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18 F-rhPSMA-7.3 ( 18 F-flotufolastat) is a high-affinity prostate-specific membrane antigen-targeted diagnostic radiopharmaceutical for PET imaging in patients with prostate cancer. Here, we report findings from the SPOTLIGHT study (NCT04186845), assessing the performance of 18 F-flotufolastat PET/CT for identifying prostate-specific membrane antigen-positive lesions confirmed by standard of truth (SoT) in men with biochemical recurrence of prostate cancer and negative conventional imaging at baseline. Methods: Men with biochemical recurrence received 296 MBq of 18 F-flotufolastat intravenously and then underwent PET/CT 50-70 min later. 18 F-flotufolastat PET/CT findings were evaluated by 3 masked central readers and verified using histopathology or follow-up confirmatory imaging (CT, MRI, bone scan, or 18 F-fluciclovine PET/CT) as the SoT. The present analysis evaluated all patients who had negative conventional imaging at baseline, underwent 18 F-flotufolastat PET/CT, and had SoT verification by histopathology or follow-up confirmatory imaging to report detection rate (DR), which is the number of patients with at least 1 PET-positive lesion, divided by the number of evaluable patients, and verified DR (VDR), which is the proportion of patients with at least 1 true-positive lesion as verified by SoT, of all patients scanned (PET-positive and PET-negative scans). DR and VDR were calculated and stratified according to prior therapy. Majority read data (agreement between ≥2 readers) are reported. Results: In total, 171 patients with negative baseline conventional imaging and SoT by histopathology or post-PET confirmatory imaging were evaluated. By majority read, the overall 18 F-flotufolastat DR among these patients was 95% (163/171; 95% CI, 91.0%-98.0%), and 110 of 171 of these patients had at least 1 true-positive lesion identified (VDR, 64%; 95% CI, 56.7%-71.5%). In the postprostatectomy group (133/171), 8.3% of patients had at least 1 true-positive lesion in the prostate bed, 28% in pelvic lymph nodes, and 35% in other sites. Among those who had received radiotherapy (36/171), 50% of patients had true-positive detections in the prostate, 8.3% in pelvic lymph nodes, and 36% in other sites. Conclusion: 18 F-flotufolastat frequently identified true-positive prostate cancer lesions in patients with negative conventional imaging. 18 F-flotufolastat may help to better define sites of disease recurrence and inform salvage therapy decisions than does conventional imaging, potentially leading to improved outcomes., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Background: Erdafitinib is indicated for the treatment of adults with locally advanced/metastatic urothelial carcinoma and susceptible FGFR3/2 alterations progressing on/after one or more lines of prior platinum-based chemotherapy., Objective: To better understand the frequency and management of select treatment-emergent adverse events (TEAEs) to enable optimal fibroblast growth factor receptor inhibitor (FGFRi) treatment., Design Setting and Participants: Longer-term efficacy and safety results of the BLC2001 (NCT02365597) trial in patients with locally advanced and unresectable or metastatic urothelial carcinoma were studied., Intervention: Erdafitinib schedule of 8 mg/d continuous in 28-d cycles, with uptitration to 9 mg/d if serum phosphate level was <5.5 mg/dl and no significant TEAEs occurred., Outcome Measurements and Statistical Analysis: Adverse events were graded using National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. The Kaplan-Meier methodology was used for the cumulative incidence of the first onset of TEAEs by grade. Time to resolution of TEAEs was summarized descriptively., Results and Limitations: At data cutoff, the median treatment duration was 5.4 mo among 101 patients receiving erdafitinib. Select TEAEs (total; grade 3) were hyperphosphatemia (78%; 2.0%), stomatitis (59%; 14%), nail events (59%; 15%), non-central serous retinopathy (non-CSR) eye disorders (56%; 5.0%), skin events (55%; 7.9%), diarrhea (55%; 4.0%), and CSR (27%; 4.0%). Select TEAEs were mostly of grade 1 or 2, and were managed effectively with dose modifications, including dose reductions or interruptions, and/or supportive concomitant therapies, resulting in few events leading to treatment discontinuation. Further work is needed to determine whether management is generalizable to the nonprotocol/general population., Conclusions: Identification of select TEAEs and appropriate management with dose modification and/or concomitant therapies resulted in improvement or resolution of most TEAEs in patients, allowing for continuation of FGFRi treatment to ensure maximum benefit., Patient Summary: Early identification and proactive management are warranted to mitigate or possibly prevent erdafitinib side effects to allow for maximum drug benefit in patients with locally advanced or metastatic bladder cancer., (© 2023 The Authors.)

PROOF 302 is an ongoing randomized, double-blind, placebo-controlled, adjuvant phase III trial (NCT04197986) in approximately 218 patients from 120 centers worldwide. Eligibility criteria include post-surgical high-risk muscle-invasive upper tract urothelial cancer (85% of patients) or urothelial bladder cancer (15%), susceptible FGFR3 alterations (activating mutations, gene fusions or rearrangements), ≤120 days following radical surgery and ineligible for/or refusing cisplatin-based (neo)adjuvant chemotherapy. Patients receive either oral infigratinib 125 mg or placebo daily on days 1-21 of a 28-day cycle for up to 52 weeks or until recurrence, unacceptable toxicity or death. Primary end point: centrally determined disease-free survival (DFS); secondary end points: investigator-assessed DFS, metastasis-free survival, overall survival and safety/tolerability; exploratory end points: correlative biomarker analysis, quality-of-life and infigratinib pharmacokinetics.

Background: Erdafitinib, a pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor, was shown to be clinically active and tolerable in patients with advanced urothelial carcinoma and prespecified FGFR alterations in the primary analysis of the BLC2001 study at median 11 months of follow-up. We aimed to assess the long-term efficacy and safety of the selected regimen of erdafitinib determined in the initial part of the study., Methods: The open-label, non-comparator, phase 2, BLC2001 study was done at 126 medical centres in 14 countries across Asia, Europe, and North America. Eligible patients were aged 18 years or older with locally advanced and unresectable or metastatic urothelial carcinoma, at least one prespecified FGFR alteration, an Eastern Cooperative Oncology Group performance status of 0-2, and progressive disease after receiving at least one systemic chemotherapy or within 12 months of neoadjuvant or adjuvant chemotherapy or were ineligible for cisplatin. The selected regimen determined in the initial part of the study was continuous once daily 8 mg/day oral erdafitinib in 28-day cycles, with provision for pharmacodynamically guided uptitration to 9 mg/day (8 mg/day UpT). The primary endpoint was investigator-assessed confirmed objective response rate according to Response Evaluation Criteria In Solid Tumors version 1.1. Efficacy and safety were analysed in all treated patients who received at least one dose of erdafitinib. This is the final analysis of this study. This study is registered with ClinicalTrials.gov, NCT02365597., Findings: Between May 25, 2015, and Aug 9, 2018, 2328 patients were screened, of whom 212 were enrolled and 101 were treated with the selected erdafitinib 8 mg/day UpT regimen. The data cutoff date for this analysis was Aug 9, 2019. Median efficacy follow-up was 24·0 months (IQR 22·7-26·6). The investigator-assessed objective response rate for patients treated with the selected erdafitinib regimen was 40 (40%; 95% CI 30-49) of 101 patients. The safety profile remained similar to that in the primary analysis, with no new safety signals reported with longer follow-up. Grade 3-4 treatment-emergent adverse events of any causality occurred in 72 (71%) of 101 patients. The most common grade 3-4 treatment-emergent adverse events of any cause were stomatitis (in 14 [14%] of 101 patients) and hyponatraemia (in 11 [11%]). There were no treatment-related deaths., Interpretation: With longer follow-up, treatment with the selected regimen of erdafitinib showed consistent activity and a manageable safety profile in patients with locally advanced or metastatic urothelial carcinoma and prespecified FGFR alterations., Funding: Janssen Research & Development., Competing Interests: Declaration of interests EFB has received grants or contracts from Pfizer and Astellas Pharma; honoraria from Exelixis and Bayer; and stocks or stock options from Exelixis, Becton Dickinson, Calithera Biosciences, Gilead Sciences, Medtronic, Clovis Oncology, and Macrogenics, outside of the submitted work. ID has received grants or contracts from Roche/Genentech, AstraZeneca, and Astellas Pharma; consulting fees from Roche/Genentech, MSD Oncology, Bayer, Bristol Myers Squibb, Seattle Genetics, Pharmacyclics Janssen Oncology, and Novartis; honoraria from Bristol Myers Squibb, Ipsen, Roche/Genentech, Janssen Oncology, MSD Oncology, Astellas Pharma, and EUSA Pharma; and has been reimbursed for travel, accommodations, or expenses from Roche/Genentech, AstraZeneca Spain, and Ipsen, outside of the submitted work. MTF has received consulting fees from Janssen Oncology; honoraria from Genentech and Janssen Oncology; and has been reimbursed for travel, accommodations, or expenses from Medivation/Astellas and Genentech, outside of the submitted work. JG-D has received consulting fees from Bristol Myers Squibb and Clovis Oncology; honoraria from Roche, Bristol Myers Squibb, AstraZeneca, PharmaMar, GlaxoSmithKline, Amgen, Clovis Oncology, and Janssen-Cilag; and other financial or non-financial interests from Pfizer, Bristol Myers Squibb, Roche, AstraZeneca, Merck, GamaMabs Pharma, and InvitroCue, outside of the submitted work. RAH has received personal fees from Aspen Parkside Hospital, during the conduct of the study; consulting fees from Bristol Myers Squibb, Roche, Merck Sharp & Dohme, Janssen Oncology, Nektar, and Bayer; honoraria from Janssen Oncology; support for attending meetings or travel from Janssen Oncology, Roche/Genentech, MSD Oncology, and Nektar; other financial or non-financial interests from Merck Sharp & Dohme, Roche, Bristol Myers Squibb, and Janssen; has patents planned, issued, or pending from Janssen; and has a leadership or fiduciary role at Cancer Clinic London Limited Liability Partnership, outside of the submitted work. MJ has received consulting fees from Sanofi; and other financial interests from AstraZeneca and Pfizer, outside of the submitted work. YL has received consulting fees from Janssen, Astellas Pharma, Roche, AstraZeneca, MSD Oncology, Clovis Oncology, Seattle Genetics, and Bristol Myers Squibb; and has been reimbursed for accommodations or expenses from Astellas Pharma, Janssen Oncology, Roche, AstraZeneca, MSD Oncology, Clovis Oncology, Seattle Genetics, and Bristol Myers Squibb, outside of the submitted work. BM has received consulting fees from Pfizer, Roche, AstraZeneca, Bayer, Astellas Pharma, and Janssen, and for an immediate family member from Roche, Pfizer, and Amgen; support for attending meetings or travel from Janssen-Cilag and for an immediate family member from Roche; and other financial or non-financial interests from Roche, Janssen, and Bayer, outside of the submitted work. MM received personal fees from Janssen Oncology, during the conduct of the study. AN received personal fees from Bayer, during the conduct of the study; consulting fees from Merck Sharp & Dohme, Roche, Bayer, AstraZeneca, Clovis Oncology, Janssen, Seattle Genetics/Astellas, Bristol Myers Squibb, GlaxoSmithKline, and Ferring; honoraria from Roche, Merck, AstraZeneca, Janssen, Foundation Medicine, and Bristol Myers Squibb; support for attending meetings or travel from Roche, Merck Sharp & Dohme, AstraZeneca, Janssen, and Rainier Therapeutics; stocks or stock options for an immediate family member from Bayer; and other financial or non-financial interests from Merck Sharp & Dohme, AstraZeneca, and Ipsen, outside of the submitted work. AO'H received personal fees from Janssen, during the conduct of the study. AES-W received personal fees form Janssen, during the conduct of the study. AOS-R received support from the National Institutes of Health, Michael and Sherry Sutton Fund for Urothelial Cancer, Janssen, Takeda, Bristol Myers Squibb, BioClin Therapeutics, Nektar, Merck Sharp & Dohme, and Basilea; consulting fees from Janssen, Merck, National Comprehensive Cancer Network, Bristol Myers Squibb, AstraZeneca, Bavarian Nordic, Seattle Genetics, Nektar, Genentech, EMD Serono, Mirati Therapeutics, and Basilea; and has patents planned, issued, or pending related to molecular testing in muscle invasive bladder cancer, outside of the submitted work. STT has received consulting fees from Medivation, Astellas Pharma, Dendreon, Janssen, Bayer, Genentech, Endocyte, Immunomedics, Karyopharm Therapeutics, Abbvie, Tolmar, QED Therapeutics, Amgen, Sanofi, Pfizer, Clovis Oncology, Novartis, Genomic Health, and Point Biopharma; support for attending meetings or travel from Sanofi, Immunomedics, and Amgen; and other financial or non-financial interests from Lilly, Sanofi, Janssen, Astellas Pharma, Progenics, Millennium, Amgen, Bristol Myers Squibb, Dendreon, Rexahn Pharmaceuticals, Bayer, Genentech, Newlink Genetics, Inovio Pharmaceuticals, AstraZeneca, Immunomedics, Novartis, Aveo, Boehringer Ingelheim, Merck, Stem CentRx, Karyopharm Therapeutics, Abbvie, Medivation, Endocyte, Exelixis, and Clovis Oncology, outside of the submitted work. YZ has received consulting fees from Roche/Genentech, Eisai, Amgen, Castle Biosciences, Novartis, Exelixis, Pfizer, Cardinal Health, Bayer, Janssen, TTC Oncology, and Clovis Oncology; and support for attending meetings or travel from Newlink Genetics, outside of the submitted work., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Poly(ADP-ribose) polymerase (PARP) inhibitors have antitumour activity against metastatic castration-resistant prostate cancers with DNA damage response (DDR) alterations in genes involved directly or indirectly in homologous recombination repair (HRR). In this study, we assessed the PARP inhibitor talazoparib in metastatic castration-resistant prostate cancers with DDR-HRR alterations., Methods: In this open-label, phase 2 trial (TALAPRO-1), participants were recruited from 43 hospitals, cancer centres, and medical centres in Australia, Austria, Belgium, Brazil, France, Germany, Hungary, Italy, the Netherlands, Poland, Spain, South Korea, the UK, and the USA. Patients were eligible if they were men aged 18 years or older with progressive, metastatic, castration-resistant prostate cancers of adenocarcinoma histology, measurable soft-tissue disease (per Response Evaluation Criteria in Solid Tumors version 1.1 [RECIST 1.1]), an Eastern Cooperative Oncology Group performance status of 0-2, DDR-HRR gene alterations reported to sensitise to PARP inhibitors (ie, ATM, ATR, BRCA1, BRCA2, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, RAD51C), had received one or two taxane-based chemotherapy regimens for metastatic disease, and progressed on enzalutamide or abiraterone, or both, for metastatic castration-resistant prostate cancers. Eligible patients were given oral talazoparib (1 mg per day; or 0·75 mg per day in patients with moderate renal impairment) until disease progression, unacceptable toxicity, investigator decision, withdrawal of consent, or death. The primary endpoint was confirmed objective response rate, defined as best overall soft-tissue response of complete or partial response per RECIST 1.1, by blinded independent central review. The primary endpoint was assessed in patients who received study drug, had measurable soft-tissue disease, and had a gene alteration in one of the predefined DDR-HRR genes. Safety was assessed in all patients who received at least one dose of the study drug. This study is registered with ClinicalTrials.gov, NCT03148795, and is ongoing., Findings: Between Oct 18, 2017, and March 20, 2020, 128 patients were enrolled, of whom 127 received at least one dose of talazoparib (safety population) and 104 had measurable soft-tissue disease (antitumour activity population). Data cutoff for this analysis was Sept 4, 2020. After a median follow-up of 16·4 months (IQR 11·1-22·1), the objective response rate was 29·8% (31 of 104 patients; 95% CI 21·2-39·6). The most common grade 3-4 treatment-emergent adverse events were anaemia (39 [31%] of 127 patients), thrombocytopenia (11 [9%]), and neutropenia (ten [8%]). Serious treatment-emergent adverse events were reported in 43 (34%) patients. There were no treatment-related deaths., Interpretation: Talazoparib showed durable antitumour activity in men with advanced metastatic castration-resistant prostate cancers with DDR-HRR gene alterations who had been heavily pretreated. The favourable benefit-risk profile supports the study of talazoparib in larger, randomised clinical trials, including in patients with non-BRCA alterations., Funding: Pfizer/Medivation., Competing Interests: Declaration of interests JSdB reports consulting fees from Astellas Pharma, AstraZeneca, Bayer, BioXcel Therapeutics, Boehringer Ingelheim, Celgene, Daiichi Sankyo, Eisai, Genmab, GSK, Janssen Oncology, Menarini Silicon Biosystems, Merck Serono, MSD, Orion Pharma GmbH, Pfizer, Roche/Genentech, Sanofi, Sierra Oncology, and Taiho Pharmaceutical; funding or support to his institution for laboratory and clinical work from Astex Pharmaceuticals, AstraZeneca, Bayer, Celgene, Cellcentric, Daiichi Sankyo, Genentech, GSK, MedImmune, Medivation, Merck Serono, MSD, Orion Pharma GmbH, Sanofi, Sierra Oncology, and Taiho Pharmaceutical; honoraria from Astellas Pharma, AstraZeneca, BioXcel Therapeutics, Daiichi Sankyo, Janssen Oncology, Menarini Silicon Biosystems, Pfizer, Roche/Genentech, Sanofi, and Sierra Oncology; travel, accommodation, and expenses from Astellas Pharma, AstraZeneca, Genmab, GSK, Orion Pharma GmbH, Qiagen, Sanofi, Taiho Pharmaceutical, and Vertex; and is named as an inventor, with no financial interest, on a patent (number 8,822,438). NM reports consulting fees from Astellas Pharma, Bristol-Myers Squibb, Genzyme, Janssen-Cilag, MSD Oncology, and Roche; funding or clinical trial and laboratory research support to his institution from Astellas Pharma, Janssen-Cilag, Pfizer, Roche/Genentech, and Sanofi; and accommodation and expenses from Astellas Pharma, Bristol-Myers Squibb, MSD Oncology, and Roche. GVS reports payment or honoraria from AstraZeneca, Eli Lilly, MSD, Pfizer, Roche, Johnson & Johnson, and Takeda; consulting fees from Eli Lilly, BeiGene, and AstraZeneca; institutional grants or contracts from MSD and Tesaro; support for attending meetings and travel from Bayer; and is a past president of the International Association for the Study of Lung Cancer. EC reports consulting fees to her institution from Astellas Pharma, AstraZeneca, Bayer, Clovis, Janssen, MSD, and Pfizer; payment or honoraria to herself from Astellas Pharma, AstraZeneca, Bayer, Clovis, Janssen, Pfizer, and Roche; grants or contracts to her institution from AstraZeneca, Bayer, Janssen, and Synlab; support for attending meetings and travel from AstraZeneca, Bayer, and Janssen; and is an unpaid member of the European Society for Medical Oncology faculty. TD reports participation on a Data Monitoring Safety Board or Advisory Board for Advanced Accelerator Applications, Bayer, Bristol-Myers Squibb, Exelixis, and Janssen. ASte reports consulting fees (personal) from Ipsen Pharma, Janssen, and Roche; participation on a Data Safety Monitoring Board or Advisory Board for Astellas Pharma, AstraZeneca, Ferring, and Synergo; and research grant funding from Amgen, Ipsen Pharma, and Karl Storz AG. CSH reports consulting fees from AstraZeneca, Bayer, Blue Earth Diagnostics, Clovis Oncology, Ferring, Hinova Pharmaceuticals, Janssen, and Pfizer; funding for research work to her institution from Aragon Pharmaceuticals, Astellas Pharma, AstraZeneca, Bayer, Clovis Oncology, eFFECTOR Therapeutics, Emergent BioSolutions, Ferring, Medivation, Pfizer, and Roche; honoraria from Astellas Pharma; and accommodation and expenses from Bayer, Blue Earth Diagnostics, Clovis Oncology, Ferring, Hinova Pharmaceuticals, Janssen Oncology, and Pfizer. FS reports consulting fees to himself from Astellas Pharma, AstraZeneca, Bayer, Bristol-Myers Squibb, Janssen, Myovant, Novartis, Pfizer, and Sanofi; grants or contracts to his institution from Astellas Pharma, AstraZeneca, Bayer, Bristol-Myers Squibb, Janssen, Myovant, Novartis, Pfizer, and Sanofi; and payment or honoraria from Astellas Pharma, AstraZeneca, Bayer, Bristol-Myers Squibb, Myovant, Novartis, Janssen, Pfizer, and Sanofi. CB reports consulting fees from Astellas Pharma, Janssen, Merck, and Pfizer. IMvO reports consulting fees from Astellas Pharma, Bayer, Janssen, and MSD/AstraZeneca; grants or contracts from Astellas Pharma, Bayer, Janssen, and MSD/AstraZeneca; payment or honoraria from Astellas Pharma, Bayer, Janssen, and MSD/AstraZeneca; and support for attending meetings and travel from Astellas Pharma. ADL, MM, H-CC, CGH, and AC are employees of Pfizer and hold Pfizer stock and stock options. KF reports payment or honoraria to his institution from Astellas Pharma, Bayer, Janssen, and Sanofi, and participation on a Data Monitoring Safety Board or Advisory Board to his institution for Amgen, Astellas Pharma, AstraZeneca, Bayer, Clovis, Janssen, Pfizer, and Sanofi. ASti and MTF declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Retrospective analyses of randomized trials suggest that Black men with metastatic castration-resistant prostate cancer (mCRPC) have longer survival than White men. The authors conducted a prospective study of abiraterone acetate plus prednisone to explore outcomes by race., Methods: This race-stratified, multicenter study estimated radiographic progression-free survival (rPFS) in Black and White men with mCRPC. Secondary end points included prostate-specific antigen (PSA) kinetics, overall survival (OS), and safety. Exploratory analysis included genome-wide genotyping to identify single nucleotide polymorphisms associated with progression in a model incorporating genetic ancestry. One hundred patients self-identified as White (n = 50) or Black (n = 50) were enrolled. Eligibility criteria were modified to facilitate the enrollment of individual Black patients., Results: The median rPFS for Black and White patients was 16.6 and 16.8 months, respectively; their times to PSA progression (TTP) were 16.6 and 11.5 months, respectively; and their OS was 35.9 and 35.7 months, respectively. Estimated rates of PSA decline by ≥50% in Black and White patients were 74% and 66%, respectively; and PSA declines to <0.2 ng/mL were 26% and 10%, respectively. Rates of grade 3 and 4 hypertension, hypokalemia, and hyperglycemia were higher in Black men., Conclusions: Multicenter prospective studies by race are feasible in men with mCRPC but require less restrictive eligibility. Despite higher comorbidity rates, Black patients demonstrated rPFS and OS similar to those of White patients and trended toward greater TTP and PSA declines, consistent with retrospective reports. Importantly, Black men may have higher side-effect rates than White men. This exploratory genome-wide analysis of TTP identified a possible candidate marker of ancestry-dependent treatment outcomes., (© 2021 American Cancer Society.)

Purpose: MEDI3726 is an antibody-drug conjugate targeting the prostate-specific membrane antigen and carrying a pyrrolobenzodiazepine warhead. This phase I study evaluated MEDI3726 monotherapy in patients with metastatic castration-resistant prostate cancer after disease progression on abiraterone and/or enzalutamide and taxane-based chemotherapy., Patients and Methods: MEDI3726 was administered at 0.015-0.3 mg/kg intravenously every 3 weeks until disease progression/unacceptable toxicity. The primary objective was to assess safety, dose-limiting toxicities (DLT), and MTD/maximum administered dose (MAD). Secondary objectives included assessment of antitumor activity, pharmacokinetics, and immunogenicity. The main efficacy endpoint was composite response, defined as confirmed response by RECIST v1.1, and/or PSA decrease of ≥50% after ≥12 weeks, and/or decrease from ≥5 to <5 circulating tumor cells/7.5 mL blood., Results: Between February 1, 2017 and November 13, 2019, 33 patients received MEDI3726. By the data cutoff (January 17, 2020), treatment-related adverse events (TRAE) occurred in 30 patients (90.9%), primarily skin toxicities and effusions. Grade 3/4 TRAEs occurred in 15 patients (45.5%). Eleven patients (33.3%) discontinued because of TRAEs. There were no treatment-related deaths. One patient receiving 0.3 mg/kg had a DLT of grade 3 thrombocytopenia. The MTD was not identified; the MAD was 0.3 mg/kg. The composite response rate was 4/33 (12.1%). MEDI3726 had nonlinear pharmacokinetics with a short half-life (0.3-1.8 days). The prevalence of antidrug antibodies was 3/32 (9.4%), and the incidence was 13/32 (40.6%)., Conclusions: Following dose escalation, no MTD was identified. Clinical responses occurred at higher doses, but were not durable as patients had to discontinue treatment due to TRAEs., (©2021 American Association for Cancer Research.)

Targeting the androgen receptor by depriving testosterone with gonadotropin-releasing hormone agonists or antagonists, or surgical castration, has been the backbone of metastatic prostate cancer treatment. Although most prostate cancers initially respond to androgen deprivation, metastatic castration-resistant prostate cancer evolves into a heterogeneous disease with diverse drivers of progression and mechanisms of therapeutic resistance. Development of castrate resistance phenotype is associated with lethality despite the recent noteworthy strides gained via increase in therapeutic options. Identification of novel therapeutics to further improve survival and achieve durable responses in metastatic castration-resistant prostate cancer is a clinical necessity. In this review, we outline the existing avengers for treatment of metastatic castration-resistant prostate cancer by clinical presentation, placing into context the clinical state of the patient, such as burden of disease and symptoms. Doing so might aid in the ability to optimize the sequence of agents and allow for maximal exposure to life-prolonging therapeutics. Realizing the limitations of the androgen signaling inhibition, we explore the androgen-indifferent prostate cancer: the mutants. Classically, these subtypes have been associated with variant histology, but androgen-indifferent prostate cancer features are now frequently observed in association with heterogeneous morphologies, including double-negative prostate cancers, lacking both androgen receptor and neuroendocrine features, or clinicopathologic criteria, such as the aggressive variant prostate cancer criteria. The framework of new avengers against metastatic castration-resistant prostate cancer based on mechanism, including DNA repair, immune checkpoint inhibition, PTEN/PI3K/AKT pathway, prostate-specific membrane antigen targets, bispecific T-cell engagers, and radionuclide therapies, is summarized in this review.

Background: Inhibition of the programmed cell death protein 1 (PD-1) pathway has demonstrated clinical benefit in metastatic urothelial cancer (mUC); however, response rates of 15% to 26% highlight the need for more effective therapies. Bruton tyrosine kinase (BTK) inhibition may suppress myeloid-derived suppressor cells (MDSCs) and improve T-cell activation., Methods: The Randomized Phase 2 Trial of Acalabrutinib and Pembrolizumab Immunotherapy Dual Checkpoint Inhibition in Platinum-Resistant Metastatic Urothelial Carcinoma (RAPID CHECK; also known as ACE-ST-005) was a randomized phase 2 trial evaluating the PD-1 inhibitor pembrolizumab with or without the BTK inhibitor acalabrutinib for patients with platinum-refractory mUC. The primary objectives were safety and objective response rates (ORRs) according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). Immune profiling was performed to analyze circulating monocytic MDSCs and T cells., Results: Seventy-five patients were treated with pembrolizumab (n = 35) or pembrolizumab plus acalabrutinib (n = 40). The ORR was 26% with pembrolizumab (9% with a complete response [CR]) and 20% with pembrolizumab plus acalabrutinib (10% with a CR). The grade 3/4 adverse events (AEs) that occurred in ≥15% of the patients were anemia (20%) with pembrolizumab and fatigue (23%), increased alanine aminotransferase (23%), urinary tract infections (18%), and anemia (18%) with pembrolizumab plus acalabrutinib. One patient treated with pembrolizumab plus acalabrutinib had high MDSCs at the baseline, which significantly decreased at week 7. Overall, MDSCs were not correlated with a clinical response, but some subsets of CD8+ T cells did increase during the combination treatment., Conclusions: Both treatments were generally well tolerated, although serious AE rates were higher with the combination. Acalabrutinib plus pembrolizumab did not improve the ORR, PFS, or OS in comparison with pembrolizumab alone in mUC. Baseline and on-treatment peripheral monocytic MDSCs were not different in the treatment cohorts. Proliferating CD8+ T-cell subsets increased during treatment, particularly in the combination cohort. Ongoing studies are correlating these peripheral immunome findings with tissue-based immune cell infiltration., (© 2020 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Purpose: Platinum-based chemotherapy for first-line treatment of metastatic urothelial cancer is typically administered for a fixed duration followed by observation until progression. "Switch maintenance" therapy with PD-1 blockade at the time of chemotherapy cessation may be attractive for mechanistic and pragmatic reasons., Patients and Methods: Patients with metastatic urothelial cancer achieving at least stable disease on first-line platinum-based chemotherapy were enrolled. Patients were randomly assigned double-blind 1:1 to switch maintenance pembrolizumab 200 mg intravenously once every 3 weeks versus placebo for up to 24 months. Patients with disease progression on placebo could cross over to pembrolizumab. The primary objective was to determine the progression-free survival. Secondary objectives included determining overall survival as well as treatment outcomes according to PD-L1 combined positive score (CPS)., Results: Between December 2015 and November 2018, 108 patients were randomly assigned to pembrolizumab (n = 55) or placebo (n = 53). The objective response rate was 23% with pembrolizumab and 10% with placebo. Treatment-emergent grade 3-4 adverse events occurred in 59% receiving pembrolizumab and 38% of patients receiving placebo. Progression-free survival was significantly longer with maintenance pembrolizumab versus placebo (5.4 months [95% CI, 3.1 to 7.3 months] v 3.0 months [95% CI; 2.7 to 5.5 months]; hazard ratio, 0.65; log-rank P = .04; maximum efficiency robust test P = .039). Median overall survival was 22 months (95% CI, 12.9 months to not reached) with pembrolizumab and 18.7 months (95% CI, 11.4 months to not reached) with placebo. There was no significant interaction between PD-L1 CPS ≥ 10 and treatment arm for progression-free survival or overall survival., Conclusion: Switch maintenance pembrolizumab leads to additional objective responses in patients achieving at least stable disease with first-line platinum-based chemotherapy and prolongs progression-free survival in patients with metastatic urothelial cancer.

Background: Prostate-specific membrane antigen (PSMA) is a well-established therapeutic and diagnostic target overexpressed in both primary and metastatic prostate cancers. PSMA antibody-drug conjugate (PSMA ADC) is a fully human immunoglobulin G1 anti-PSMA monoclonal antibody conjugated to monomethylauristatin E, which binds to PSMA-positive cells and induces cytotoxicity. In a phase 1 study, PSMA ADC was well tolerated and demonstrated activity as measured by reductions in serum prostate-specific antigen (PSA) and circulating tumor cells (CTCs). To further assess PSMA ADC, we conducted a phase 2 trial in metastatic castration-resistant prostate cancer (mCRPC) subjects who progressed following abiraterone/enzalutamide (abi/enz) therapy., Methods: A total of 119 (84 chemotherapy-experienced and 35 chemotherapy-naïve) subjects were administered PSMA ADC 2.5 or 2.3 mg/kg IV q3w for up to eight cycles. Antitumor activity (best percentage declines in PSA and CTCs from baseline and tumor responses through radiological imaging), exploratory biomarkers, and safety (monitoring of adverse events [AEs], clinical laboratory tests, and Eastern Cooperative Oncology Group performance status) were assessed., Results: PSA declines ≥50% occurred in 14% of all treated (n = 113) and 21% of chemotherapy-naïve subjects (n = 34). CTC declines ≥50% were seen in 78% of all treated (n = 77; number of subjects with ≥5 CTCs at baseline and a posttreatment result) and 89% of chemotherapy-naïve subjects (n = 19); 47% of all treated and 53% of chemotherapy-naïve subjects had a transition from ≥5 to less than 5 CTCs/7.5 mL blood at some point during the study. PSA and CTC reductions were associated with high PSMA expression (CTCs or tumor tissue) and low neuroendocrine serum markers. In the chemotherapy-experienced group, the best overall radiologic response to PSMA ADC treatment was stable disease in 51 (60.7%) subjects; 5.7% of subjects in the chemotherapy-naïve group had partial responses. The most common treatment-related AEs ≥Common Terminology Criteria for AE (CTCAE) grade 3 were neutropenia, fatigue, electrolyte imbalance, anemia, and neuropathy. The most common serious AEs were dehydration, hyponatremia, febrile neutropenia, and constipation. Two subjects who received 2.5 mg/kg died of sepsis., Conclusions: PSMA ADC demonstrated some activity with respect to PSA declines, CTC conversions/reductions, and radiologic assessments in abi/enz treated mCRPC subjects. Clinically significant treatment-related AEs included neutropenia and neuropathy., (© 2019 Wiley Periodicals, Inc.)

Background: Prostate-specific membrane antigen (PSMA) is a well-characterized target that is overexpressed selectively on prostate cancer cells. PSMA antibody-drug conjugate (ADC) is a fully human IgG1 monoclonal antibody conjugated to the microtubule disrupting agent monomethyl auristatin E (MMAE), which is designed to specifically bind PSMA-positive cells, internalize, and then release its cytotoxic payload into the cells. PSMA ADC has demonstrated potent and selective antitumor activity in preclinical models of advanced prostate cancer. A Phase 1 study was conducted to assess the safety, pharmacokinetics, and preliminary antitumor effects of PSMA ADC in subjects with treatment-refractory prostate cancer., Methods: In this first-in-man dose-escalation study, PSMA ADC was administered by intravenous infusion every three weeks to subjects with progressive metastatic castration-resistant prostate cancer (mCRPC) who were previously treated with docetaxel chemotherapy. The primary endpoint was to establish a maximum tolerated dose (MTD). The study also examined the pharmacokinetics of the study drug, total antibody, and free MMAE. Antitumor effects were assessed by measuring changes in serum prostate-specific antigen (PSA), circulating tumor cells (CTCs), and radiologic imaging., Results: Fifty-two subjects were administered doses ranging from 0.4 to 2.8 mg/kg. Subjects had a median of two prior chemotherapy regimens and prior treatment with abiraterone and/or enzalutamide. Neutropenia and peripheral neuropathy were identified as important first-cycle and late dose-limiting toxicities, respectively. The dose of 2.5 mg/kg was determined to be the MTD. Pharmacokinetics were approximately dose-proportional with minimal drug accumulation. Reductions in PSA and CTCs in subjects treated with doses of ≥1.8 mg/kg were durable and often concurrent., Conclusions: In an extensively pretreated mCRPC population, PSMA ADC demonstrated acceptable toxicity. Antitumor activity was observed over dose ranges up to and including 2.5 mg/kg. The observed anti-tumor activity supported further evaluation of this novel agent for the treatment of advanced metastatic prostate cancer., (© 2019 Wiley Periodicals, Inc.)

Maternal and fetal sources of thyroid hormone are important for the development of many organ systems. Thyroid hormone deficiency causes variable intellectual disability and hearing impairment in mouse and man, but the basis for this variation is not clear. To explore this variation, we studied two thyroid hormone-deficient mouse mutants with mutations in pituitary-specific transcription factors, POU1F1 and PROP1, that render them unable to produce thyroid stimulating hormone. DW/J-Pou1f1 dw/dw mice have profound deafness and both neurosensory and conductive hearing impairment, while DF/B-Prop1 df/df mice have modest elevations in hearing thresholds consistent with developmental delay, eventually achieving normal hearing ability. The thyroid glands of Pou1f1 mutants are more severely affected than those of Prop1 df/df mice, and they produce less thyroglobulin during the neonatal period critical for establishing hearing. We previously crossed DW/J-Pou1f1 dw/+ and Cast/Ei mice and mapped a major locus on Chromosome 2 that protects against hypothyroidism-induced hearing impairment in Pou1f1 dw/dw mice: modifier of dw hearing (Mdwh). Here we refine the location of Mdwh by genotyping 196 animals with 876 informative SNPs, and we conduct novel mapping with a DW/J-Pou1f1 dw/+ and 129/P2 cross that reveals 129/P2 mice also have a protective Mdwh locus. Using DNA sequencing of DW/J and DF/B strains, we determined that the genes important for thyroid gland function within Mdwh vary in amino acid sequence between strains that are susceptible or resistant to hypothyroidism-induced hearing impairment. These results suggest that the variable effects of congenital hypothyroidism on the development of hearing ability are attributable to genetic variation in postnatal thyroid gland folliculogenesis and function.

Purpose: Seviteronel (INO-464) is a selective cytochrome P450c17a (CYP17) 17,20-lyase (lyase) and androgen receptor (AR) inhibitor with antitumor activity in vitro and in vivo This open-label phase I clinical study evaluated the safety, tolerability, pharmacokinetics and activity of once-daily seviteronel in male chemotherapy-naïve subjects with castration-resistant prostate cancer (CRPC). Patients and Methods: Seviteronel was administered at 600 mg once daily with dose titration (DT) and in modified 3 + 3 dose escalation once-daily cohorts at 600, 750, and 900 mg without DT. The primary objectives of this study were to establish safety, tolerability, and the MTD of seviteronel in chemotherapy-naïve subjects with or without prior treatment with FDA-approved CRPC treatments, abiraterone acetate (AA), and enzalutamide. Secondary objectives were to assess pharmacokinetics, PSA, tumor response, and endocrine results. Results: Twenty-one subjects were enrolled. No dose-limiting toxicities (DLT) were observed through 750 mg once daily. Most treatment-emergent adverse events (AE) reported at grade 1-2. The most commonly reported AEs were fatigue (71%), dizziness (52%), blurred vision (38%), and dysgeusia (33%), with most AEs improving after dose reduction or dose interruption. Conclusions: Once-daily seviteronel was generally well tolerated in this phase I study of men with CRPC, a majority of which had progressed on prior AA or enzalutamide, or both. Of the doses evaluated, 600 mg once daily was chosen as the recommended phase II dose for future studies in subjects with CRPC. Clin Cancer Res; 24(21); 5225-32. ©2018 AACR ., (©2018 American Association for Cancer Research.)

Background: Chemotherapy may exert immunomodulatory effects, thereby combining favorably with the immune checkpoint blockade. The pharmacodynamic effects of such combinations, and potential predictive biomarkers, remain unexplored., Objective: To determine the safety, efficacy, and immunomodulatory effects of gemcitabine and cisplatin (GC) plus ipilimumab and explore the impact of somatic DNA damage response gene alterations on antitumor activity., Design, Setting, and Participants: Multicenter single arm phase 2 study enrolling 36 chemotherapy-naïve patients with metastatic urothelial cancer. Peripheral blood flow cytometry was performed serially on all patients and whole exome sequencing of archival tumor tissue was performed on 28/36 patients., Intervention: Two cycles of GC followed by four cycles of GC plus ipilimumab., Outcome Measurements and Statistical Analysis: The primary endpoint was 1-yr overall survival (OS). Secondary endpoints included safety, objective response rate, and progression-free survival., Results and Limitations: Grade ≥3 adverse events occurred in 81% of patients, the majority of which were hematologic. The objective response rate was 69% and 1-yr OS was 61% (lower bound 90% confidence interval: 51%). On exploratory analysis, there were no significant changes in the composition and frequency of circulating immune cells after GC alone. However, there was a significant expansion of circulating CD4 cells with the addition of ipilimumab which correlated with improved survival. The response rate was significantly higher in patients with deleterious somatic DNA damage response mutations (sensitivity=47.6%, specificity=100%, positive predictive value=100%, and negative predictive value=38.9%). Limitations are related to the sample size and single-arm design., Conclusions: GC+ipilimumab did not achieve the primary endpoint of a lower bound of the 90% confidence interval for 1-yr OS of >60%. However, within the context of a small single-arm trial, the results may inform current approaches combining chemotherapy plus immunotherapy from the standpoint of feasibility, appropriate cytotoxic backbones, and potential predictive biomarkers., Trial Registration: ClinicalTrials.gov NCT01524991., Patient Summary: Combining chemotherapy and immune checkpoint blockade in patients with metastatic urothelial cancer is feasible. Further studies are needed to refine optimal combinations and evaluate tests that might identify patients most likely to benefit., (Copyright © 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Purpose: Preclinical evidence suggests that both docetaxel and enzalutamide target androgen receptor translocation and signaling. This phase Ib study assessed the safety, tolerability, and pharmacokinetics of docetaxel when administered with enzalutamide as first-line systemic chemotherapy in men with metastatic castration-resistant prostate cancer (mCRPC)., Experimental Methods: Docetaxel-naïve patients received 21-day cycles of docetaxel (75 mg/m(2)). Enzalutamide (160 mg/day) was administered daily starting on day 2 of cycle 1. Patients were allowed to stop and restart docetaxel at any time following cycle 2. Treatment continued indefinitely until unacceptable toxicity or discontinuation due to investigator or patient preference., Results: A total of 22 patients received docetaxel, of whom 21 also received enzalutamide. Docetaxel was administered for a median of 5.0 cycles and enzalutamide for a median of 12.0 months. With concomitant treatment, geometric mean docetaxel exposure decreased by 11.8%, whereas peak concentrations decreased by 3.7% relative to docetaxel alone. The most common toxicities observed during the period of concomitant therapy were neutropenia (86.4%) and fatigue (77.3%). Common toxicities observed with post-docetaxel enzalutamide were constipation (23.8%), decreased appetite (19.0%), fatigue (19.0%), and musculoskeletal pain (19.0%). Treatment with enzalutamide and docetaxel resulted in prostate-specific antigen decreases in almost all patients based on exploratory analysis of available baseline and on-study prostate-specific antigen data., Conclusions: The combination of docetaxel and enzalutamide is feasible, although higher rates of neutropenia and neutropenic fever than anticipated were observed. Reductions in docetaxel exposure with enzalutamide coadministration were not considered clinically meaningful. This combination warrants further study in a larger mCRPC population. Clin Cancer Res; 22(15); 3774-81. ©2016 AACR., (©2016 American Association for Cancer Research.)

Background: Patients with metastatic urothelial carcinoma have few treatment options after failure of platinum-based chemotherapy. In this trial, we assessed treatment with atezolizumab, an engineered humanised immunoglobulin G1 monoclonal antibody that binds selectively to programmed death ligand 1 (PD-L1), in this patient population., Methods: For this multicentre, single-arm, two-cohort, phase 2 trial, patients (aged ≥18 years) with inoperable locally advanced or metastatic urothelial carcinoma whose disease had progressed after previous platinum-based chemotherapy were enrolled from 70 major academic medical centres and community oncology practices in Europe and North America. Key inclusion criteria for enrolment were Eastern Cooperative Oncology Group performance status of 0 or 1, measurable disease defined by Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1), adequate haematological and end-organ function, and no autoimmune disease or active infections. Formalin-fixed paraffin-embedded tumour specimens with sufficient viable tumour content were needed from all patients before enrolment. Patients received treatment with intravenous atezolizumab (1200 mg, given every 3 weeks). PD-L1 expression on tumour-infiltrating immune cells (ICs) was assessed prospectively by immunohistochemistry. The co-primary endpoints were the independent review facility-assessed objective response rate according to RECIST v1.1 and the investigator-assessed objective response rate according to immune-modified RECIST, analysed by intention to treat. A hierarchical testing procedure was used to assess whether the objective response rate was significantly higher than the historical control rate of 10% at an α level of 0·05. This study is registered with ClinicalTrials.gov, number NCT02108652., Findings: Between May 13, 2014, and Nov 19, 2014, 486 patients were screened and 315 patients were enrolled into the study. Of these patients, 310 received atezolizumab treatment (five enrolled patients later did not meet eligibility criteria and were not dosed with study drug). The PD-L1 expression status on infiltrating immune cells (ICs) in the tumour microenvironment was defined by the percentage of PD-L1-positive immune cells: IC0 (<1%), IC1 (≥1% but <5%), and IC2/3 (≥5%). The primary analysis (data cutoff May 5, 2015) showed that compared with a historical control overall response rate of 10%, treatment with atezolizumab resulted in a significantly improved RECIST v1.1 objective response rate for each prespecified immune cell group (IC2/3: 27% [95% CI 19-37], p<0·0001; IC1/2/3: 18% [13-24], p=0·0004) and in all patients (15% [11-20], p=0·0058). With longer follow-up (data cutoff Sept 14, 2015), by independent review, objective response rates were 26% (95% CI 18-36) in the IC2/3 group, 18% (13-24) in the IC1/2/3 group, and 15% (11-19) overall in all 310 patients. With a median follow-up of 11·7 months (95% CI 11·4-12·2), ongoing responses were recorded in 38 (84%) of 45 responders. Exploratory analyses showed The Cancer Genome Atlas (TCGA) subtypes and mutation load to be independently predictive for response to atezolizumab. Grade 3-4 treatment-related adverse events, of which fatigue was the most common (five patients [2%]), occurred in 50 (16%) of 310 treated patients. Grade 3-4 immune-mediated adverse events occurred in 15 (5%) of 310 treated patients, with pneumonitis, increased aspartate aminotransferase, increased alanine aminotransferase, rash, and dyspnoea being the most common. No treatment-related deaths occurred during the study., Interpretation: Atezolizumab showed durable activity and good tolerability in this patient population. Increased levels of PD-L1 expression on immune cells were associated with increased response. This report is the first to show the association of TCGA subtypes with response to immune checkpoint inhibition and to show the importance of mutation load as a biomarker of response to this class of agents in advanced urothelial carcinoma., Funding: F Hoffmann-La Roche Ltd., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

The treatment of metastatic renal cell carcinoma (mRCC) has changed dramatically in the past decade. As the number of available agents, and related volume of research, has grown, it is increasingly complex to know how to optimally treat patients. The authors are practicing medical oncologists at the US Oncology Network, the largest community-based network of oncology providers in the country, and represent the leadership of the Network's Genitourinary Research Committee. We outline our thought process in approaching sequential therapy of mRCC and the use of real-world data to inform our approach. We also highlight the evolving literature that will impact practicing oncologists in the near future., Competing Interests: Conflicts of interest: Hirsch: research funding—Pfizer, Bristol Meyers Squibb, Dendron, GlaxoSmithKline, Astellas, Sanofi; advisory board—Astellas, Pfizer, Hospira, Sandoz, Genentech; and stock/ownership interest—SignalPath Research, Flatiron Health. Hutson: research, speaker, advisory board/consultant: Pfizer, Novartis, Bayer, BMS, Eisai, Aveo. Burke: advisory boards—Gilead, Incyte, Millennium, Janssen Pfizer; travel—TG Therapeutics. Vogelzang: research funding from Pfizer, Novartis, Bayer, BMS, and Exelixis. Hauke, Doshi, Fleming, and Agrawal declare no potential conflict of interest with respect to research, authorship and/or publication of this article.

Objectives: Preclinical urothelial carcinoma models suggest activity of dasatinib, an oral SRC-family kinase (SFK) inhibitor. We sought to determine the feasibility and biologic activity of neoadjuvant dasatinib (Neo-D) in patients with muscle-invasive urothelial carcinoma of the bladder (miUCB) preceding radical cystectomy (RC)., Materials and Methods: A prospective multisite phase II trial was conducted. Key eligibility criteria included: resectable miUCB (T2-T4a, N0, M0), and Eastern Cooperative Oncology Group performance status 0 to 1. Patients received oral Neo-D 100mg once daily for 28±7 days followed by RC 8 to 24 hours after the last dose. The primary end point was feasibility, defined as≥60% of patients with miUCB completing therapy without treatment-related dose-limiting toxicity (DLT). Pre- and posttreatment tumor immunohistochemistry of phosphorylated SFK (pSFK), Ki-67, and cleaved caspase (Cas)-3 results were analyzed by paired t test., Results: The study completed full accrual with enrollment of 25 patients of whom 23 were evaluable for feasibility. The study achieved its primary end point with 15 patients (65%) completing therapy without treatment-related DLTs. DLTs included: fatigue (n = 2), pulmonary embolism, abdominal pain, supraventricular tachycardia, enteric fistula, hematuria, and dyspnea (n = 1 each). At RC, 5 patients (23%) had

Background: AT-101 (A), a small molecule oral inhibitor of the Bcl-2 family, has activity alone and in combination with docetaxel (Taxotere) and prednisone (DP) in metastatic castration-resistant prostate cancer (mCRPC). A randomized, double-blind, placebo-controlled phase II trial compared DP combined with either AT-101 (A) or placebo in chemonaive mCRPC., Patients and Methods: Men with progressive mCRPC despite androgen deprivation were eligible and randomized 1:1. Patients received docetaxel (75 mg/m2 day 1) and prednisone 5 mg orally twice daily every 21 days with either AT-101 (40 mg) or placebo twice daily orally on days 1-3. The primary end point was overall survival (OS)., Results: Two hundred and twenty-one patients were randomly assigned. Median OS for AT-101 plus docetaxel-prednisone (ADP) and placebo-DP was 18.1 versus 17.8 months [hazard ratio (HR) 1.07, 95% confidence interval 0.72-1.55, P=0.63]. Secondary end points were also not statistically different. Grade 3/4 toxic effects for ADP versus placebo-DP were cardiac events (5% versus 2%), lymphopenia (23% versus 16%), neutropenia (47% versus 40%), ileus (2% versus 0%) and pulmonary embolism (6% versus 2%). In a subgroup of high-risk mCRPC (n=34), outcomes appeared to favor ADP (median OS 19 versus 14 months)., Conclusions: AT-101 was tolerable but did not extend OS when combined with DP in mCRPC; a potential benefit was observed in high-risk patients.

Purpose: Cetuximab (C), a chimeric monoclonal antibody that binds epidermal growth factor receptor (EGFR), is active against androgen-independent prostate cancer cell lines and might enhance the activity of chemotherapy. The efficacy of combining cetuximab with mitoxantrone (M) plus prednisone (MP) was evaluated in progressive metastatic castrate-resistant prostate cancer (CRPC) after receiving docetaxel., Materials and Methods: Patients with progression after receiving docetaxel were eligible and randomized 2:1 to CMP or MP. Therapy was mitoxantrone 12 mg/m(2) intravenously (I.V.) on day 1, oral prednisone 10 mg daily in both arms, and cetuximab 250 mg/m(2) I.V. (400 mg/m(2) day 1, cycle 1) on days 1, 8, and 15 in the CMP arm. Cycles were repeated every 21 days. Radiologic assessments of disease and PSA (prostate-specific antigen) occurred every 4 cycles. The primary endpoint was time to progression (TTP)., Results: A total of 115 patients were enrolled, 75 in the CMP and 40 in the MP arm: the median TTP was 4.9 and 6.6 months, respectively; the measurable disease response rate was 2% and 4%, the PSA response rate 7.7% and 17.6%, and median survival 11.9 and 15.7 months, respectively. Key grade 3-4 toxicities were neutropenia 44% and 25.6%, anemia 6.7% and 7.7%, thrombocytopenia 6.7% and 2.6%, and fatigue 8% in both arms. In an unplanned exploratory analysis, median TTP with (n = 24) and without rash (n = 51) in the CMP arm was 10.3 months vs. 2.8 months (P = .004). On multivariable analysis,rash was significantly associated with TTP (hazard ratio [HR] = 0.43; P = .01)., Conclusions: The treatment with CMP is not recommended in unselected men with docetaxel-treated CRPC, although rash might help develop tailored therapy., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Objective: The present investigation used event-related potentials (ERPs, N400 and N300) to determine the extent to which individuals at low and high risk for child physical abuse (CPA) have pre-existing positive and negative child-related schemata that can be automatically activated by ambiguous child stimuli., Methods: ERP data were obtained from individuals at low (n=13) and high risk (n=12) for CPA and used in a procedure check, from which a sub-group of low-risk (n=7) and high-risk (n=7) individuals were selected for inclusion in the main study. ERP data were collected during the presentation of a priming paradigm consisting of non-child pictures (primes) and congruent and incongruent word descriptors (targets). ERP data also were collected during a second priming paradigm consisting of ambiguous child pictures (primes) and positive and negative word descriptors (targets). Data from this second paradigm were used to test the hypothesis that low-risk and high-risk individuals' putative pre-existing child-related schemata (i.e., positive schemata in low-risk individuals and negative schemata in high-risk individuals) provide a context that influences whether targets (positive or negative word descriptors) are congruent or incongruent with ambiguous child picture primes., Results: Analyses revealed the expected larger N400 waves in response to non-child picture, incongruent word pairs. There were no N400 differences between risk groups nor were there any risk group interactions, indicating that all participants responded in a similar manner to the non-child picture, congruent/incongruent word presentations. However, when ambiguous child picture primes were used with positive and negative word descriptors, low-risk individuals showed greater N400 and N300 responses to negative, relative to positive, word descriptors; whereas high-risk individuals showed no ERP differences with respect to positive and negative word descriptors., Conclusions: ERP evidence supports the view that low-risk individuals have greater accessibility to pre-existing positive (relative to negative) child-related schemata, which may reduce the likelihood of negative child-related evaluations. In contrast, high-risk individuals have pre-existing positive and negative child-related schemata that are equally accessible. Hence, high-risk, relative to low-risk, individuals appear to have greater accessibility to negative child-related schemata that may increase the likelihood of negative child-related evaluations and attributions that have been linked to CPA risk., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Background: Systemic therapy options are limited for metastatic castration-resistant prostate cancer (CRPC) patients who progress following docetaxel (Taxotere). This phase II trial evaluated sunitinib malate in patients with progressing metastatic CRPC following prior docetaxel., Patients and Methods: Patients with metastatic CRPC progressing following one to two chemotherapy regimens including docetaxel were included. The primary end point was progression-free survival (PFS) per radiographic and clinical evaluations. Oral sunitinib was administered 50 mg/day 4-weeks on followed by 2-weeks off per cycle up to a maximum of eight cycles or until clinical progression or intolerable toxicity., Results: Thirty-six patients with a median age of 69.5 years were accrued. The median PFS was 19.4 weeks with a 12-week PFS of 75.8%. Four patients (12.1%) had a > or =50% prostate-specific antigen (PSA) decline and seven (21.2%) had a > or =30% PSA decline. Two of 18 patients (11.1%) with measurable disease demonstrated 30% declines by RECIST and eight (44.4%) displayed some shrinkage. A decline in pain score > or =2 points occurred in 13.6% of 22 assessable patients. Drug discontinuation due to toxic effects occurred in 52.8% of patients., Conclusion: Sunitinib malate demonstrated promising activity in metastatic CRPC progressing after prior docetaxel.

Key members (a.k.a. "champions") within specific work units were provided with a brief training session designed to increase awareness of the benefits associated with influenza vaccination. The champions were responsible for encouraging members of their work units to accept an influenza vaccination and in some cases had the requisite training to administer the vaccination on site. Work units were randomly assigned to either champion present or champion absent conditions. Results show increased vaccination compliance for groups where a champion was present (N = 23). An independent sample t-test revealed a significant difference between the two groups t = 2.30, p < .03 which resulted in a percentage change from 41% in the unchampioned group to 52% in the championed group. Analyses which included only those units that had a fully trained champion (N = 13) produced a similar percentage increase in vaccine uptake from 41% to 54% (although this did not reach statistical significance; p = .08). Overall, the presence of a unit champion did produce a clinically relevant increase in vaccination rates in championed work units. This result has implications for future vaccination campaigns in hospital settings. Future research targeting the barriers and drivers of influenza vaccination among HCWs is recommended.

Genetic cases of congenital pituitary hormone deficiency are common and many are caused by transcription factor defects. Mouse models with orthologous mutations are invaluable for uncovering the molecular mechanisms that lead to problems in organ development and typical patient characteristics. We are using mutant mice defective in the transcription factors PROP1 and POU1F1 for gene expression profiling to identify target genes for these critical transcription factors and candidates for cases of pituitary hormone deficiency of unknown aetiology. These studies reveal critical roles for Wnt signalling pathways, including the TCF/LEF transcription factors and interacting proteins of the groucho family, bone morphogenetic protein antagonists and targets of notch signalling. Current studies are investigating the roles of novel homeobox genes and pathways that regulate the transition from proliferation to differentiation, cell adhesion and cell migration. Pituitary adenomas are a common human health problem, yet most cases are sporadic, necessitating alternative approaches to traditional Mendelian genetic studies. Mouse models of adenoma formation offer the opportunity for gene expression profiling during progressive stages of hyperplasia, adenoma and tumorigenesis. This approach holds promise for the identification of relevant pathways and candidate genes as risk factors for adenoma formation, understanding mechanisms of progression, and identifying drug targets and clinically relevant biomarkers., (Copyright 2009 S. Karger AG, Basel.)

The novel neurological mutant Cincinatti arose by genomic duplication of exon 5 in the glycine receptor gene Glra1. The mutant transcript results in premature protein truncation. A direct repeat of the pentamer GGGGC is present adjacent to the breakpoints and may have mediated the duplication event by a replication slippage mechanism.

To the investigator and clinician, prostate-specific antigen (PSA) level is a seemingly perfect outcome measure because it is easily assessable, quantitative, reproducible, and inexpensive. Whether post-therapy decline in PSA reflects true clinical benefit, and whether post-therapy declines can be used as an intermediate endpoint for accelerated drug approval is still open to question. At present, no drug has been approved strictly on the basis of a post-treatment decline in PSA, as it is unproven that such PSA changes are surrogates for true clinical benefits. Post-therapy PSA changes have been associated with improved survival in patients with castrate metastatic disease. The role of PSA changes as potential surrogates of clinical benefit have only been explored to a limited degree because to date, only two prospective randomized trials showing a survival benefit have been reported. Such trials are necessary, but not a sufficient pre-requisite to explore the potential role of any outcome measure as an intermediate endpoint. The clear demonstration that a post-therapy PSA change can account for all of the treatment effects seen is not yet available. A cytotoxic drug that does not produce any PSA decline is unlikely to be effective, but the converse is not always true because not all PSA rises represent a treatment failure. It is important to recognize that there are a range of clinical benefits to patients that can improve the quality and possibly the duration of survival, independent of PSA.

Purpose: To evaluate the pharmacokinetics of weekly docetaxel in a cohort of older patients with metastatic cancer and to explore the relationship of pharmacokinetic variables, Erythromycin Breath Test results, age, geriatric assessment variables, and toxicity to therapy., Experimental Design: Twenty patients ages > or = 65 years with metastatic breast, prostate, or lung cancer entered an Institutional Review Board-approved protocol to evaluate the pharmacokinetics of weekly docetaxel administered at 35 mg/m2 i.v. for 3 weeks followed by a 1-week break. The Erythromycin Breath Test and geriatric assessment were done before the first dose. Blood samples were collected for pharmacokinetic analysis with the first dose of docetaxel., Results: Of the 20 patients who entered the study, 19 were evaluable. There were no age-related differences in the pharmacokinetics of weekly docetaxel. Fifty-eight percent (11 of 19) experienced grade > or = 3 toxicity: 16% (3 of 19) grade > or = 3 hematologic toxicity, and 53% (10 of 19) grade > or = 3 nonhematologic toxicity. There was an association between the Erythromycin Breath Test results and docetaxel pharmacokinetic variables; however, there was no association between Erythromycin Breath Test results or docetaxel pharmacokinetics with frequency of grade > or = 3 toxicity., Conclusions: Despite no statistically significant age-related differences in weekly docetaxel pharmacokinetics, over half of these older patients experienced a grade > or = 3 toxicity at the 35 mg/m2 starting dose. We advocate a starting dose of 26 mg/m2 on this weekly schedule and dose escalating if no toxicity.

Insufficient attention has been paid to whether disclosure rates of sensitive or stigmatizing information vary as a function of method of inquiry. Methods vary both in terms of the anonymity afforded the participant and the opportunity to make a connection with the researcher, both of which might affect participants' willingness to disclose such information. In this investigation, 215 undergraduate students were randomly assigned to complete identical questionnaires using one of the three most common methods of data collection (in-person interview, telephone interview, and paper-and-pencil questionnaire) or an automated telephonic data collection (ATDC) system. Questions on six topic areas of increasing social sensitivity (study habits, substance use, physical and sexual aggression, victimization and perpetration) were included. The results indicated that there were no differences in disclosure rates due to methods and no method by topic interaction, but the two telephonic methods both produced significantly higher participation rates than the two other methods. The results suggest that, at least for a college student sample, an automated telephonic system produces data comparable to that of more traditional methods, while offering greater convenience, economy, and participation.

This study replicates and extends the research of Rosenbaum, Rabenhorst, Reddy, Fleming, and Howells, which also appears in this special issue. Responses from 398 randomly assigned participants regarding differentially sensitive topics were collected via four methods of data collection: written questionnaires, face-to-face interviews, telephone interviews, and an automated telephonic data collection system (ATDC). Several significant differences in data collection methodology and topic area were found, including greater disclosure of sensitive information via the ATDC system than via face-to-face and paper-and-pencil conditions. Participants who were assigned to the ATDC condition felt significantly more comfortable answering questions compared to those in the face-to-face interview condition. Participants in the telephone interview condition reported answering significantly more carefully than participants answering via written questionnaire. Taken together, the results of this study and the previous one it replicates suggest that the ATDC produces disclosure rates that are at least equivalent to, if not greater than, those generated using traditional methods for collecting sensitive data.

Objective: The purpose of this study was to determine the compliance rate with a maternal risk-factor-based guideline for the prevention of neonatal group B streptococcal (GBS) sepsis., Methods: In August 1994, a risk-factor-based guideline for selective intrapartum prophylaxis against neonatal GBS was adopted by a group model health maintenance organization. This guideline identified the following maternal risk factors for neonatal GBS sepsis: preterm delivery, rupture of membranes for >18 h, fever/chorioamnionitis, and history of a previous GBS-affected child. Patients with one or more risk factors were to receive intrapartum antibiotic prophylaxis consisting of either ampicillin, erythromycin, or clindamycin. We conducted a retrospective chart review to record risk factors and use of antibiotics. We hypothesized that >90% of patients with risk factors would receive intrapartum chemoprophylaxis., Results: A total of 805 maternal charts were reviewed. Of these, 105 (13%) were candidates for intrapartum prophylaxis. We found an overall compliance rate of 65%. Compliance rates by risk factor were preterm delivery (51%), prolonged rupture of membranes (73%), fever/chorioamnionitis (87%), and previous affected child (100%)., Conclusions: Our results show unexpectedly low compliance rates with a risk-factor-based guideline for the prevention of neonatal GBS sepsis. Only 65% of women with any risk factor for neonatal GBS sepsis received intrapartum antibiotic prophylaxis appropriately. Educational efforts to improve compliance with a risk-factor-based guideline should specifically address mothers delivering at 34-36 weeks gestation and mothers with prolonged rupture of membranes.