The NCCN Guidelines for Bladder Cancer provide recommendations for the diagnosis, evaluation, treatment, and follow-up of patients with bladder cancer and other urinary tract cancers (upper tract tumors, urothelial carcinoma of the prostate, primary carcinoma of the urethra). These NCCN Guidelines Insights summarize the panel discussion behind recent important updates to the guidelines regarding the treatment of non–muscle-invasive bladder cancer, including how to treat in the event of a bacillus Calmette-Guérin (BCG) shortage; new roles for immune checkpoint inhibitors in non–muscle invasive, muscle-invasive, and metastatic bladder cancer; and the addition of antibody–drug conjugates for metastatic bladder cancer.

Quantitative dynamic PET with compartmental modeling has the potential to enable multiparametric imaging and more accurate quantification as compared to static PET imaging. Conventional methods for parametric imaging commonly use a single kinetic model for all image voxels and neglect the heterogeneity of physiological models, which can work well for single-organ parametric imaging but may significantly compromise total-body parametric imaging on long axial field-of-view scanners. In this paper, we evaluate the necessity of voxel-wise compartmental modeling strategies, including time delay correction and model selection, for total-body multiparametric imaging. Methods: Ten subjects (5 patients with metastatic cancer and 5 healthy volunteers) were scanned on the uEXPLORER total-body PET/CT system following injection of 370 MBq 18 F-fluorodeoxyglucose (FDG). Dynamic data were acquired for 60 minutes. Total-body parametric imaging was performed using two approaches. One is the conventional method that uses a single irreversible two-tissue compartmental model with and without time delay correction. The second approach selects the best kinetic model from three candidate models for individual voxels. The differences between the two approaches were evaluated for parametric imaging of micro kinetic parameters and FDG net influx rate Ki. Results: Time delay correction had a non-negligible effect on kinetic quantification of various organs and lesions. The effect was larger in lesions with higher blood volume. Parametric imaging of Ki with the standard two-tissue model introduced artifacts in vascular regions, which was overcome by the voxel-wise model selection strategy. Conclusions: The time delay and appropriate kinetic model vary in different organs and lesions. Modeling of the time delay of the blood input function and model selection improved total-body multiparametric imaging.

Niclosamide has preclinical activity against a wide range of cancers. In prostate cancer, it inhibits androgen receptor variant 7 and synergizes with abiraterone. The approved niclosamide formulation has poor oral bioavailability. The primary objective of this phase Ib trial was to identify a maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of a novel reformulated orally-bioavailable niclosamide/PDMX1001 in combination with abiraterone and prednisone in men with castration-resistant prostate cancer (CRPC). Eligible patients had progressing CRPC, adequate end-organ function, and no prior treatment with abiraterone or ketoconazole. Patients were treated with escalating doses of niclosamide/PDMX1001 and standard doses of abiraterone and prednisone. Peak and trough niclosamide plasma levels were measured. Common Terminology Criteria for Adverse Events (CTCAE) v4.0 and Prostate Cancer Working Group 2 criteria were used to evaluate toxicities and responses. Nine patients with metastatic CRPC were accrued, with no dose-limiting toxicities observed at all dose levels. The recommended Phase II dose of niclosamide/PDMX1001 was 1200 mg orally (PO) three times daily plus abiraterone 1000 mg PO once daily and prednisone 5 mg PO twice daily. Trough and peak niclosamide concentrations exceeded the therapeutic threshold of > 0.2 µM. The combination was well tolerated with most frequent adverse effects of diarrhea. Five out of eight evaluable patients achieved a PSA response; two achieved undetectable PSA and radiographic response. A novel niclosamide/PDMX1001 reformulation achieved targeted plasma levels when combined with abiraterone and prednisone, and was well tolerated. Further study of niclosamide/PDMX1001 with this combination is warranted.

Background TMPRSS2-ERG gene fusions are frequently found in prostate cancer and are pathognomomic for prostatic origin. In a series of cancer cases assayed with comprehensive genomic profiling (CGP) in the course of clinical care, we reviewed the frequency of TMPRSS2-ERG fusions in patient tumors of various histologic subtypes. Methods Frequency of TMPRSS2-ERG fusions was determined in comprehensive genomic profiles from 64,263 cancer cases submitted to Foundation Medicine to assess genomic alterations suggesting benefit from targeted therapy. Genomic results from an index case of prostate cancer that underwent evolution from adenocarcinoma to pure squamous cell carcinoma are presented. Results TMPRSS2-ERG fusions were identified for 0.86% (250/29030) of male patients and not found for female patients (0/35233). TMPRSS2-ERG fusions were detected in six tumors that were classified as squamous carcinoma, five of which were of unknown primary site. The index case is a patient with a large left retrovesical mass diagnosed as squamous carcinoma by morphologic examination and a history of Gleason 9 prostate cancer with prior prostatectomy and salvage radiation therapy. TMPRSS2-ERG was detected by genomic profiling in the squamous cell tumor, the primary adenocarcinoma of the prostate, and in a metachronous prostatic adenocarcinoma metastasis. Based on these results, the patient received androgen deprivation therapy. A phylogenetic tree demonstrating clonal and histopathologic evolution of prostate cancer in the index patient was constructed. Conclusions In this large CGP dataset, TMPRSS2-ERG fusion was seen in ~30% of prostate cancers regardless of histologic type; the fusion was on occasion detected in advanced cancers not initially carrying a diagnosis of prostate carcinoma. CGP of advanced cancers in men may reveal prostatic origin by detection of the pathognomomic TMPRSS2-ERG fusion gene.

IMPORTANCE Preclinical studies suggest that inhibition of single-stranded DNA repair by ataxia telangiectasia and Rad3 (ATR) may enhance the cytotoxicity of cisplatin, gemcitabine, and other chemotherapeutic agents. Cisplatin with gemcitabine remains the standard up-front therapy for treatment in patients with metastatic urothelial cancer.OBJECTIVE To determine whether the use of the selective ATR inhibitor, berzosertib, could augment the activity of cisplatin with gemcitabine. DESIGN, SETTING, AND PARTICIPANTSIn a phase 2 randomized clinical trial, 87 patients across 23 centers in the National Cancer Institute Experimental Therapeutics Clinical Trials Network were randomized to receive either cisplatin with gemcitabine alone (control arm) or cisplatin with gemcitabine plus berzosertib (experimental arm). Key eligibility criteria included confirmed metastatic urothelial cancer, no prior cytotoxic therapy for metastatic disease, 12 months or more since perioperative therapy, and eligibility for cisplatin receipt based on standard criteria. The study was conducted from January 27, 2017, to December 15, 2020. INTERVENTIONSIn the control arm, cisplatin, 70 mg/m 2 , was given on day 1 and gemcitabine, 1000 mg/m 2 , was given on days 1 and 8 of a 21-day cycle. In the experimental arm, cisplatin, 60 mg/m 2 , was given on day 1; gemcitabine, 875 mg/m 2 , on days 1 and 8; and berzosertib, 90 mg/m 2 , on days 2 and 9 of a 21-day cycle. MAIN OUTCOMES AND MEASURESThe primary end point of the study was progression-free survival. The analysis was on all patients who started therapy. RESULTSOf the total of 87 patients randomized, 41 patients received cisplatin with gemcitabine alone and 46 received cisplatin with gemcitabine plus berzosertib. Median age was 67 (range, 32-84) years, and 68 patients (78%) were men. Median progression-free survival was 8.0 months for both arms (Bajorin risk-adjusted hazard ratio, 1.22; 95% CI, 0.72-2.08). Median overall survival was shorter with cisplatin with gemcitabine plus berzosertib compared with cisplatin with gemcitabine alone (14.4 vs 19.8 months; Bajorin risk-adjusted hazard ratio, 1.42; 95% CI, 0.76-2.68). Higher rates of grade 3 vs grade 4 thrombocytopenia (59% vs 39%) and neutropenia (37% vs 27%) were observed with cisplatin with gemcitabine and berzosertib compared with cisplatin with gemcitabine alone; consequently, more dose reductions were needed in the experimental arm. Patients in the experimental arm received a median cisplatin dose of 250 mg/m 2 , which was significantly lower than the median dose of 370 mg/m 2 in the control arm (P < .001). CONCLUSIONS AND RELEVANCEThe addition of berzosertib to cisplatin with gemcitabine did not prolong progression-free survival relative to cisplatin with gemcitabine alone in patients with metastatic urothelial cancer, and a trend toward inferior survival was observed with this combination. Berzosertib plus cisplatin with gemcitabine was associated with significantly higher hematologic toxicities despite attenuated dosing of cisplatin with g...