bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of concomitant prostate cancer therapy on efficacy and safety of relugolix versus leuprolide in men with advanced prostate cancer: Subgroup analysis from the phase III HERO study.
Authors: George Daniel J. , Shore Neal D. , Saad Fred , Cookson Michael , Saltzstein Daniel , Tutrone Ronald F. , Akaza Hideyuki , Bossi Alberto , Wong Elaine K. , Selby Bryan , Fan Xiaolin , Walling Jackie , Tombal Bertrand
Published: March 2021

106

Background: In the phase 3 HERO study, the oral GnRH receptor antagonist, relugolix, demonstrated suppression of testosterone to castrate levels in 96.7% of patients, which was superior to leuprolide, and a 54% lower risk of major adverse cardiovascular events relative to leuprolide. To characterize the impact of concomitant prostate cancer treatments with the use of relugolix in advanced prostate cancer from the HERO study, a subgroup analysis for patients receiving various therapies was undertaken. Methods: The HERO study was designed to evaluate relugolix in men with advanced prostate cancer. Overall, 934 patients were randomized 2:1 to receive relugolix 120 mg orally once daily or leuprolide injections every 12 weeks for 48 weeks. In the setting of rising PSA, patients could receive enzalutamide (ENZ) or docetaxel (DOC) 2 months after study initiation. Assessments included sustained testosterone suppression to castrate levels (<50 ng/dL) through 48 weeks and safety parameters. Subgroups analyzed included patients with or without concomitant ENZ, DOC, and any radiation therapy (RT). A sensitivity analysis of the primary endpoint was performed excluding patients who received concomitant therapies that may affect testosterone. Results: Overall, 125 patients (13.4%) took at least one concomitant therapy that could impact testosterone levels. RT was received by 15.9% and 18.8% of patients in the relugolix and leuprolide groups, respectively. ENZ was the most frequently used therapy in the relugolix group (2.7%), with similar use in the leuprolide group (1.9%). DOC was used by 1.3% and 1.6% of patients in the relugolix and leuprolide groups, respectively. All other relevant concomitant therapy were used in <1% of population. The sensitivity analysis results indicated that use of these concomitant therapy that could affect testosterone levels did not impact the primary endpoint. Castration rates were similar with and without concomitant use of ENZ and DOC, or RT (table). No clinically relevant differences in adverse events were observed between patients with or without concomitant use of ENZ, DOC, or RT in either treatment group. Conclusions: While the numbers are small, treatment with relugolix was associated with a similar efficacy and safety profiles in patients who received concomitant administration of ENZ, DOC, or RT to that observed in patients not receiving those concomitant treatments. Clinical trial information: NCT03085095. [Table: see text]
SPOP mutations in prostate cancer: Clinical and genomic features.
Authors: Nakazawa Mari , Fang Mike , Issacsson Velho Pedro , Antonarakis Emmanuel S.
Published: March 2021

151

Background: Point mutations in the gene encoding speckle-type pox virus and zinc finger protein (SPOP) are the most frequently identified mutations in prostate cancer, occurring at a frequency of 6-15% across localized and disseminated cancers. Recently, SPOP gene alterations have gained attention as they appear to define a novel subclass of prostate cancers. Previous studies show that patients with mutant SPOP (mtSPOP) had superior responses to androgen deprivation therapy (ADT) and exhibit more favorable responses to abiraterone compared to wild type SPOP (wtSPOP). Methods: We retrospectively identified 59 prostate cancer patients at a single institution (Johns Hopkins) with somatic SPOP mutations from genomic testing of primary tumors (n=45), metastatic lesions (n=12), or liquid biopsies (n=2). Patient records were reviewed to determine baseline characteristics, therapies received, and clinical outcomes. The primary outcomes included best PSA response and progression-free survival (PFS) on ADT in the hormone sensitive prostate cancer (HSPC) setting and on abiraterone and/or enzalutamide in the first-line castration resistant prostate cancer (CRPC) setting. PFS was defined as either PSA, radiographic, or clinical progression. Results: The median age at diagnosis was 64 years (range 46 to 85). 17/59 (28.8%) were Black. F133 was the most frequently mutated residue, occurring in 33 (55.9%) instances (Table). There were two patients who harbored two mutations in the SPOP gene. The most frequently co-occurring mutation was in APC (15/59 [25.4%] patients), resulting in Wnt pathway activation. Concurrent ERG fusions were not observed with this cohort (0/59 [0%] patients). 41/59 (69.4%) were diagnosed with Gleason 8-10 disease. 21/59 (35.5%) were diagnosed with de novo metastatic disease. 50/59 (84.7%) patients received ADT for recurrent or metastatic disease. Median PFS on ADT was 40.7 (95% CI 23.4-71.9) months. Of the 27/59 (45.8%) patients who progressed to CRPC, 20/59 (33.9%) patients received abiraterone and 13/59 (22.0%) received enzalutamide; 9/59 (15.3%) patients received both agents. Median PFS was 7.8 (95% CI 6.7-NR) months on abiraterone and 7.3 (95% CI 3.2-NR) months on enzalutamide. Other notable therapies received in the CRPC setting include docetaxel (5/59 [8.5%] patients), cabazitaxel (5/59 [8.5%] patients), and PARP inhibitor olaparib or rucaparib (4/59 [6.8%] patients). Conclusions: SPOP mutations define a unique subset of prostate cancers enriched for black patients, high Gleason scores, absence of ERG fusions, and Wnt pathway activation. Clinical outcomes to first-line ADT appear longer than expected for genomically-unselected patients. [Table: see text]
Racial disparities in depression incidence, management, and mortality after prostate cancer diagnosis.
Authors: Parikh Ravi Bharat , Gallo Joseph J. , Cashy John , Robinson Kyle William , Narayan Vivek , Wong Yu-Ning , Jayadevappa Ravishankar , Chhatre Sumedha
Published: March 2021

201

Background: Depressive disorder is a common cause of morbidity among men with prostate cancer (PC) and may contribute to known racial disparities in PC outcomes. We estimated the incidence, management, and impact of depressive disorder (depression) on overall mortality among African American (AA) and non-Hispanic White (W) Veterans with localized PC. Methods: In this retrospective cohort study, we used linked administrative, survey, and electronic health record data from the Veterans Health Administration (VA) Corporate Data Warehouse to identify AA and W Veterans with no preexisting depression who were diagnosed with localized PC between January 1, 2004 and December 31, 2013. Patients were followed through December 31, 2019. The primary outcomes were incident depression (defined from diagnosis codes and PHQ-2 and -9 screenings between six months to five years after PC diagnosis), receipt of anti-depressant therapy, and all-cause mortality. We used logistic and Cox regression models, adjusted for sociodemographic factors, PSA, Gleason score, and prostate cancer treatment, to estimate associations with all outcomes, using race-by-depression and race-by-treatment interaction terms to investigate racial disparities. Results: Among 32,194 Veterans diagnosed with localized prostate cancer (median age 67 years [interquartile range [IQR] 62 to 73 years], median follow-up 9.9 years [IQR 8.0 to 12.1 years]), 8,177 (25.4%) were AA. Overall, 8,285 (25.7%) Veterans were diagnosed with depression after PC diagnosis, and 2,525 (30.5%) of depressed Veterans received an antidepressant. Compared to Veterans without depression, Veterans with incident depression had higher all-cause mortality (adjusted hazard ratio [aHR] 1.30 [95% CI 1.25-1.35]). Race moderated all outcomes: AAs were more likely than Ws to be diagnosed with depression. However, among those with depression, AAs were less likely than Ws to receive an antidepressant. Interaction analyses showed that the HR of all-cause mortality associated with depression among AAs was significantly greater than that of Ws. Antidepressant receipt was not associated with improved mortality (aHR 1.05 [95% CI 0.97-1.13]); this finding was not moderated by race. Conclusions: Depression was common among men with prostate cancer within a large equal-access health care system, and African American men had more adverse depression-related outcomes than White men. Identifying and managing incident depression should be a key target of efforts to improve prostate cancer outcomes and disparities. [Table: see text]
Frequency, management, and resource use of adverse events (AEs) in nonmetastatic castrate-resistant prostate cancer (nmCRPC) patients receiving apalutamide or enzalutamide: A real-world study.
Authors: Jiang Shan , Varghese Della , Appukkuttan Sreevalsa , Corman Shelby , Kebede Nehemiah , Gnanasakthy Kajan , Macahilig Cynthia , Waldeck A. Reginald , Hussain Arif
Published: March 2021

217

Background: Second generation androgen receptor inhibitors (SGARIs), apalutamide (APA) and enzalutamide (ENZ) and darolutamide, are approved in the United States (US) for the treatment of nmCRPC. The objectives of this study were to describe the frequency of AEs and actions taken to manage AEs among nmCRPC patients treated with APA or ENZ and their downstream resource implications. Methods: This is a further descriptive analysis of a retrospective chart review study conducted in 43 US nmCRPC-treating sites. In our sample, the 43 physicians identified 699 nmCRPC patients initiating treatment with APA (N = 368) or ENZ (N = 333) with 2 patients receiving both, between February 1, 2018 and December 31, 2018 and AEs were collected as reported in regular clinical practice. A representative subset of patients, experiencing at least 1 AE for either APA (N = 125) or ENZ (N = 125), were selected randomly from the initial cohort, and their detailed chart data were extracted to understand the actions taken to manage AEs. Results: Of the initial cohort of nmCRPC patients, 72.0% and 78.7% of men receiving APA (N = 368) and ENZ (N = 333) experienced ≥1 AE, respectively. The three most common AEs reported were fatigue/asthenia (APA, 30.2%; ENZ, 38.7%), hot flush (APA, 14.1%; ENZ, 13.5%), and arthralgia (APA, 14.4%; ENZ, 12.9%). Cognitive and mental changes were observed in 5.4% (APA) and 7.8% (ENZA) men. The subset analysis of randomly selected patients experiencing ≥1 AE (APA, 125; ENZ, 125) were mostly Caucasian (APA, 72.8%; ENZ, 71.2%), ECOG score 0-1 (APA, 84%; ENZ, 88%), median prostate specific antigen (PSA) value 13 ng/ml and 11 ng/ml (APA, ENZ; respectively). Actions to address AEs included treatment of AE, SGARI discontinuation, dose reduction and hospitalization (Table). Specifically, treatment discontinuation due to AE was observed in 8.0% (APA) and 12.8 (%) of men. AEs were often not resolved (APA, 43.6%; ENZ, 39.4%), and the median duration of days to resolve AEs were 60.0 for APA and 56.0 for ENZ. Conclusions: This real-world study highlights the clinical and resource use burden of AEs among nmCRPC patients treated with APA and ENZ. The results demonstrate the importance of safety and tolerability as key considerations in shared clinician-patient decision-making regarding SGARI therapy in nmCRPC. [Table: see text]
Phase 3 trial of lenvatinib (LEN) plus pembrolizumab (PEMBRO) or everolimus (EVE) versus sunitinib (SUN) monotherapy as a first-line treatment for patients (pts) with advanced renal cell carcinoma (RCC) (CLEAR study).
Authors: Motzer Robert J. , Porta Camillo , Eto Masatoshi , Powles Thomas , Grünwald Viktor , Hutson Thomas E. , Alekseev Boris , Rha Sun Young , Kopyltsov Evgeny , Méndez Vidal María José , Hong Sung-Hoo , Kapoor Anil , Alonso Gordoa Teresa , Goh Jeffrey C. , Merchan Jaime R. , Smith Alan D. , Mody Kalgi , Perini Rodolfo F. , Xing Dongyuan , Choueiri Toni K.
Published: March 2021

269

Background: In pts with advanced RCC, second-line treatment with LEN + EVE prolonged progression-free survival (PFS) compared with EVE alone. LEN + PEMBRO, also showed preliminary efficacious evidence in a phase 1/2 RCC study. Here, we describe the investigational study results of first-line LEN + PEMBRO or LEN + EVE versus SUN in pts with advanced RCC. Methods: Pts were randomized (1:1:1) to receive LEN 20 mg orally once daily + PEMBRO 200 mg IV every 3 weeks (wks); or LEN 18 mg + EVE 5 mg orally once daily; or SUN 50 mg orally once daily (4 wks on/2 wks off). Eligible pts had advanced RCC with no prior systemic therapy. Randomization was stratified by geographic region and MSKCC prognostic group. The primary endpoint was PFS by Independent Review Committee per RECIST v1.1. Secondary endpoints included overall survival (OS), objective response rate (ORR) and safety. A sequential approach was used to test PFS first, then OS and ORR. PFS and OS were compared across arms by a stratified log-rank test; hazard ratios (HRs) were estimated by a stratified Cox regression model. Results: 1069 pts were randomized (Table). After a median follow-up of 27 months (data cutoff August 28, 2020), PFS was significantly improved with LEN + PEMBRO (median 24 months [mos]) vs SUN (median 9 mos; HR 0.39, 95% CI 0.32–0.49) and LEN + EVE (median 15 mos) vs SUN (HR 0.65, 95% CI 0.53–0.80). OS was significantly longer with LEN + PEMBRO vs SUN (HR 0.66, 95% CI 0.49–0.88), whereas OS with LEN + EVE vs SUN was not statistically different (HR 1.15, 95% CI 0.88–1.50). ORR was significantly greater with LEN + PEMBRO (ORR 71%; complete response [CR] 16%) vs SUN (ORR 36%; CR 4%; odds ratio 4.35, 95% CI 3.16–5.97) and LEN + EVE (ORR 54%; CR 10%) vs SUN (odds ratio 2.15, 95% CI 1.57–2.93). Grade ≥3 treatment-related adverse events occurred in 72% of pts in the LEN + PEMBRO arm and 73% of pts in the LEN + EVE arm compared with 59% of pts in the SUN arm. Conclusions: LEN + PEMBRO demonstrated significant improvements in PFS, OS and ORR vs SUN. LEN + EVE demonstrated significant improvements in PFS and ORR vs SUN. Safety was manageable and consistent with the known single-agent profiles. Clinical trial information: NCT02811861 . [Table: see text]
Stereotactic radiotherapy and pembrolizumab for oligometastatic renal tumors: The RAPPORT trial.
Authors: Siva Shankar , Bressel Mathias , Wood Simon , Shaw Mark , Loi Sherene , Sandhu Shahneen Kaur , Tran Ben , Azad Arun , Lewin Jeremy Howard , Cuff Katharine , Neha Nitika , Colyer Duncan , Neeson Paul J. , Liu Howard , Chander Sarat , Moon Daniel , Goad Jeremy , Murphy Declan G. , Lawrentschuk Nathan , Pryor David
Published: March 2021

277

Background: Pembrolizumab monotherapy, whilst not standard of care, has demonstrated efficacy in clear cell renal cell carcinoma (ccRCC). The first-line KEYNOTE-427 study demonstrated an overall response rate (ORR) of 34%, and a median progression-free survival (PFS) of 7.1 mo (McDermott D et al. J Clin Oncol 2020; 38:S15; 5069-5069). Stereotactic ablative body radiotherapy (SABR) is an option for oligometastatic ccRCC, but patients often develop distant progression or relapse within irradiated sites. The RAPPORT study (NCT02855203) was a multi-institutional single arm, phase I/II study evaluating safety and efficacy of SABR and pembrolizumab. Methods: Patients with up to 2 lines of prior systemic therapy with 1-5 oligometastases from ccRCC were eligible. A single fraction of 20Gy SABR to all metastatic sites was given (or 10 fractions of 3 Gy of conventional radiotherapy [CRT] if SABR was not feasible), followed by pembrolizumab 200mg administered Q3W for 8 cycles. The primary objective was safety (CTCAEv4.03), with secondary key objectives of efficacy (RECIST1.1) by disease control rate (DCR), defined as complete response (CR), partial response (PR) or stable disease for at least 6 months, ORR, PFS and overall survival (OS). Results: Thirty patients were enrolled and received protocol treatment. The median follow-up was was 2.3 years. The median age was 62 (range 47-80) years, 23 patients (77%) were male. Twenty-three patients (77%) were treatment naïve, 1 patient (3%) had a prior interleukin-2 therapy and 6 patients (20%) had a prior tyrosine kinase inhibitor. Nine patients (30%) had prior metastasectomy. Eighty-three oligometastases were treated (median of 3 per patient), of which 64 (77%) received SABR, and 19 (23%) received CRT. There were 8 adrenal, 11 bone, 43 lung, 12 lymph node and 9 soft tissue metastases irradiated. Four patients (13% [95%CI: 4-31%]) had one or more grade 3 treatment-related AE: Pneumonitis (n=2), dyspnoea (n=1) and elevated ALP/ALT (n=1). There were no grade 4 or 5 AEs. All eight cycles of pembrolizumab were completed by 24 (80%) patients. DCR was 83% (95%CI: 65-94%). ORRs are tabulated below. Median PFS was 15.6 mo. Estimated 1 and 2-year OS was 90% (95%CI: 72-97%) and 74% (95%CI: 53-87%), respectively, while PFS was 60% (95%CI: 40-75%) and 45% (95%CI: 27-62%), respectively. Freedom from local progression at 2-years was 92% (95%CI: 80-97%). Conclusions: The combination of SABR and pembrolizumab in oligometastatic renal cell carcinoma is well tolerated with excellent local control. Durable responses and encouraging PFS were observed with this approach, which warrants further investigation. Clinical trial information: NCT02855203 . [Table: see text]
Biomarker-based phase II study of sapanisertib (TAK-228), an mTORC1/2 inhibitor in patients with refractory metastatic renal cell carcinoma (mRCC).
Authors: McGregor Bradley Alexander , Adib Elio , Xie Wanling , Stadler Walter Michael , Zakharia Yousef , Michaelson M Dror , Alva Ajjai Shivaram , Farah Subrina , Nassar Amin , Harshman Lauren C , Kwiatkowski David J. , McKay Rana R. , Choueiri Toni K.
Published: March 2021

306

Background: Approved rapalogs inhibit mTORC1 and have limited activity in mRCC, possibly due to compensatory feedback loops. Sapanisertib addresses the incomplete inhibition of the mTOR pathway through targeting of both mTORC1 and mTORC2 with antitumour activity demonstrated in patients with mRCC. In this multicenter, single arm phase II trial, we evaluated the efficacy of sapanisertib in patients with mRCC progressing on standard therapies (NCT03097328). Methods: Eligible mRCC patients had an ECOG performance status of 0-2 and had progressed on standard therapies. Prior therapy with rapalogs (everolimus, temsirolimus) and variant RCC histologies were permitted. Patients had a baseline biopsy and received treatment with sapanisertib 30 mg by mouth weekly until unacceptable toxicity or disease progression. The primary endpoint was overall response rate (ORR) by RECIST 1.1. Tissue biomarkers of mTOR pathway activation were explored. Results: We enrolled 38 mRCC patients (clear cell = 28; variant histology = 10) between August 2017 and November 2019. The majority had intermediate (76%) or poor risk (11%) by IMDC criteria. Twenty (53%) had received ≥ 3 lines of therapy; 13 (34%) patients received prior rapalogs. Median follow-up was 10.4 months (range 1-27.4) and median duration of therapy was 1.6 (range 0.3-13.8) months. ORR by central review was 2 of 38 (5.3% 90%CI: 1%-15.6%). 31.6% of all patients and 30.7% of those with prior rapalog exposure had some tumor shrinkage during course of treatment. Median progression free survival (PFS) was 2.5 months (95% CI 1.8,3.7). Twelve patients (32%) developed treatment-related grade 3 adverse events (AEs) with no grade 4 or 5 toxicity reported; 6 patients (16%) required dose reduction and 4 (11%) discontinued therapy for AEs. Oncopanel tumor sequencing identified alterations in the mTOR pathway in 6 of 29 patients ( MTOR n = 2, PTEN n = 3, TSC1 n = 1.) Reduced PTEN expression by immunohistochemistry was seen in 7 of 19 patients. There was no association between mTOR pathway mutations or PTEN loss and response to sapanisertib. Conclusions: In this study we demonstrate minimal activity of sapanisertib in patients with treatment refractory mRCC with no clear benefit among patients with mTOR/PTEN pathway alterations. Additional treatment strategies are needed for patients with refractory mRCC.
Efficacy of gemcitabine plus doxorubicin (Gem + Dox) in patients with renal medullary carcinoma (RMC).
Authors: Wilson Nathaniel , Wiele Andrew James , Surasi Devaki Shilpa , Rao Priya , Sircar Kanishka , Shah Amishi Yogesh , Genovese Giannicola , Karam Jose A. , Wood Christopher G. , Tannir Nizar M. , Msaouel Pavlos
Published: March 2021

324

Background: Renal medullary carcinoma (RMC) is one of the most lethal renal cell malignancies with a median overall survival (OS) of only 13 months from diagnosis (Shah et al. BJU Int., 2017). RMC predominantly affects young individuals of African descent and is characterized by loss of the tumor suppressor SMARCB1 in all cases. Platinum-based chemotherapy produces a best response rate of 29% and is the recommended front line therapy for RMC (Msaouel et al. Clin Genitourin Cancer, 2019). However, there is little data on subsequent therapies. We recently showed that loss of SMARCB1 induces replication stress that renders RMC cells vulnerable to nucleoside analogs such as gemcitabine (Gem) and topoisomerase inhibitors such as doxorubicin (Dox) (Msaouel et al. Cancer Cell, 2020). We therefore hypothesized that Gem + Dox would demonstrate clinical activity against RMC. Methods: We conducted a retrospective study of patients who were treated with Gem + Dox for metastatic RMC at our institution. A blinded board-certified radiologist reviewed all restaging images to assess best radiographic response as defined by RECIST v1.1 and, when applicable, date of progression. Adverse events (AEs) were evaluated using the CTCAE version 5.0 grading estimated from chart documentation. Results: Between 01/2005 and 09/2020, we identified 16 patients with RMC that were treated with Gem + Dox and were evaluable for survival outcomes (Table). All but 1 patient (94%) had received prior platinum-based chemotherapy. Gem + Dox produced a partial response in 3/14 evaluable patients (21.4%) and stable disease as best response in 10/14 (71.4%), resulting in a median progression-free survival of 3.0 months (mo) with 95% CI 1.5-4.5 mo. The median overall survival (OS) from the start of Gem + Dox was 9.8 mo (95% CI 3.3-16.2) and the median OS from diagnosis was 18.6 mo (95% CI 11.3-25.9). Gem + Dox was well tolerated with no grade ≥ 4 AEs and the most common grade 2 or 3 AE’s were cytopenias (3/17), nausea (3/17), and fatigue (2/17). There were no grade ≥ 2 reported events of cardiotoxicity, but 3 patients discontinued treatment due to reaching recommended maximum dose of Dox. Conclusions: Gem + Dox demonstrated clinical benefit in patients with RMC and was well tolerated in most patients, supporting its use in patients with RMC whose disease progressed on prior platinum-based chemotherapy. Further investigation is warranted to determine and target mechanisms of resistance. [Table: see text]
Outcomes for patients in the pembrolizumab+axitinib arm with advanced renal cell carcinoma (RCC) who completed two years of treatment in the phase III KEYNOTE-426 study.
Authors: Plimack Elizabeth R. , Powles Thomas , Bedke Jens , Pouliot Frédéric , Stus Viktor , Waddell Tom , Gafanov Rustem , Nosov Dmitry , Alekseev Boris , McDermott Raymond S. , Markus Maurice , Tartas Sophie , Kryzhanivska Anna , Bondarenko Igor , Szczylik Cezary , Lin Jianxin , Perini Rodolfo F. , Molife L. Rhoda , Atkins Michael B. , Rini Brian I.
Published: March 2021

327

Background: In the randomized, open-label, phase III KEYNOTE-426 study (NCT02853331), pembrolizumab + axitinib significantly improved overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) versus sunitinib as first-line therapy for advanced RCC. Per protocol, patients could discontinue pembrolizumab or axitinib and continue the other agent. Pembrolizumab was stopped for all patients at 2 years. Axitinib could be continued until progression or toxicity. This exploratory subgroup analysis of KEYNOTE-426 describes outcomes of patients who completed 2 years of pembrolizumab. Methods: Patients included in KEYNOTE-426 were treatment naive, with clear cell RCC, KPS ≥70%, and measurable disease (RECIST v1.1). Patients were randomly assigned 1:1 to receive pembrolizumab 200 mg intravenously every 3 weeks for up to 35 doses + axitinib 5 mg orally twice daily or sunitinib 50 mg once daily (4 weeks on/2 weeks off) until progression, toxicity, or withdrawal. Primary end points of the original analysis were OS and PFS. Key secondary end points were ORR and safety. Results: Of 432 patients treated with pembrolizumab + axitinib, 129 (29.9%) completed 2 years of study therapy. Median (range) age of these patients was 61 (36-82) years, and 72.1% were male; 42 (32.6%) and 87 (67.4%) patients had International mRCC Database Consortium favorable and intermediate/poor risk, respectively, consistent with the intention-to-treat population (31.9% vs 68.1%). Median (range) follow-up (time from randomization to data cutoff) was 31.1 (24.0-37.7) months. For patients who completed 2 years of study therapy, the OS rates at 36 months was 93.8% (95% CI, 85.5%-97.4%). The PFS rates at 24 and 36 months were 72.7% (95% CI, 64.0%-79.7%) and 57.7% (95% CI, 46.3%-67.5%), respectively. The ORR was 85.3%, and the CR rate was 14.0%. 59.7% of patients experienced grade 3-5 treatment-related adverse events and 8.5% experienced grade 3-5 immune-mediated adverse events. Conclusions: In this exploratory analysis, a significant proportion of patients in the pembrolizumab + axitinib arm completed 2 years of pembrolizumab with ongoing clinical benefit. Clinical trial information: NCT02853331 .
Clinical utility of the AJCC eighth edition pT1 subclassification and impact on practice patterns in stage I seminoma.
Authors: Badia Rohit R , Woldu Solomon L. , Patel Hiten Dilip , Singla Nirmish , Srivastava Arnav , Cheaib Joseph G , Pierorazio Phillip M. , Bagrodia Aditya
Published: March 2021

377

Background: The American Joint Committee on Cancer 8th edition staging guidelines for testicular cancer established a 3 cm cutoff to subclassify stage T1 seminomas (<3 cm = pT1a and ≥3 cm = pT1b). The efficacy of this cutoff in predicting metastatic disease and impact on treatment patterns has not been studied. Methods: We retrospectively reviewed patients with pT1 testicular seminoma in the National Cancer Database from 2004-2016. Receiver operating curves (ROC) were used to determine the efficacy of the 3 cm tumor cutoff in identifying metastatic disease, and multivariable regression was used to compute the effect of tumor size on the rate of adjuvant therapy among stage I patients. Results: 10,134 patients with pT1 seminoma were evaluated. The current size cutoff of 3 cm for subclassification did not exhibit high discrimination in identifying metastatic disease (area under ROC: 0.546). Surveillance has grown as the preferred treatment after orchiectomy – 32.1% in 2004 to 81.2% in 2015. However, the rate of adjuvant therapy for pT1, stage I seminomas associated positively with tumor size even with adjustment for year of diagnosis. For tumors above 3 cm, the odds ratio stabilized around 1.9. By using the 3cm cutoff to guide adjuvant therapy, up to 85% of T1b patients may be overtreated. Conclusions: The 3 cm cutoff for subclassification of stage I seminoma does not predict metastatic recurrence but is associated with increased receipt of adjuvant therapy. A 3 cm cutoff and the pT1a/b classification may therefore contribute to overtreatment in many young patients with a long life expectancy for whom minimizing adverse effects should be prioritized.
Do females have worse surgical outcomes after radical cystectomy? Impact of gender on 30-day complications in a national cohort.
Authors: Kotamarti Srinath , Silver Michael , Wood Andrew , Teper Ervin , Silver David , Schulman Ariel
Published: March 2021

402

Background:: Men have higher rates of bladder cancer and are more likely to undergo cystectomy than women, yet women seem to have worse oncologic outcomes. This is attributed to biologic factors including adverse histologic variants and social factors including delay in diagnosis. There is early evidence that women also have worse surgical outcomes. We further examined the role of gender in 30-day perioperative outcomes following radical cystectomies in a national cohort. Methods: We examined the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) from 2012 to 2016. The database was searched for CPT codes reflecting radical cystectomy and a diagnosis of “cancer of the bladder.” Frailty was estimated by the modified frailty index (functional status, diabetes, chronic obstructive pulmonary disorder, history of chronic heart failure, and hypertension requiring medication.) To compare demographic and perioperative characteristics between genders, Chi-Square analyses were performed for categorical variables, student’s t test to compare averages, and the Wilcoxon rank sum test for operative time and length of stay (LOS). Results: 4,681 radical cystectomies were identified including 842 (18.0%) females. Of the female cohort, average age was 68.6 (+/-11.2 years), 77.3% was Caucasian and 278 (33%) had a BMI of at least 30. There were no differences appreciated between genders with regards to age, average ASA score, frailty, or minimally-invasive approach (all p=NS). Compared to males, female gender was associated with longer operative time (350 vs. 336 min, p<0.009), length of stay (LOS) (8 vs 7, p<0.001) and lower rates of discharge to home (79.9% vs 87.0%, p<0.0001). Reoperation (4.8% vs. 6.0%), readmission (22.2% vs 20.6%), and death within 30 days (1.9% vs. 2.0%) were similar. Clavien 3 or greater was also similar among gender (Table). Conclusions: Female patients comprise a minority of radical cystectomies with slightly longer LOS and less home discharge than men, yet 30-day major complications, reoperation and mortality appear similar. [Table: see text]
The prognostic impact of bone metastasis in urothelial carcinoma treated with first-line platinum-based chemotherapy.
Authors: Alqaisi Husam , Veitch Zachary William Neil , Stecca Carlos , Kaiser Jeenan , North Scott A. , Samnani Sunil , Alimohamed Nimira S. , Sridhar Srikala S.
Published: March 2021

415

Background: Metastatic urothelial carcinoma (mUC) is an aggressive disease with a median overall survival (OS) of ≈ 15 months. In the first-line setting, key prognostic factors include ECOG performance status, white blood cell count, and response to treatment per the Galsky nomogram. Bone metastases (BM) in mUC are associated with morbidity and mortality but are grouped with visceral disease; hence, their impact on prognosis is not well established. We aimed to assess the survival impact of BM in mUC patients treated with first-line platinum-based chemotherapy (PBC). Methods: A retrospective collection of patient and tumor characteristics, with clinical response to treatment (complete response [CR], partial response [PR]; stable disease [SD] or progressive disease [PD]) for patients treated at Princess Margaret Cancer Centre, Tom Baker Cancer Centre, and Cross Cancer Institute from 2005-2018 was performed. Progression-free survival (PFS) and OS were estimated using the Kaplan-Meier method. Univariate (UVA) followed by multivariate analysis (MVA) of patient variables [Cox] using PFS and OS was performed. Results: Overall 376 mUC patients were included; 222 (59%) had soft-tissue metastases (STM) only, 70 (19%) had bone-only metastases, and 84 (22%) had both STM and BM. Overall, 35% had PR or CR, 19% had SD, and 39% had PD (7%: unknown response). The median PFS and OS for the whole cohort were 5.6 months (95%CI: 4.8-6.4) and 9.7 months (95% CI: 8.8-10.8) respectively. Select UVA by metastatic site showed inferior PFS for bone-only (p=0.03) and combination STM and BM (p=0.017). Only combination STM and BM were significant on UVA for OS (p=0.002). MVA showed that bone-only metastases (p=0.03) and ECOG 3-4 (p<0.0001) were associated with worse PFS (Table). Predictors of worse OS were the combination of STM and BM (p=0.02), ECOG 3-4 (p=0.001), and WBCs ≥ULN (p=0.02), (Table). Conclusions: BM are a significant predictor of worse outcomes for mUC patients treated with first-line PBC. Consideration as a treatment stratification factor for future studies is suggested. Strategies for the treatment of mUC patients with BM (ie: bone targeted agents) in the first-line setting should be addressed in future trials. [Table: see text]
Impact of angiotensin blockade on response to PD1/L1 inhibitors for patients with metastatic urothelial carcinoma (mUC).
Authors: Skelton William Paul , Jain Rohit K. , Curran Catherine , Pond Gregory Russell , Naqvi Syeda Mahrukh Hussnain , Kim Youngchul , Nuzzo Pier Vitale , Alaiwi Sarah Abou , Nassar Amin , Jain Rakesh K. , Sonpavde Guru
Published: March 2021

453

Background: The renin-angiotensin system (RAS) is involved in regulation of angiogenesis and cell proliferation. Preclinical data also indicate that angiotensin inhibition may improve drug delivery by enhancing tumor perfusion partly by downregulating transforming growth factor (TGF)-β. Since (TGF)-β appears to be associated with resistance in patients (pts) with metastatic urothelial carcinoma (mUC) receiving PD1/L1 inhibitors, we hypothesized that angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARBs) may enhance the outcomes of mUC pts receiving PD1/L1 inhibitors. Methods: Data from mUC pts who received PD1/L1 inhibitors as monotherapy were obtained: pts from the Dana-Farber Cancer Institute (DFCI) served as the discovery dataset, while data from Moffitt Cancer Center (MCC) served as the validation dataset. Data for ACEI and ARB administration was collected with concurrent administration defined as ongoing therapy from the time of starting PD1/L1 inhibitor treatment. A logistic regression was used to investigate the impact of concurrent ACEI/ARB on any regression of tumor (ART, any decrease in size of tumor on scan) as the primary endpoint defined as any tumor regression after controlling for known prognostic factors (performance status, sites of metastasis, neutrophil/lymphocyte ratio, platelet count, hemoglobin). Overall survival (OS), the secondary endpoint, was analyzed using Cox proportional hazards regression. Results: Data was available for 178 pts from DFCI (discovery dataset) with mUC who received a PD1/L1 inhibitor of whom 153 (86%) had received prior platinum and 33 pts (18.5%) received concurrent AECI/ARBs. Multivariable analysis controlling for known prognostic factors revealed that patients who received ACEIs or ARBs had greater ART (HR 3.0 [95% CI 1.25-7.17], p = 0.014) and improved OS, (HR 0.49 [95% CI 0.28-0.88] p = 0.016). In the MCC validation dataset, 101 pts were available of whom 59 (58.4%) had received prior platinum and 22 pts (21.8%) received concurrent ACEI/ARBs. Univariate analysis showed that those patients who were treated with ACEI/ARB had an improved ART (OR 3.32 [95% CI 1.22-9.06] p = 0.019). On multivariable analysis, there was a borderline significant association of ACEI/ARB with ART (OR = 3.03, p = 0.075), but no association was observed with OS. Conclusions: In this hypothesis-generating study, concurrent angiotensin inhibitors including ACEI or ARBs were associated with tumor regression in mUC pts receiving PD-1/L1 inhibitors. The inconsistent association with OS may be partly due to modest sample size and comorbidities associated with the need for ACEI/ARBs. These results require validation in a prospective study.
Efficacy of immune checkpoint blockade in patients with advanced upper tract urothelial cancer and mismatch repair deficiency or microsatellite instability (MSI).
Authors: Andreev-Drakhlin Alexander , Shah Amishi Yogesh , Adriazola Ana Cecilia , Shaw Leah , Lopez Lidia , James Marihella , Matin Surena F. , Alhalabi Omar , Gao Jianjun , Siefker-Radtke Arlene O. , Goswami Sangeeta , Xiao Lianchun , Venkatesan Aradhana M. , Campbell Matthew T
Published: March 2021

487

Background: Tumors deficient in DNA mismatch repair (dMMR) exhibit a microsatellite unstable phenotype characterized by high tumor mutational burden and an immunogenic tumor microenvironment. Despite the histology-agnostic approval of pembrolizumab for advanced dMMR/MSI cancers, responsiveness of dMMR/MSI upper tract urothelial cancers (UTUC) to immune checkpoint (IC) blockade remains largely unknown. Methods: Consecutive records of patients (pts) from a single institution with locally advanced unresectable or metastatic dMMR/MSI UTUC who received IC therapy were analyzed. The primary endpoint was assessment of objective response rate (ORR) using RECIST v1.1. Secondary endpoints were progression-free survival (PFS) and overall survival (OS) using the Kaplan-Meier technique. dMMR/MSI status was evaluated by immunohistochemistry (IHC) and/or polymerase chain reaction (PCR). Results: Ten pts were identified with locally advanced unresectable (N = 3) or metastatic (N = 7) dMMR/MSI UTUC who received therapy with IC blockade (pembrolizumab = 7, nivolumab = 2, atezolizumab = 1). Median age was 65.5 (range = 46 – 90). Six pts were male. Seven pts had germline dMMR. MSI was detected by PCR in three pts and dMMR by IHC in seven pts (PMS2/MLH1 loss = 4, MSH2 loss = 1, MLH1 loss = 1, MSH6 loss = 1). Five pts received systemic chemotherapy (2 cisplatin based, 1 carboplatin based, 2 other) prior to IC therapy with two pts (40%) achieving partial response (PR). At a median follow-up of 15.5 months (range: 2 – 43 months), all pts were alive, and none experienced disease progression. PFS and OS at 15.5 months were 100%. The observed ORR was 90% (CI, 55.5%, 99.8%), including 8 pts who achieved complete remission (CR). The median time to best response was 4 months (range: 2 – 8 months). Toxicity leading to treatment discontinuation: 1 (grade 3) pancytopenia, 1 (grade 2) pneumonitis, 1 (grade 2) SICCA-like symptoms. Conclusions: Immunotherapy with IC inhibitors demonstrates excellent clinical activity in advanced dMMR/MSI UTUC. Further studies integrating these agents earlier in the disease course are warranted in this rare but important subgroup. Given the extremely high complete response rate in this population consideration of preference to IC therapy as initial therapy should be entertained if these findings are validated.
Prognostic significance of human papilloma virus (HPV) in penile cancer: A National Cancer Database (NCDB) study.
Authors: Chennamadhavuni Adithya , An Josiah , Mott Sarah L. , Garje Rohan
Published: March 2021

5

Background: HPV is associated with 30 - 50% of penile cancers, with some studies showing improved outcomes in these patients. This study evaluated the effect of HPV infection on penile cancer outcomes. Methods: The national cancer database (NCDB) was utilized to identify HPV tested penile cancer patients at the time of diagnosis from 2004 – 2016. Chi-squared tests and Cox regression models were used in analysis. Results: Out of 486 patients with penile squamous cell cancer, 139 (29%) were HPV +ve, and 347 (71%) were HPV -ve. Greater than 50% of HPV +ve were < 65 years old, Caucasian, from low-income areas ( < $48,000), and had public or no insurance. Similar incidence patterns were noted in HPV- ve patients. 77% pts who were HPV +ve had a moderate to poorly differentiated tumor. Most HPV +ve presented with early-stage cancer, and 12% were stage IV at diagnosis. 5-year overall survival (OS) was better among HPV +ve 62% vs. 50% in HPV -ve patients. Multivariable analysis (MVA) shows superior survival among patients with age < 65 years, low comorbidity score (0-1), and earlier stage at diagnosis. Patients with HPV +ve adjusted for age, comorbidities, stage, and treatment showed significantly improved survival. HPV -ve patients had 1.49 times increased risk of death compared to HPV +ve. Conclusions: HPV positive penile cancer is associated with significantly improved survival independent of age, comorbidities, stage, and treatment modality. This study reiterates the prognostic significance of HPV status and testing for HPV status at diagnosis should be a standard practice. [Table: see text]
Relationship between Drug Overdose Mortality and Coverage of Drug-Related Issues in US Television Political Campaign Advertising in the 2012 and 2016 Election Cycles
Authors: Kennedy-Hendricks Alene , Fowler Erika Franklin , Bandara Sachini , Baum Laura M. , Gollust Sarah E. , Niederdeppe Jeff , Barry Colleen L.
Published: March 2021

Context: Understanding the role of drug-related issues in political campaign advertising can provide insight on the salience of this issue and the priorities of candidates for elected office. This study sought to quantify the share of campaign advertising mentioning drugs in the 2012 and 2016 election cycles and to estimate the association between local drug overdose mortality and drug mentions in campaign advertising across US media markets.

Methods: The analysis used descriptive and spatial statistics to examine geographic variation in campaign advertising mentions of drugs across all 210 US media markets, and it used multivariable regression to assess area-level factors associated with that variation.

Findings: The share of campaign ads mentioning drugs grew from 0.5% in the 2012 election cycle to 1.6% in the 2016 cycle. In the 2016 cycle, ads airing in media markets with overdose mortality rates in the 95th percentile were more than three times as likely to mention drugs as ads airing in areas with overdose mortality rates in the 5th percentile.

Conclusions: A small proportion of campaign advertising mentioned drug-related issues. In the 2016 cycle, the issue was more prominent in advertising in areas hardest hit by the drug overdose crisis and in advertising for local races.
Prospects for Enforcing Prohibitions on Off-Label Drug Promotion after United States v. Caronia: An Analysis of Litigated Cases
Authors: Liu Sheng , Mello Michelle M. , Kesselheim Aaron S.
Published: March 2021

Context: Food and Drug Administration (FDA) rules restrict pharmaceutical manufacturers from promoting drugs for non-FDA-approved (off-label) indications. When manufacturers violate this rule, it has in many cases led to unsafe prescribing. However, in 2012, a federal circuit court ruled in United States v. Caronia that truthful off-label promotion was protected under the First Amendment, threatening government enforcement in this area.

Methods: The authors extracted cases from the WestLawNext database that mentioned Caronia from 2012 to 2019. They collected information about plaintiff, procedural history, product and manufacturer involved, and case outcome. Cases were categorized as either “follows,” “does not follow,” or “distinguishes” from Caronia. The authors qualitatively reviewed the full text of each case to verify whether Caronia was given substantive discussion for perceptions of off-label promotion, application of commercial speech rights, and how courts interpreted Caronia.

Findings: Among 42 cases in the study cohort, 22 (52%) followed Caronia's core holding that truthful, non-misleading off-label promotion was not actionable under FDA rules. By contrast, 20 cases (48%) treated Caronia negatively, either declining to follow (9 cases) or distinguishing it (11 cases).

Conclusions: Enforcement on off-label marketing became more challenging after Caronia. This gives manufacturers greater flexibility to promote drugs for unapproved uses despite the substantial public health risks.
Metabolomics and lipidomics in Caenorhabditis elegans using a single-sample preparation
Authors: Molenaars Marte , Schomakers Bauke V. , Elfrink Hyung L. , Gao Arwen W. , Vervaart Martin A. T. , Pras-Raves Mia L. , Luyf Angela C. , Smith Reuben L. , Sterken Mark G. , Kammenga Jan E. , van Kampen Antoine H. C. , Janssens Georges E. , Vaz Frédéric M. , van Weeghel Michel , Houtkooper Riekelt H.
Published: March 2021

Comprehensive metabolomic and lipidomic mass spectrometry methods are in increasing demand; for instance, in research related to nutrition and aging. The nematode Caenorhabditis elegans is a key model organism in these fields, owing to the large repository of available C. elegans mutants and their convenient natural lifespan. Here, we describe a robust and sensitive analytical method for the semi-quantitative analysis of >100 polar (metabolomics) and >1000 apolar (lipidomics) metabolites in C. elegans, using a single-sample preparation. Our method is capable of reliably detecting a wide variety of biologically relevant metabolic aberrations in, for example, glycolysis and the tricarboxylic acid cycle, pyrimidine metabolism and complex lipid biosynthesis. In conclusion, we provide a powerful analytical tool that maximizes metabolic data yield from a single sample.

This article has an associated First Person interview with the joint first authors of the paper.
Relations between the EU, Turkey, and Japan: dissonances in the strategic triangle
Authors: Higashino Atsuko
Published: March 2021

This paper considers how the three sets of bilateral relations, between the European Union (EU) and Japan, the EU and Turkey, and Turkey and Japan, have developed (or been underdeveloped) and how the three have failed to form a strategic triangle that could potentially be beneficial for dealing with regional and international problems more efficiently. One of the main arguments is that, although all three sides of this triangle have developed significant economic relationships, their political relationships are less consolidated. Such a phenomenon is largely illustrated by the following three elements of this triangle: a deteriorated relationship between the EU and Turkey, an underutilised relationship between Japan and the EU, and an extant relationship between Japan and Turkey. This paper analyses the elements that have impeded or continue to hinder constructive political dialogue. It concludes that the potential for improvement in the three sets of bilateral relations is slight, in the short term, with Japan, in particular, finding it increasingly difficult to strike a good balance between developing the relationship with the EU while maintaining historical ties with Turkey.
Utilizing passive sensing data to provide personalized psychological care in low-resource settings
Authors: Byanjankar Prabin , Poudyal Anubhuti , Kohrt Brandon A , Maharjan Sujen Man , Hagaman Ashley , van Heerden Alastair
Published: March 2021

Background: With the growing ubiquity of smartphones and wearable devices, there is an increased potential of collecting passive sensing data in mobile health. Passive data such as physical activity, Global Positioning System (GPS), interpersonal proximity, and audio recordings can provide valuable insight into the lives of individuals. In mental health, these insights can illuminate behavioral patterns, creating exciting opportunities for mental health service providers and their clients to support pattern recognition and problem identification outside of formal sessions. In the Sensing Technologies for Maternal Depression Treatment in Low Resource Settings (StandStrong) project, our aim was to build an mHealth application to facilitate the delivery of psychological treatments by lay counselors caring for adolescent mothers with depression in Nepal.

Methods: This paper describes the development of the StandStrong platform comprising the StandStrong Counselor application, and a cloud-based processing system, which can incorporate any tool that generates passive sensing data. We developed the StandStrong Counselor application that visualized passively collected GPS, proximity, and activity data. In the app, GPS data displays as heat maps, proximity data as charts showing the mother and child together or apart, and mothers’ activities as activity charts. Lay counselors can use the StandStrong application during counseling sessions to discuss mothers’ behavioral patterns and clinical progress over the course of a five-week counseling intervention. Achievement Awards based on collected data can also be automatically generated and sent to mothers. Additionally, messages can be sent from counselors to mother’s personal phones through the StandStrong platform.

Discussion: The StandStrong platform has the potential to improve the quality and effectiveness of psychological services delivered by non-specialists in diverse global settings.