had significantly lower median OS compared to patients with GAs that did not have a PIK3CA GA (5.9 mo vs. 16.0 mo). In patients with AR and/or MYC GA(s), median OS improved in those with reduced AR or MYC PCN during therapy compared to those without such a reduction (25.1 mo vs. 15.9 mo). Conclusions: The association of select GAs with survival provides an additional tool for assessing mCRPC prognosis and informing management. Serial monitoring of ctDNA GAs is also useful to guide prognosis and therapeutic response.

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. SUMMARY: Although no clear consensus has emerged regarding the best sequencing of available therapeutics, trial results continue to support moving available therapies earlier in the disease course. Data continue to build for novel radiopharmaceuticals soon to likely be approved for treatment of castration-resistant disease.

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. These same patients were then classified as AVPC or non-AVPC and compared to determine the uniqueness of CEA-associated gene alterations. RESULTS: Patients with elevated CEA demonstrated higher rates of liver metastasis (37.5% vs. 19.1%, p = 0.02) and decreased median overall survival from CRPC diagnosis (28.7 vs. 73.2 mo, p < 0.0001). In addition, patients with elevated CEA were more likely to harbor copy number amplifications (CNAs) in AR, PIK3CA, MYC, BRAF, CDK6, MET, CCNE1, KIT, RAF1, and KRAS. Based on variant allele frequency we also defined "clonal" single-nucleotide variants (SNVs) thought to be driving disease progression in each patient and found that CEA expression was negatively correlated with clonal AR SNVs and positively correlated with clonal TP53 SNVs. Of these genetic associations, only the increases in clonal TP53 SNVs and KRAS amplifications were recapitulated among patients with AVPC when compared to patients without AVPC. CONCLUSIONS: Together these findings suggest that CEA expression in CRPC is associated with aggressive clinical behavior and gene alterations distinct from those in AVPC.

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.gov number: NCT01215136). Patients who were cisplatin-ineligible with previously untreated advanced UC were enrolled. Patients with both impaired renal function and poor performance status were enrolled into cohort 1; patients with either were enrolled into cohort 2. Patients received everolimus 10 mg daily alone (cohort 1) or with paclitaxel 80 mg/m2 on days 1, 8, and 15 of each 28-day cycle (cohort 2). The primary outcome was clinical benefit at 4 months. Secondary outcomes were adverse events, progression-free survival (PFS), and 1-year overall survival (OS). Exploratory endpoints included genomic correlates of outcomes. The trial was not designed for comparison between cohorts. RESULTS: A total of 36 patients were enrolled from 2010 to 2018 (cohort 1, N = 7; cohort 2, N = 29); the trial was terminated due to slow accrual. Clinical benefit at 4 months was attained by 0 (0%, 95% confidence interval [CI] 0-41.0%) patients in cohort 1 and 11 patients (37.9%, 95% CI 20.7-57.7%) in cohort 2. Median PFS was 2.33 (95% CI 1.81-Inf) months in cohort 1 and 5.85 (95% CI 2.99-8.61) months in cohort 2. Treatment was discontinued due to adverse events for 2 patients (29%) in cohort 1 and 11 patients (38%) in cohort 2. Molecular alterations in microtubule associated genes may be associated with treatment benefit but this requires further testing. CONCLUSION: Everolimus plus paclitaxel demonstrates clinical activity in cisplatin-ineligible patients with metastatic UC, although the specific contribution of everolimus cannot be delineated. Patients with both impaired renal function and borderline functional status may be difficult to enroll to prospective trials. (ClinicalTrials.gov Identifier NCT01215136).

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. SUMMARY: Although no clear consensus has emerged, evolving data continue to refine the selection of systemic therapies in treatment naïve metastatic prostate cancer. With potentially less cardiotoxic androgen deprivation therapies, novel radioisotopes, targeted pharmaceuticals, and immune therapy combinations, progress appears to be on the horizon in improving outcomes for men with advanced 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. End points included best overall response and progression-free survival (PFS) per RECIST V.1.1, overall survival (OS) and safety. Post hoc analyses included objective response rates (ORRs) in subgroups defined by established high-risk/poor-prognosis characteristics and association between time to response and outcome. RESULTS: 249 patients received avelumab; efficacy was assessed in 242 postplatinum patients. Median follow-up was 31.9 months (range 24-43), and median treatment duration was 2.8 months (range 0.5-42.8). The confirmed ORR was 16.5% (95% CI 12.1% to 21.8%; complete response in 4.1% and partial response in 12.4%). Median duration of response was 20.5 months (95% CI 9.7 months to not estimable). Median PFS was 1.6 months (95% CI 1.4 to 2.7 months) and the 12-month PFS rate was 16.8% (95% CI 11.9% to 22.4%). Median OS was 7.0 months (95% CI 5.9 to 8.5 months) and the 24-month OS rate was 20.1% (95% CI 15.2% to 25.4%). In post hoc exploratory analyses, avelumab showed antitumor activity in high-risk subgroups, including elderly patients and those with renal insufficiency or upper tract disease; ORRs were numerically lower in patients with liver metastases or low albumin levels. Objective response achieved by 3 months versus later was associated with longer OS (median not reached (95% CI 18.9 months to not estimable) vs 7.1 months (95% CI 5.2 to 9.0 months)). Safety findings were consistent with previously reported 6-month analyses. CONCLUSIONS: After ≥2 years of follow-up, avelumab showed prolonged efficacy and acceptable safety in patients with platinum-treated advanced/metastatic urothelial carcinoma, including high-risk subgroups. Survival appeared longer in patients who responded within 3 months. Long-term safety findings were consistent with earlier reports with avelumab treatment in this patient population.

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. SUMMARY: In this review, we summarize the recent data supporting the early use of novel androgen receptor inhibitors in advanced prostate cancer and aim to also frame how these drugs may fit within the existing context of docetaxel and abiraterone. We present recent series examining sequencing of approved therapies while searching for predictive biomarkers. Finally, we examine trials evaluating novel agents that target certain biological pathways to highlight the likely future directions for progress in the clinical management of advanced prostate cancer.

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. OBJECTIVES: The purpose of our study is to retrospectively analyze dose intensity, tolerability, and duration of exposure in mRCC patients who received cabozantinib at our institution. METHODS: In this retrospective, single-center chart review, we identified 35 adult patients who received at least one cycle cabozantinib for mRCC during a two-year period. Dosing patterns were reviewed for each patient to allow calculation of median dose intensity and median duration of exposure. RESULTS: The median dose intensity for cabozantinib was 55.4% and the median actual daily dose was 33.2 mg. Median duration of cabozantinib exposure was 10.4 months. Several alternative dosing strategies were employed with 60% of patients requiring at least one dose intervention to manage toxicities. CONCLUSIONS: Patients in this analysis received a median actual daily dose of 33.4 mg, less than the reported median doses in the METEOR and CABOSUN trials. However, our median duration of cabozantinib treatment was 10.4 months compared to 8.3 months and 6.5 months in these respective trials. Further investigation is warranted to determine if alternative dosing strategies and lower median actual daily doses produce survival results comparable to published clinical trials.

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. Patient-specific genomic anomalies, in particular DNA repair defects, provide targets for therapy with poly(ADP-ribose) polymerase inhibitors alone and in combination with other interventions. Adjustments in the dose and administration schedule of the accompanying steroid may improve the efficacy of abiraterone. Novel radiopharmaceuticals and immunotherapies suggest progress is on the horizon for men with castration-resistant prostate cancer. SUMMARY: In this review, we will highlight the avenues of research leading to optimization of therapies for men with advanced prostate cancer. Known therapeutics, such as docetaxel and abiraterone, are being used earlier in the disease course in the setting of metastatic castration-sensitive prostate cancer, and next-generation antiandrogens in the setting of nonmetastatic castration-resistant disease. Existing interventions are being optimized, including a maneuver to salvage abiraterone response with steroid switch. Finally, individualized therapies directed at specific genomic aberrations, a radiopharmaceutical targeting prostate-specific membrane antigen, and immune therapy combinations are providing potentially additional treatment options for patients with refractory disease.

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. The association between genomic alterations and outcomes was investigated. RESULTS: Of 514 men with mCRPC, 482 (94%) had ≥1 circulating tumor DNA (ctDNA) alteration. The most common recurrent somatic mutations were in TP53 (36%), androgen receptor (AR) (22%), adenomatous polyposis coli (APC) (10%), neurofibromin 1 (NF1) (9%), epidermal growth factor receptor (EGFR), catenin beta-1 (CTNNB1), and AT-rich interactive domain-containing protein 1A (ARID1A) (6% each); and BRCA1, BRCA2, and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) (5% each) The most common genes with increased copy numbers were AR (30%), MYC (20%), and BRAF (18%). Clinical outcomes were available for 163 patients, 46 of whom (28.8%) were untreated for mCRPC. A higher number of ctDNA alterations, AR alterations, and amplifications of MYC and BRAF were associated with worse failure-free survival and/or OS. On multivariable analysis, MYC amplification remained significantly associated with OS. Prior therapy and serial profiling demonstrated the evolution of alterations in AR and other genes. CONCLUSIONS: ctDNA frequently was detected in this large cohort of "real-world" patients with mCRPC, and the alterations appeared to be similar to previously reported tumor tissue alterations. A higher number of alterations, and AR and MYC alterations, appear to compromise clinical outcomes, suggesting a role for immune checkpoint inhibitors and novel AR and BET inhibitors in selected 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. Kaplan-Meier and Cox regression analyses were used to assess the effect of irAEs and corticosteroids on progression-free survival (PFS). RESULTS: A total of 45 irAEs were recorded for 157 patients. Twenty-one patients received systemic corticosteroids. Patients who developed irAEs, as well as those who received systemic corticosteroids, had improved PFS by Kaplan-Meier estimate. Multivariate Cox regression showed that irAEs were associated with improved PFS (hazard ratio of 0.33, P <0.001) which persisted even with use of systemic corticosteroids (hazard ratio of 0.38, P = 0.03). CONCLUSIONS: irAEs are associated with improved PFS in patients receiving anti-PD-1/PD-L1 therapy. This association does not appear to be altered by the use of systemic corticosteroids.

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. Genomic analysis of both circulating tumor cells and circulating tumor nucleic acids is being examined as a potential method for selecting existing therapies and identifying novel therapeutic targets. Finally, immunotherapy combinations are being evaluated in the setting of advanced prostate cancer. SUMMARY: In this review, we hope to summarize the recent data supporting the use of early abiraterone in castration-sensitive metastatic prostate cancer and discuss how this data might be incorporated with previous trials showing a survival advantage to early docetaxel. We present recent series examining sequencing of approved therapies as well as trials evaluating novel biomarkers and genomic analyses designed to help choose from among approved therapies or evaluate drugs in development. Lastly, we review ongoing trials examining novel immunotherapy combinations in advanced prostate cancer.

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. Indeed, CTC enumeration using the CellSearch® platform is validated as a prognostic factor and warrants consideration as a stratification factor in randomized trials. Changes in quantities of CTCs using CellSearch also are prognostic and may be employed to detect a signal of activity of new agents. Molecular profiling of both CTCs and ctDNA for androgen receptor (AR) variants has been associated with outcomes in the setting of novel androgen inhibitors. Serial profiling to detect the evolution of new alterations may inform drug development and help develop precision medicine. The costs of these assays and the small quantities in which they are detectable in blood are a limitation, and novel platforms are required to address this challenge. The presence of multiple platforms to assay CTCs and ctDNA also warrants the consideration of a mechanism to allow comparison of data across platforms. Further validation and the continued development and standardization of these promising modalities will facilitate their adoption in the clinic.

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. Cytogenetic data were available from first and, when applicable, subsequent relapses for 15 patients diagnosed with CN FLT3-ITD AML. Among 12 patients with documented FLT3-ITD at first and, when applicable, subsequent relapse, 10 had cytogenetic changes, including nine with rare structural abnormalities. The high frequency of rare structural chromosome abnormalities at relapse in our case series supports a role of genomic instability in the genesis of relapse, and suggests that reactive oxygen species-generating and DNA repair pathways might be therapeutic targets in FLT3-ITD AML.

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. The only pretreatment characteristic that differed significantly between responders and non-responders was percent marrow blasts (median 42% vs. 65%; p = 0.01). Median overall survival was 9.0 months; it was 19.4 and 2.3 months for responders and non-responders, respectively (p < 0.001). Thus 10-day decitabine therapy has efficacy in patients with AML considered unfit for chemotherapy, and may serve as a backbone for the addition of other novel agents.