bluuebunny/crossref_metadata_2025 huggingface dataset:
Patients with an extremely high prostate-specific antigen at prostate cancer diagnosis: A single institution analysis.
Authors: Qin Qian , Bikkasani Krishna , Oh William K. , Liaw Bobby Chi-Hung , Galsky Matt D. , Tsao Che-Kai
Published: March 2019

309

Background: High prostate specific antigen (PSA) at diagnosis is associated with worse outcomes in patients (pt) with prostate cancer. However, treatment selection and clinical outcome in those diagnosed with an extremely high PSA (> 500 ng/ml) are not well characterized, and we aim to better study this unique pt population. Methods: Using the Mount Sinai Genitourinary (GU) Cancer Biorepository, an IRB approved database containing all consented GU cancer pts seen between 2010-2018, we identified 23 pts with a PSA >500 at prostate cancer diagnosis. Descriptive analysis was performed to capture clinical characteristics, treatment selection and response, and outcomes in this cohort. Results: The median age and PSA at diagnosis were 64 (54-85) and 1057 ng/ml (528-11,418). At presentation, 1 pt had localized versus 22 pts had metastatic disease, 3 were asymptomatic, and sites of metastasis included lymph nodes (LN) only (n=3), bone only (n=8), or LNs and bone (n=11). Pts were initiated on either first line androgen deprivation (ADT) or ADT plus docetaxel if seen after 2015 (1 refused). All pts had >90% PSA response to first line therapy, with median PSA nadir 4.38 ng/ml (0.06-153), duration of response 6 months (1-33), and time to castration-resistant prostate cancer (CRPC) 14.5 months (5-99). There are differences in treatment selection and outcomes for pts treated with ADT vs. ADT plus docetaxel first line (see table). Conclusions: In pts with PSA >500 at prostate cancer diagnosis, we have observed significant heterogeneity in clinical presentation and response to treatment. In pts treated with first line ADT plus docetaxel, we observed 2 of 7 pts with extended treatment response (> 42 months). Differences in disease biology may account for this observation, and molecular characterization will be needed to better understand this subset. [Table: see text]
PRINT: Prostate cancer intensive, non-cross reactive therapy for CRPC—Early observations of feasibility and efficacy.
Authors: Liaw Bobby Chi-Hung , Tsao Che-Kai , Galsky Matt D. , Bakst Richard Lorne , Stewart Robert , Stock Richard , Oh William K.
Published: March 2019

310

Background: Optimal sequencing of approved therapeutic agents in mCRPC is not known. The standard approach, is to treat until resistance then switch. The PRINT trial explores the efficacy of treating mCRPC with a rapidly-cycling, non-cross reactive regimen as a way to more effectively treat an intrinsically heterogeneous disease, to delay or prevent drug resistance, and minimize treatment toxicity. Methods: Patients were treated with 3 consecutive treatment modules, each of 12 weeks' duration: 1. abiraterone acetate 1000 mg PO daily and prednisone 5 mg PO BID; 2. cabazitaxel 20 mg/m2 IV and carboplatin AUC 4 IV q3 weeks; 3. enzalutamide 160 mg PO daily and radium-223 50 kBq/kg IV q4 weeks (in those with bone metastases). After completion of this 9 month regimen, patients are followed on ADT alone. Primary endpoint is PSA or radiographic time to disease progression. Results: From 3/2017 to 10/2018, 28 of 40 planned men with mCRPC were enrolled, 19 (67.9%) with bone metastases. PSA response rates ( > 90%/ > 50%), compared to baseline, following each treatment module: 1. 50%/78.6%; 2. 50%/92.7%; 3. 64.39%/92.7%. Currently, 14 patients have completed the study regimen with median follow up of 3.6 months, 8 of whom continue without any additional therapy. Of the patients evaluable for primary endpoint, median time to PSA progression is 96+ days (95% CI 82-110+ days). The regiment was well tolerated, grade 3/4 adverse effects include: hyperglycemia (17.9%), diarrhea (7.1%), anemia (3.6%), fatigue (3.6%), neutropenia (3.6%), thrombocytopenia (3.6%). Measurable response and molecular correlate data will be presented. Conclusions: Treatment of mCRPC with a rapidly-cycling non-cross reactive regimen is feasible, demonstrates significant antitumor benefits, and is well tolerated. Further follow up will determine if PRINT delays progression compared with standard approaches. Clinical trial information: NCT02903160.
Protection of prostate cancer cells from GSK-3β-induced oxidative stress by Il-8 through activating the mTOR signaling pathway.
Authors: Sun Yi , Yang Lu , Wei Qiang
Published: March 2019

311

Background: Both oxidative stress and inflammation play important roles in prostate cancer cell apoptosis or proliferation. However, the mechanisms underlying these processes remain unclear. Thus, we chose IL-8 as the bridge between inflammation and cancer cell oxidative stress-induced death and confirmed its connection with mTOR and GSK-3beta. Methods: We overexpressed GSK-3beta and observed the effect of GSK-3beta on reactive oxygen species (ROS) and cell death induced by oxidative stress. Then, IL-8 was upregulated or downregulated to determine its impact on preventing cells from damage by GSK-3beta-induced oxidative stress. In addition, we confirmed the role of mTOR in this process through its overexpression or knockdown. Real-time PCR, Western blotting, transcription, Cell Counting Kit 8, flow cytometry and other techniques were used. Results: IL-8 promotes prostate cancer cell proliferation and decreases apoptosis, while GSK-3beta induces cell death by oxidative stress through the activation of the caspase-3 signaling pathway by increasing ROS. In addition, mTOR can also decrease the activation of the caspase-3 signaling pathway by inhibiting GSK--3beta and thus decreasing ROS production. Moreover, the inhibitory effect of IL-8 on GSK-3beta occurs through the regulation of mTOR. Conclusions: The results of this study highlight the importance of GSK-3beta, which increases the production of ROS and then induces oxidative stress in tumor cells, while IL-8 and mTOR attenuate the oxidative stress to protect prostate cancer cells through the inhibitor GSK-3beta.
The association of PSA levels and survival outcomes in patients with chemotherapy-naïve, castration-resistant prostate cancer (CRPC) who were treated with androgen receptor signaling axis targeting agent (ARAT): A Japanese cohort study.
Authors: Shimomura Tatsuya , Mori Keiichiro , Yamamoto Toshihiro , Onuma Hajime , Inaba Hiroyuki , Hata Kenichi , Kimura Takahiro , Egawa Shin
Published: March 2019

315

Background: PSA decline is used as one of the treatment outcome of androgen receptor signaling axis targeting agent (ARAT) in general. However, correlation between PSA decline and survival outcome is not discussed enough. In this study we evaluated how PSA decline influence the survival outcome of ARAT against chemo-naive castration resistant prostate cancer (CRPC). Methods: A total of 200 chemo-naïve CRPC cases treated with ARAT (abiraterone acetate or enzalutamide) were included in this study. We investigated the relationship between PSA response rate and survival outcome (PSA progression free survival (PSA-PFS), Failure free survival (FFS) and overall survival (OS)). Results: PSA response rate correlated with PSA-PFA, TFS and OS significantly (p<0.0001, <0.0001, 0.0009, respectively). And we categorized PSA decline in four groups, group 1: no PSA decline, group 2: 0-50%, group 3: 50%-90%, group 4: over 90%. Median PSA-PFS were 2M (group 1), 4M (group 2), 10M (group 3) and 16M (group 4) (p<0.0001). Median FFS were 3M (group 1), 6M (group 2), 12M (group 3) and 27M (group 4) (p<0.0001). Median OS were 28M (group 1), 36M (group 2), not reached (group 3 and 4) (p=0.0056). In terms of OS, there is a big different between PSA decline <50% and ≥50% in survival curve. And we compare the factors influencing PSA decline ≥50%. PSA and age at initiating ARAT are significant factors predicting PSA decline 50%. Lower PSA and lower age correlated PSA decline ≥50%. Conclusions: PSA decline strongly correlated with PSA-PFS, FFS and OS in this study. It would be a surrogate marker predicting survival outcomes of chemo-naïve CRPC cases treated with ARAT. Further investigation is warranted to confirm these results.
The outcome of loco-regional radiotherapy in metastatic castration-resistant prostate cancer patients treated with abiraterone acetate.
Authors: Yildirim Berna , Cem Onal , KOse Fatih , Oymak Ezgi , Sedef Ali Murat , Besen Ali Ayberk , Aksoy Sercan , Guler Ozan Cem , Sumbul Ahmet Taner , Mertsoylu Huseyin , Ozyigit Gokhan
Published: March 2019

316

Background: To evaluate the potential benefit of curative radiotherapy (RT) to primary tumor in metastatic castration resistant prostate cancer (mCRPC) patients treated with abiraterone. Methods: The clinical parameters of 106 mCRPC patients treated with abiraterone in the either pre- or post-chemotherapy setting were retrospectively evaluated. All patients had PSA progression or radiographic progression suitable for metastasis according to the RECIST guidelines with or without PSA progression. Patients were either oligometastatic (≤5 metastases) at diagnosis or became oligometastatic after systemic treatment were analyzed. Local RT to primary tumor and pelvic lymphatics was delivered in 44 patients (41%), while 62 patients (59%) did not have RT to primary tumor. Results: Median follow-up times for patients overall and for those who survived were 14.2 months (range, 2.3–54.9 months) and median OS for entire cohort was 21.9 months. The median OS was significantly higher in patients treated with local RT to primary tumor compared to patients without local RT (p = 0.04). Local RT to prostate and pelvic lymphatics significantly diminished local recurrence rate ( p = 0.003). In univariate analysis, a decline in PSA levels ≥50% of baseline was significant prognostic factor for both OS and PFS in entire cohort and in patients receiving prostate RT. In multivariate analysis, PSA response ≥50 of baseline obtained ≥3 weeks after abiraterone therapy is the only significant prognostic factor for better OS and PFS. Additionally, local RT to prostate is nearly significant prognosticator for improved OS. Patients treated with primary RT to prostate had significantly less progression under abiraterone and longer abiraterone period compared to patients without local prostate RT. Conclusions: Local prostate RT significantly improves OS and local control but not PFS, in mCRPC treated with abiraterone. Patients treated with primary RT to prostate had significantly less progression under abiraterone and longer abiraterone period compared to patients without local prostate RT.
Regional variations in online education test performance for prostate cancer care.
Authors: Jaganathan Hamsa , Roc Anne , Turell Wendy , George Daniel J.
Published: March 2019

317

Background: Regional variations in prostate cancer (PC) care in the US remain an issue with inconsistent clinician adherence to quality measures endorsed by national health services. To assess potential disparities in PC care among US-based healthcare providers (HCPs), we compared test performance of clinician participants in PC continuing medical education (CME) activities across 4 US regions. This would enable targeted education with region-specific strategies to effectively manage PC and promote consistent, high-quality care for all patients. Methods: PlatformQ Health developed and executed 3 online CME activities in PC (live broadcast and on-demand). The 1st 2 activities attracted 448 learners July 2016-2017. The 3rd activity attracted 319 learners to date May-Nov 2018. Self-reported US-based practicing HCPs (294) were included in this study. The percent of correct answers to CME tests pre-activity, post-activity, and at 8-weeks were collected and tested for significance (using 1 and 2 factor ANOVA tests) among 4 US regions: Northeast, Midwest, South, and West. CME test questions included case studies, new data on castration-resistant PC, and managing adverse events. Results: No significant difference was observed among the 4 regions in the pretest scores (p = 0.080, α = 0.05). While there was a significant improvement in performance among learners between pretest and posttest (p = 0.001), no significant regional variations were observed. There was also a significant improvement in performance from pretest to the follow-up test, which validates retention of knowledge 8 weeks after the education (p = 0.0016). However, learners from the South region performed significantly better than learners from the other regions (p < 0.05) when it came to 8-week retention. Conclusions: Education can improve knowledge and competence in PC management among US-based HCPs. Future studies, including post- test surveys regarding practice integration, should identify reasons for regional discrepancies in test performances among providers specializing in PC. A broader understanding towards PC care variations can help tailor CME activities specific to regional issues and identify region-specific best practices and learning gaps.
Synergistic effects of the PARP inhibitor olaparib and pharmacological ascorbate in castration-resistant prostate cancer.
Authors: Gordon Nicolas , Schiewer Matthew Joseph , Gallagher Peter , Mandigo Amy C , Dylgjeri Emanuela , McNair Christopher , De Leeuw Renee , Jones Jennifer K , Neupane Neermala Poudel , Shafi Ayesha A , Brand Lucas , Kelly William Kevin , Knudsen Karen E.
Published: March 2019

326

Background: The administration of ascorbate has proved lethal to and highly selective for a variety of cancer cell types; however, despite an increasingly impressive body of evidence, there has not been a robust effort to translate the observed in vitro and in vivo outcomes to the clinic. This is partially due to the fact that the mechanism by which ascorbate exerts its anti-cancer effect is still under investigation. A simplified model depicts ascorbate as a pro-drug for reactive oxygen species (ROS), which accumulate intracellularly and generate DNA damage. It was therefore hypothesized that poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi), by inhibiting DNA damage repair, would augment the toxicity of ascorbate. Methods: In vitro and in vivo models systems queried for anti-tumor effects of PARP inhibitors and ascorbate. Results: Two distinct castration-resistant prostate cancer (CRPC) models were sensitive to ascorbate at physiologically attainable concentrations. These in vitro models were then subjected to treatment with three different PARP inhibitors (olaparib, niraparib, and talazoparib) alone and in combination with ascorbate. The addition of a sub-lethal dose of ascorbate significantly increased cell death across a range of doses for all three PARP inhibitors. A combination index was generated for olaparib and ascorbate in both CRPC models; the results suggest a strongly synergistic relationship between olaparib and ascorbate. Use of a CRPC in vivo model demonstrated that the combination of olaparib and ascorbate significantly increased tumor doubling time compared to vehicle controls and monotherapy. This in vivo efficacy was even more profound in an additional model using castrated mice to mimic the effect of hormone therapy. Additional mechanistic studies are in progress to further investigate the potential for ascorbate and olaparib combination therapy. Conclusions: Ultimately, these data suggest the combination of ascorbate and PARP inhibitors could be an effective treatment for CRPC.
The impact of intraductal carcinoma of the prostate on the grade group system.
Authors: Kato Masashi , Yamamoto Akiyuki , Ishida Ryo , Kimura Tohru , Sano Tomoyasu , Gotoh Momokazu , Tsuzuki Toyonori
Published: March 2019

34

Background: The 2014 International Society of Urological Pathology (ISUP) and WHO 2016 classifications proposed a new grade group system for prostate cancer. Intraductal carcinoma of the prostate (IDC-P) is newly recognized on them and is reported to be strongly associated with high-grade and high-volume invasive prostate cancer. Although the presence of the IDC-P influences biochemical failure in radical prostatectomy patients, no data are available regarding the significance of IDC-P in integrating to the classification grade group system. The aim of this study is to enhance the utility of grade group system integrating into the presence of IDC-P. Methods: We retrospectively evaluated 1019 patients with prostate cancer who underwent radical prostatectomy without neoadjuvant or adjuvant therapy at the hospitals that the authors were affiliated with between 2005 and 2013. Data on age, PSA level at diagnosis, clinical T stage (cT), pathological T stage (pT), presence of Gleason pattern 5 (GP5), presence of IDC-P, and surgical margin status were analyzed to predict PSA recurrence after prostatectomy. Results: The median patient age was 67 (range, 45–80) years. The median initial PSA was 6.8 ng/ml (range, 0.4–82 ng/ml). The median follow-up period was 82 (range, 0.7–148) months. IDC-P was detected in 157 patients (15.4%). Among these patients, IDC-P positive rate increased correlated with upgrading. The grade group were as follows: Group 1 without IDC-P, 16.0% (n=163); Group 2 without IDC-P, 46.1% (n=470); Group 3 without IDC-P, 15.7% (n=160); Group 4 without IDC-P, 2.6% (n=27); and Group 5 without IDC-P, 4.1% (n=42); Group 2 with IDC-P, 2.9% (n=29); Group 345 with IDC-P, 12.6% [n=128; Group 3 (n=60); Group 4 (n=13); Group 5 (n=55)] Group 3, 4, and 5 with IDC-P showed a significantly worse prognosis than any other groups without IDC-P and Group 2 with IDC-P (p<.0001). In a multivariate analysis, integrating IDC-P into ISUP Grade, PSA level at diagnosis, and surgical margin status significantly predicted the prognosis (P < .0001). Conclusions: Integrating the presence of IDC-P into the grade group system will improve the accuracy of patients’ outcome prediction.
Keynote 057: Phase II trial of Pembrolizumab (pembro) for patients (pts) with high-risk (HR) nonmuscle invasive bladder cancer (NMIBC) unresponsive to bacillus calmette-guérin (BCG).
Authors: Balar Arjun Vasant , Kulkarni Girish S. , Uchio Edward M. , Boormans Joost , Mourey Loic , Krieger Laurence Eliot Miles , Singer Eric A. , Bajorin Dean F. , Kamat Ashish M. , Grivas Petros , Seo Ho Kyung , Nishiyama Hiroyuki , Konety Badrinath R. , Nam Kijoeng , Kapadia Ekta , Frenkl Tara L. , De Wit Ronald
Published: March 2019

350

Background: The PD-1 inhibitor pembro has durable antitumor activity in pts with metastatic urothelial carcinoma. Upregulation of the PD-1 pathway has been observed in BCG-resistant NMIBC, suggesting pembro may benefit. Efficacy and safety of pembro in pts with HR, BCG-unresponsive NMIBC was evaluated in the single-arm phase 2 KEYNOTE-057 study; updated results for pts with carcinoma in situ (CIS) with or without papillary tumor (cohort A) are reported. Methods: Pts with histologically confirmed HR, BCG-unresponsive CIS with or without papillary disease, who received adequate BCG therapy and were unable/unwilling to undergo radical cystectomy received pembro 200 mg Q3W for 24 mo or until recurrence, progression, or unacceptable toxicity. Pts with HR NMIBC or progressive disease during treatment were required to discontinue. Primary end point: complete response rate (CRR); key secondary end points: duration of response and safety. Results: 103 pts (median age 73 years; CIS alone 71.8%; median number of prior BCG instillations 12) have enrolled in cohort A. 3-mo CRR rate was 38.8% (95% CI 29.4%-48.9%) by central assessment. Among 40 pts who achieved CR at 3 mo, 72.5% maintained CR at last follow-up (median 14.0 mo; range 4.0-26.3) and median CR duration has not been reached (range 0+ to 14.1+ mo). 80.2% of pts had a CR duration of ≥6 mo (Kaplan-Meier method). 10 (25.0%) experienced recurrent NMIBC after CR; at the time of analysis, none progressed to muscle invasive or metastatic disease. Treatment-related adverse events (AEs) occurred in 65 (63.1%) pts; most frequent were pruritus (10.7%), fatigue (9.7%), diarrhea (8.7%), hypothyroidism (5.8%), and maculopapular rash (5.8%). Grade 3/4 treatment-related AEs occurred in 13 (12.6%) pts; 1 death was considered treatment-related (colitis in patient inadequately treated with steroids). Immune-mediated AEs occurred in 19 (18.4%) pts. Conclusions: Pembro had encouraging activity in pts with HR, BCG-unresponsive CIS with or without papillary tumors and a safety profile consistent with that of previous experience. Updated data using additional follow-up will be presented. Clinical trial. Clinical trial information: NCT02625961.
Sacituzumab govitecan (IMMU-132) in patients with previously treated metastatic urothelial cancer (mUC): Results from a phase I/II study.
Authors: Tagawa Scott T. , Faltas Bishoy Morris , Lam Elaine Tat , Saylor Philip James , Bardia Aditya , Hajdenberg Julio , Morgans Alicia K. , Lim Emerson A. , Kalinsky Kevin , Simpson Pamela S. , Galsky Matt D. , Goswam Trishna , Wegener William A. , Petrylak Daniel Peter
Published: March 2019

354

Background: Patients (pts) with mUC who progress after platinum (PLT)-based chemotherapy and immune checkpoint inhibitor (CPI) therapy have poor outcomes and limited treatment options. Sacituzumab govitecan (SG) is a novel antibody-drug conjugate. It consists of a monoclonal antibody targeting Trop-2, an epithelial cell surface antigen overexpressed in UC, conjugated to the active metabolite of irinotecan (SN38). Methods: We performed a phase I/II basket study in pts with advanced solid tumors receiving intravenous SG administered on day 1 and 8 of 21-day cycles, until progression or unacceptable toxicity. CT/MRI scans were obtained at 8-week intervals for response assessment. We evaluated pts with mUC who progressed after ≥1 prior systemic therapy and were treated with SG at the 10 mg/kg dose level. Endpoints included safety, objective response rate (ORR) by RECIST 1.1, clinical benefit rate (CBR; complete response [CR], partial response [PR], or else SD ≥6-mo), and Kaplan-Meier estimated duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Results: 45 pts (41M/4F; median age 67, range 49-90; ECOG 0/1: 31%/69%) received a median of 2 (range: 1-6) prior treatment lines, including PLT-based chemotherapy (95%) and CPI (38%). 33 had visceral metastases involving liver (n=15), lung (n=27), and other organs (n=5). The ORR was 31% (14/45), with 2 CR and 12 PR. In pts with visceral involvement, the ORR was 27% (9/33). The ORR in CPI-treated pts was 23% (4/17). The median DOR was 12.6 mo (2 pts continuing >2 y), and the CBR was 47% (21/45). Median PFS and OS were 7.3 mo and 18.9 mo, respectively. The AE profile was consistent with prior reports. Grade ≥3 AEs in ≥5% of pts were neutropenia/neutrophil count decreased (38%), anemia (11%), hypophosphatemia (11%), diarrhea (9%), fatigue (9%), and febrile neutropenia (7%). Conclusions: SG demonstrated clinical activity in pts with relapsed/refractory mUC, including CPI-treated pts and pts with visceral disease. A single-arm, open-label, global phase 2 trial is underway to evaluate antitumor activity and safety of SG in advanced UC.(TROPHY-U-01; NCT03547973). Clinical trial information: NCT03547973.
BMS-986205, an indoleamine 2, 3-dioxygenase 1 inhibitor (IDO1i), in combination with nivolumab (nivo): Updated safety across all tumor cohorts and efficacy in advanced bladder cancer (advBC).
Authors: Luke Jason J. , Tabernero Josep , Joshua Anthony , Desai Jayesh , Varga Andrea I. , Moreno Victor , Gomez-Roca Carlos A. , Markman Ben , De Braud Filippo G. , Patel Sandip Pravin , Carlino Matteo S. , Siu Lillian L. , Curigliano Giuseppe , Liu Zhaohui , Ishii Yuko , Wind-Rotolo Megan , Basciano Paul Andrew , Azrilevich Alex , Gelmon Karen A.
Published: March 2019

358

Background: Nivo (antiPD-1) has shown durable responses and manageable safety (ORR, 19.6%; grade 3‒4 treatment-related AEs [TRAEs], 18%) in advBC (Sharma et al. Lancet Oncol 2017), but prolonging survival in more pts requires additional approaches to overcome tumor evasion mechanisms. IDO1 allows tumor escape through kynurenine (KYN) production, which stimulates regulatory T cells and suppresses effector T-cell proliferation. Anti─PD-1 can upregulate IDO1, supporting the rationale for combining nivo with an IDO1i. BMS-986205 is a selective, potent, once-daily (QD) oral IDO1i that works early in the IDO1 pathway to reduce KYN production. BMS-986205 + nivo showed favorable safety and efficacy in heavily pretreated pts with select solid tumors (Luke et al. SITC 2017; NCT02658890). Updated safety across all tumor cohorts and efficacy in the immuno-oncology (I-O)naive advBC cohort are reported. Methods: Dose-escalation methods in this phase 1/2a, open-label study were previously described; during expansion, pts received BMS-986205 100 or 200 mg QD + nivo 240 mg IV Q2W or 480 mg IV Q4W. Objectives included safety and ORR by RECIST v1.1 (includes unconfirmed responses). Results: As of Mar 2018, 516 pts received BMS-986205 + nivo; 45% had ≥2 prior regimens. TRAEs occurred in 57% of pts (grade 3‒4, 12%), the most common being fatigue (15%) and nausea (12%); 19 pts (4%) discontinued due to TRAEs, and 3 pts ( < 1%) died due to a TRAE (myocarditis, Stevens-Johnson syndrome, and hepatic failure). In all treated pts and within the advBC cohort (n = 30), the frequency and severity of TRAEs and rate of discontinuation due to TRAEs was lower with the 100- vs 200-mg BMS-986205 dose. Among the 27 pts with I-Onaive advBC, with a median duration of follow-up of 24 wk, ORR was 37% (3 CRs, 7 PRs), and the DCR was 56%; ORR in pts with tumor PD-L1 ≥1% (Dako PD-L1 IHC 28-8 pharmDx assay; n = 14) vs < 1% (n = 10) was 50% vs 30%. Conclusions: BMS-986205 + nivo was well tolerated in heavily pretreated pts, and tolerability was improved with the 100-mg BMS-986205 dose. Preliminary evidence of efficacy was observed in advBC, supporting further evaluation of BMS-986205 + nivo. Clinical trial information: NCT02658890.
Role of adjuvant chemotherapy in advanced stage upper urinary tract urothelial carcinoma after radical nephroureterectomy: A competing risk analysis.
Authors: Kang Minyong , Kim Hyung Suk , Joung Jae Young , Shin Yong Ho , Jeong Byong Chang , Kim Tae Jin
Published: March 2019

367

Background: To determine whether adjuvant chemotherapy (ACH) influences cancer-specific mortality, bladder cancer-specific mortality, and other-cause mortality in patients with locally advanced upper tract urothelial carcinoma (UTUC) following radical nephroureterectomy (RNU) through the use of competing risk analysis. Methods: Among 785 patients with UTUC who underwent RNU from 1994 through 2015, we analyzed 338 individuals with locally advanced UTUC (pathologic T3–T4 and/or positive lymph nodes) without distant metastases. Patients were classified into two groups according to receipt of ACH. The study endpoints were UTUC-, bladder cancer- and other cause-specific survivals. The association of potential risk factors with outcome was tested with the Fine and Gray regression model. Results: Overall, 42.6% (n = 144) received ACH following RNU. During a median follow-up duration of 31.5 months, rates of UTUC-, bladder cancer-, and other cause-mortalities were 32.5% (n = 110), 5.0% (n = 17), and 4.1% (n = 14), respectively. Of note, there were no significant differences in overall survival between the observation and ACH groups according to the competing risks of death (UTUC, bladder cancer, and other causes of death). Multivariate analysis showed that only older age at surgery (≥ 65 years; hazard ratio [HR] = 1.71) and positive resection margin (HR = 7.25) remained as poor predictors of UTUC-specific and bladder cancer-specific survival, respectively. Additionally, no factors were identified as independent predictors of other causes of death. Conclusions: In summary, through competing risk analysis, we demonstrated that postoperative chemotherapy did not improve UTUC-specific and bladder-cancer specific survival, nor other cause-specific survival, in patients with locally advanced UTUC who underwent RNU. These results can offer practical information for clinicians regarding treatment decision making in these patients, who are at high risk of death due to competing causes.
Reducing overuse of PSA screening in primary care practices.
Authors: Litvin Cara B
Published: March 2019

37

Background: The United States Preventive Services Task Force and the American Urological Association both recommend against routine PSA-based screening for prostate cancer in men 70 years and older and, for men younger than 70, recommend shared-decision making to discuss the potential benefits and harms of screening before a PSA is ordered. The HIT-OVERUSE study was a 2 year group randomized study from August 2016 thru July 2018 to test a practice-based intervention to reduce overuse in primary care practices, including avoidance of routine PSA screening without shared decision-making. The purpose of this report is present the impact of this intervention on PSA screening. Methods: Twenty one primary care practices in 19 states volunteered to participate in the study. Prior to randomization, all providers received academic detailing on prostate cancer screening recommendations. Eleven practices randomized to the intervention group then received quarterly performance reports, hosted site visits for participatory planning and sent two practice representatives to a one day meeting to share ‘best practices’. The ten control practices only received performance reports. Changes in PSA testing in the past year (excluding patients with prostate cancer) were compared in control and intervention practices. Results: At the patient level, there was a significantly larger unadjusted reduction in PSA screening in men ages 40 to 69 in the past year between intervention practices (28.6 % to 19.0%) and control practices (16.5% to 12.7%) (p<0.0001). There was also a significantly larger unadjusted reduction in PSA screening in men ages 70 and older in the past year between intervention practices (25.7% to 14.7%) and control practices (21.9% to 15.6%) (p<0.0001). Adjusted changes will also be presented. Conclusions: A practice-based intervention to reduce routine PSA-screening performed without shared decision-making resulted in a greater reduction in PSA screening compared to provision of academic detailing alone. Further research could elucidate whether this type of intervention results in increased shared decision-making conversations with patients.
Comparing radical cystectomy with trimodal therapy for patients diagnosed with bladder cancer: Critical assessment of statistical methodology and interpretation of observational data.
Authors: Ray-Zack Mohamed Danny , Shan Yong , Kerr Preston , Kosarek Christopher David , Hudgins Hogan K , Jazzar Usama , Kaul Sapna , Kamat Ashish M. , Tyler Douglas S. , Swanson Todd A. , Mehta Hemalkumar B , Williams Stephen Bentley
Published: March 2019

373

Background: Treatment guidelines for muscle-invasive bladder cancer recommend radical cystectomy. However, use of trimodal therapy has increased in recent years with conflicting survival outcomes. The aim of this study was to compare radical cystectomy and trimodal therapy in terms of survival outcomes and cost of treatment according to varying statistical methodology in order to interpret findings using observational data. Methods: Patients aged 66 years or older diagnosed with clinical stage T2-4a bladder cancer from January 1, 2002-December 31, 2011 were included from the Surveillance, Epidemiology, and End Results (SEER)-Medicare database. Outcomes included cancer-specific survival, overall survival, and 6-month costs. Cox proportional hazards regression, propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) were used to control for baseline differences between patients undergoing radical cystectomy vs. trimodal therapy, and to determine predictors for overall and cancer-specific survival. Results: A total of 2,963 patients were included: 728 (24.6%) who underwent trimodal therapy were compared to 2,235 (75.4%) who underwent radical cystectomy. In all adjusted analyses, patients who underwent trimodal therapy had significantly decreased cancer-specific survival (Cox regression: Hazard Ratio (HR) 1.51, 95% Confidence Interval (CI) 1.40-1.63; PSM: HR 1.55, 95% CI 1.32-1.83; IPTW: HR 1.51, 95% CI 1.40-1.63) and overall survival (Cox regression: HR 1.54, 95% CI 1.39-1.71; PSM: HR 1.49, 95% CI 1.31-1.69; IPTW: HR 1.54, 95% CI 1.39-1.71). However, median total costs over six months were significantly higher with trimodal therapy than radical cystectomy ($171,401 vs. $99,890, p<0.001). Conclusions: Trimodal therapy was associated with decreased cancer-specific and overall survival at increased costs compared to radical cystectomy. In the absence of data from randomized controlled trials, this observational study provides further evidence to suggest the superiority of radical cystectomy over trimodal therapy in patients with muscle-invasive bladder cancer.
Presurgical anemia as a predictor of relapse and survival in bladder carcinoma treated with cystectomy.
Authors: Pinto Alvaro , García Luis Eduardo , García Esther , Herradon Noelia , Espinosa Enrique
Published: March 2019

382

Background: Bladder carcinoma is the fifth most common neoplasm in developed countries. When muscle-invasive disease is diagnosed in a localized stage, radical cystectomy is the standard treatment, with or without perioperative chemotherapy. In this retrospective study we aim to identify presurgical factors that correlate with relapse risk and survival in patients being treated with radical cystectomy without neoadjuvant chemotherapy. Methods: Patients with a history of radical cystectomy for non-metastatic muscle-invasive bladder carcinoma from 1995 to 2010 were included. They had to have an appropriate follow-up, and tissue available for further correlative studies. Demographic baseline features and therapy outcomes were collected in a retrospective fashion. Results: A total of 158 patients were included, with a median overall survival (OS) for the entire cohort of 51 months (95% IC: 17.1–84.9 months). Median relapse free survival (RFS) is 39 months (95% IC: 3.8–74.1 months). In univariate analysis, the following features were prognostic factors for RFS: ECOG performance status (0 vs ³1; 72 vs 20 months, p=0.014), hemoglobin levels (normal vs low; 144 vs 21 months, p=0.001), free surgical margins (yes vs no; 39 vs 11 months, p=0.004), lymph node status (pN0 vs pN+; 119 vs 18 months, p<0.001) and pT stage (pT2 vs pT3-4; 167 vs 20 months, p< 0.001). Other previously described factors, such as neutrophil-lymphocite ratio, thrombocytosis, creatinine clearance or the presence of hydronephrosis, were not significant in our group of patients. In the multivariate analysis, only ECOG (HR 2.32), lymph node status (HR 2.0) and hemoglobin levels (HR 1.71) were independent predictors for RFS. Conclusions: In our group of patients, apart from ECOG performance status and lymph node status, the presence of presurgical anemia could be an indicator of poorer outcomes after cystectomy. These patients should be monitored closely and maybe considered for further therapeutic procedures, such as adjuvant systemic therapy.
Assessment of the diagnostic value of microsatellite instability in the urine of bladder cancer patients.
Authors: Khaled Hussein Mustafa , Zekri Abdel-Rahman , Mohamed Mai B , Diab Fatma M , Abdellateif Mona , El Deeb Somaya Cancer , Badr Abeer M , Abdallah Sanaa O , Bahnassy Abeer Ahmed
Published: March 2019

384

Background: Microsatellite alterations in urine sediments have proved to be a promising tool for detection of bladder cancer (BC) due to its high sensitivity and specificity. Methods: We assessed the possible prognostic and predictive values of microsatellite alterations in tissue samples and urine sediments obtained from Egyptian patients with BC, and their utility as diagnostic, prognostic and predictive value. Microsatellite instability (MSI) and loss of heterozygosity (LOH) were assessed using 13 microsatellite markers in tumor tissue and urine sediments of 30 patients with BC. The concordance between MSI in tissue and urine samples was determined. Results: We found that MSI was more frequent than LOH (100% and 46.7%; respectively). D16S310, MBP and IFN-α showed the highest MSI frequency in urine samples (70%, 70% and 66.67%; respectively), while MBP, ACTBP2 and D9S171 (66.67%, 63.33%, and 60%; respectively) were the most frequently detected in tumor tissue. All markers correlated significantly with the pathological subtypes (more frequent in TCC) and hematuria. The concordance between tissue and urine was statistically significant for , D9S171, D16S476, FGA and ACTBP2 (P = 0.04, 0.015, 0.02 and 0.007; respectively). When we combined D16S476 and D9S171, the sensitivity, specificity, PPV and NPV reached (80.0%, 75.0%, 82.8% and 71.4%; respectively) for diagnosis of BC . Conclusions: Thus MSI in urine sediments could be a sensitive and reliable method for diagnosis of BC.
A phase II trial to evaluate pemetrexed clinical responses in relation to tumor methylthioadenosine phosphorylase (MTAP) gene status in patients with previously treated metastatic urothelial carcinoma.
Authors: Alhalabi Omar , Campbell Matthew T , Slack-Tidwell Rebecca , Siefker-Radtke Arlene O. , Shah Amishi Yogesh , Efstathiou Eleni , Wang Wei-Lien , Titus Mark Anton , Czerniak Bogdan , Zhang Miao , Guo Charles , Logothetis Christopher , Gao Jianjun
Published: March 2019

385

Background: According to The Cancer Genome Atlas, 26.8% of bladder tumors harbor homozygous deletion of the MTAP gene, which encodes for an essential enzyme for the salvage pathway of nucleotide synthesis. Pemetrexed is a well-known anti-folate agent that inhibits the de novo pathway of nucleotide synthesis. Therefore, we hypothesized that tumors with MTAP gene loss have a synthetic lethality to pemetrexed due to loss of both essential nucleotide synthesis pathways. We proposed a study to determine pemetrexed response rate in patients with MTAP-deficient metastatic urothelial carcinoma (mUC). Methods: We carried out a single-arm, open-label, phase II clinical trial with pemetrexed in patients with mUC and MTAP loss by immunohistochemistry. This is an interim analysis of results. Each patient receives pemetrexed (500 mg/m2) on day 1 of each 21-day cycle. Pemetrexed is continued until progression of disease (PD) and a repeat biopsy is obtained at that time. Pre- and post-treatment blood, urine and tumor samples are obtained for dynamic monitoring of immune and molecular correlates to clinical activity. Results: Six patients have been enrolled on this trial and all have received at least one previous treatment including a cisplatin-containing regimen in 5 (83%) patients and an immune checkpoint inhibitor in 4 (66%) patients. Of these 6 patients, 1 (17%) had complete response (CR); two (33%) had partial response (PR); 1 (17%) had stable disease; 1 (17%) was not evaluable; 1 (17%) had PD. Treatment was generally well tolerated with mostly grade 1 or 2 adverse events. Only 2 of 6 patients developed grade 3 anemia. Immunologic and molecular analyses are ongoing on all collected samples. Conclusions: Our study show that in heavily pretreated MTAP deficient mUC patients, pemetrexed is still an effective and well-tolerated therapy with an objective response rate (ORR=CR+PR) of 50%, which is higher than previously reported pemetrexed activity (ORR=8-28%) as first or second line treatment for mUC. Clinical trial information: NCT02693717.
Treatment of locally advanced or metastatic urothelial carcinoma: Analysis of expert and community healthcare provider practice trends.
Authors: Rosenthal Kristen , Galsky Matt D. , Milowsky Matthew I. , Petrylak Daniel Peter , Rosenberg Jonathan E. , Obholz Kevin , Plimack Elizabeth R.
Published: March 2019

389

Background: With new indications for immune checkpoint inhibitors (ICI), treatment (Tx) decisions for patients (pts) with locally advanced (LA) and metastatic (m) urothelial carcinoma (UC) are becoming more complex. Methods: In Jan 2018, 5 UC experts developed an online tool to provide specific Tx recommendations for 318 case variations based on key factors. Healthcare providers (HCP) enter pt information and their intended Tx to see expert Tx choices for that case. We compared intended Tx of HCPs vs expert recommendations for 388 cases entered in the tool from Feb 1-Aug 15, 2018, before the FDA label change for ICI requiring PD-L1 testing for cisplatin-ineligible pts. Pearson chi-squared and Fischer’s exact tests were used. Results: In LA UC, experts chose cisplatin-based chemotherapy (CT) for 94% of eligible pts vs 59% of HCP ( P < .0001). In pts ineligible for any platinum (Plt)-based CT, experts selected pembrolizumab for all cases vs only 10% of HCP ( P < .0001). In pts with untreated mUC, experts picked cisplatin-based CT in 93% of eligible cases vs 60% of HCP ( P < .0001) and experts chose pembrolizumab for 91% of pts ineligible for any Plt-based CT vs 22% of HCP ( P = .0001). For cisplatin-ineligible pts with either LA UC or mUC who may be able to tolerate carboplatin, there was more variability in expert and HCP Tx choices (Table) prior to the updated ICI indications. For pts who progressed after 1 or 2 lines of CT (including Plt CT), experts chose pembrolizumab for 99% of cases vs 28% of HCP ( P < .0001); 22% of HCP were uncertain of Tx. Although pembrolizumab was the preferred ICI by experts for these 2nd and 3rd line cases, 31% of HCP chose a different ICI. Conclusions: Tx patterns between experts and HCP differed significantly for UC across multiple settings, particularly with integration of ICIs into clinical practice. As treatment indications for ICI continue to evolve, HCP can benefit from an online tool with expert guidance to help navigate complex Tx choices. [Table: see text]
Long-term outcomes in elderly patients (pts) from IMvigor210: Atezolizumab (atezo) in metastatic urothelial cancer (mUC).
Authors: Balar Arjun Vasant , Dreicer Robert , Loriot Yohann , Perez-Gracia Jose Luis , Hoffman-Censits Jean H. , Petrylak Daniel Peter , Van Der Heijden Michiel Simon , Shen Xiaodong , Ding Beiying , Ramirez-Montagut Teresa , Rosenberg Jonathan E.
Published: March 2019

394

Background: Cisplatin-based chemotherapy is currently the standard 1L treatment for mUC, but many pts are ineligible and progression is common. Atezo (anti–PD-L1) is approved for certain types of mUC, and long-term efficacy and safety have been shown (Balar, ASCO 2018). Elderly pts in particular tend to have poor outcomes and may be chemotherapy intolerant, so this analysis sought to evaluate clinical outcomes in pts aged ≥ 65 and ≥ 75 y from the Phase II IMvigor210 study. Methods: This 2-cohort, single-arm study enrolled pts ineligible for 1L cisplatin and previously platinum-treated pts. Atezo 1200 mg IV q3w was given until PD (Cohort 1) or loss of clinical benefit (Cohort 2). RECIST v1.1 ORR (independent review; primary endpoint) and DOR and OS (secondary) were evaluated in pt subgroups based on PD-L1 status and age. Results: Evaluable pts as of July 12, 2018, are shown in the Table. In Cohort 1 pts ≥ 75 y, ORR was 29% overall, CR rate was 8%, DOR was NE and median OS was 21.4 mo. In Cohort 2 pts ≥ 75 y, ORR was 23%, CR rate was 7%, mDOR was 20.9 mo and mOS was 9.2 mo. Updated safety analyses in elderly pts will be presented. Conclusions: Efficacy outcomes in IMvigor210 elderly pts with mUC, and PD-L1 subgroup analysis appear generally consistent with those in the overall population in this long-term analysis. (Cohort 1; Balar Lancet 2017; NCT02951767). (Cohort 2; Rosenberg Lancet 2016; NCT02108652). Clinical trial information: NCT02951767 and NCT02108652. [Table: see text]
Trends in checkpoint inhibitor therapy for advanced urothelial cell carcinoma (aUC) at the end of life: Insights from real-world practice.
Authors: Parikh Ravi Bharat , Galsky Matt D. , Gyawali Bishal , Riaz Fauzia , Kaufmann Tara Laura , Cohen Aaron Benjamin , Adamson Blythe J.S. , Gross Cary Philip , Meropol Neal J. , Mamtani Ronac
Published: March 2019

395

Background: National guidelines recommend against chemotherapy use at the end of life. Five CPIs are now approved for aUC. We hypothesized that oncologists may have a lower threshold to initiate CPI in patients (pts) at the end of life, particularly among pts with poor performance status (PS), because of the perceived favorable toxicity profile of CPI. Methods: We conducted a secular trend analysis using the Flatiron Health Database, a large real-world electronic medical record-derived dataset. We used nonparametric tests of trend (p values reported as ptrend) to evaluate quarterly proportions of pts initiating CPI, chemotherapy, or no systemic therapy within 30 and 60 days of death, among 2959 pts diagnosed with aUC from 2015 to 2017. Results: 1637 pts died during follow-up and were eligible for analysis. 278 (17.0%) and 488 (29.8%) pts initiated a new line of systemic therapy in the last 30 and 60 days of life, respectively. The quarterly proportion of CPI initiators within 60 days of death increased from 1.0% to 23% during the study period ( ptrend < 0.001), with corresponding decreases in chemotherapy initiation and no systemic therapy. After CPI approval in mid-2016, CPI initiation significantly increased among pts with Eastern Cooperative Oncology Group (ECOG) PS ≥ 2 ( ptrend = 0.02) but did not significantly change among pts with PS 0-1. Initiation of any systemic therapy at the end of life doubled (17.4% to 34.8%) over the study period, driven largely by end-of-life CPI use. Compared to chemotherapy initiators, CPI initiators had slightly worse PS (table). Conclusions: In patients with aUC, there has been a dramatic rise in CPI initiation at the end of life particularly among pts with poor PS. Existing guidelines on systemic therapy initiation near the end of life should account for the increasing use of CPI. [Table: see text]
Characterization of genomic alterations as biomarkers of immune checkpoint inhibitor (ICI) response in metastatic urothelial carcinoma (mUC).
Authors: Labriola Matthew , Zhu Jason , Gupta Rajan , McCall Shannon , Jackson Jennifer , White James R , Weingartner Elizabeth , Kong Eric , Simone Peter , Papp Eniko , Gerding Kelly , Simmons John , George Daniel J. , Zhang Tian
Published: March 2019

400

Background: ICIs have expanded therapeutic options for mUC patients (pts); however, biomarkers such as PD-L1 have not served as reliable predictors of treatment efficacy. High tumor mutation burden (TMB) has been previously described as a potential biomarker for predicting ICI response in several indications, but its utility is still being explored in mUC. Here, we compare the genomic landscapes and clinical outcomes of mUC pts following ICI therapy using an investigational solid tissue-based next-generation sequencing assay to assess TMB and identify genetic correlates of ICI response. Methods: 20 pts with mUC treated with ICIs at Duke Cancer Institute were identified. Tumor samples were retrospectively evaluated with a Personal Genome Diagnostics Assay for somatic variants across > 500 genes, as well as TMB and microsatellite status. Tumor samples were also stained for PD-L1 status using the Dako 22C3 IHC assay. Deidentified clinical information was extracted from the medical record and tumor response was evaluated using RECIST 1.1 criteria. Results: Pts were grouped by overall response following ICI therapy as either responders (“R”, n = 6) or non-responders (“NR”, n = 13). Pts exhibited a wide range of TMB scores (0.7 to 30.4 mutations/Mb), with a mean TMB score of 9.60 vs. 3.87 mut/Mb in R vs NR groups, respectively; however, this difference was not statistically significant ( p = 0.284). 18 pts were evaluated for PD-L1 status, with only 2 positive samples (one in each group). Rs had significantly more mutations in histone methylation genes (KDM6A, KMT2C, and KMT2D), (67% vs 15% in NRs, p = 0.0039). FGFR3 mutations were also more frequent in R vs NR (67% vs 5%, p = 0.0339). Finally, there was a higher frequency of mutations in TP53 and BRCA1 in the NRs. Conclusions: In this mUC cohort, neither TMB nor PD-L1 correlated with response to ICI therapy. Histone modifying genes and FGFR3 mutations were more frequent in responders, whereas BRCA1 and TP53 mutations were enriched in non-responders, warranting future prospective studies to understand underlying mechanisms of ICI response and resistance in mUC.