bluuebunny/crossref_metadata_2025 huggingface dataset:
Predicting perioperative complications for partial versus radical nephrectomy in T1b-T2 renal cell carcinoma.
Authors: Shah Yash , Wang Kerith Ruoyao , Simhal Rishabh Kumar , Goldberg Hanan , Mark James Ryan , Shah Mihir S , Gomella Leonard G. , Lallas Costas D. , Chandrasekar Thenappan
Published: March 2023

737

Background: The standard of care for larger localized RCC lesions is radical (RN) or partial (PN) nephrectomy. RN is increasingly utilized to maximize oncologic benefit in complex tumors. Although PN is a more technically complex procedure, its nephron-sparing nature confers lasting renal and cardiovascular benefits. We utilized the National Surgical Quality Improvement Program (NSQIP) database to elucidate predictors of perioperative morbidity in T1b-T2 RCC patients. Methods: Using the NSQIP Nephrectomy-Targeted PUF, 2,094 patients undergoing nephrectomy between 2019-2020 for localized T1b-T2 RCC were identified. Variables of interest included surgical procedure and approach, tumor stage, demographics, pre-operative laboratory values, comorbidities, infection and venothromboembolism (VTE) prophylaxis techniques, peri-operative complications, operative time, length of hospital stay, 30-day reoperations, and 30-day readmissions. Chi square test was used to analyze univariate associations between certain comorbidities and complications. Multivariate regression analysis was utilized to compare complication rates between PN and RN after adjusting for baseline characteristics and surgical approach. p<0.05 was considered statistically significant. Results: 816 patients received PN while 1,278 received RN. PN patients had an increase in the following events: 30-day readmissions (7.0% vs. 4.7%, p=0.026), major bleeds (9.19% vs. 5.56%, p=0.001), renal failure requiring dialysis (1.23% vs. 0.31%, p=0.013), and urine leak or ureteric fistulae (1.10% vs. 0.31%, p=0.025). Open surgery was associated with increased VTE, renal failure, bleeds, urine leaks or ureteric fistulae, readmissions, and reoperations. Multivariate analysis revealed that PN remained predictive of all four aforementioned events, although further adjustment for robotic approach led to a loss of significance for renal failure and ureteric fistulae. Additional patient-specific predictors of relevant complications across procedure type included bleeding disorder and dialysis for bleeds, and renal failure, steroid use, and COPD for readmissions. Conclusions: This is the first study to evaluate the new NSQIP Nephrectomy-Targeted PUF. This population-based cohort provides unique insights into nephrectomy for pT1b-T2 localized RCC. We demonstrate significant associations between PN and specific complications, modulated by particular comorbidities, although both PN and RN were exceedingly safe. This analysis supports the development of novel risk stratification tools which account for specific patient comorbidities in predicting near term risk. Improved understanding of case-specific determinants of morbidity following PN or RN may facilitate shared decision making in localized RCC management.
Survival and hemoglobin A1c in metastatic castrate resistant prostate cancer.
Authors: Govindan Srinivas , Cheranda Nina , Luo Suhong , Riekhof Forest , Schoen Martin W.
Published: March 2023

75

Background: The two common therapies for metastatic castrate resistant prostate cancer (mCRPC), enzalutamide (ENZ) and abiraterone (AA), have different effectiveness in patients with diabetes mellitus and obesity due to different mechanisms of action, along with AA requiring the co-administration of prednisone. However, no prior study has assessed responses to treatment based on glycated hemoglobin (HbA1c) while accounting for body-mass index (BMI). Methods: Patients treated with AA or ENZ from September 10, 2014 to June 2, 2017 were identified within the Veterans Health Administration. The patients were classified by most recent HbA1c values (<5.6%, 5.6%-6.4%, 6.5%-7.1%, ≥7.2%) collected prior to the start of AA or ENZ. Kaplan Meier and Cox proportional hazards modeling was performed to assess the association between overall survival and covariates including age, Charlson Comorbidity Index, BMI, baseline PSA, and HbA1c. Results: 3421 veterans treated with AA or ENZ had HbA1c data available. 658 patients with HbA1c <5.6%, 1430 with 5.6-6.4%, 667 with 6.5%-7.1%, and 666 with HbA1c ≥7.2. Kaplan Meier analysis showed the following median survival in months with ENZ vs AA: <5.6% = 22.1 vs 24.5 (p = 0.04 by log-rank), 5.6%-6.4% = 27.7 vs 22.6 (p = 0.01), 6.5%-7.1% = 23.0 vs 19.8 (p = 0.005), ≥7.2% = 26.0 vs 21.0 (p = 0.04). Cox models showed no difference in median survival between ENZ vs AA in patients with HbA1c <5.6%, adjusted hazard ratio (aHR) 1.15 (95% CI, 0.960-1.370). However, there was significantly longer survival in patients who received ENZ compared to AA in all other groups as follows: 5.6%-6.4% aHR 0.86 (95% CI, 0.759-0.965), 6.5%-7.1% aHR 0.74 (0.623-0.879) and ≥7.2% aHR 0.80 (0.669-0.948). Additionally, in patients treated with AA, higher HbA1c values were associated with inferior survival compared to HbA1c <5.6%, aHR 1.40 (1.19-1.65) for 6.5-7.1% and aHR 1.25 (1.05-1.48) for ≥7.2%. Conclusions: In patients with HbA1c ≥5.6%, ENZ was associated with longer overall survival compared to AA, even when including baseline BMI. Additionally, in patients treated with AA, higher HbA1c values had inferior survivals compared to patients with HbA1c <5.6%. No difference in survival was observed across the HbA1c strata with ENZ. Further studies of interactions between patient factors and treatments are warranted to guide treatment selection for prostate cancer therapy.
Practice patterns and predictors of treatment intensification in patients with metastatic castration-sensitive prostate cancer.
Authors: Gotto Geoffrey T. , Yip Steven M. , Shayegan Bobby , O'Sullivan Dylan E. , Wallis Christopher J.D. , Basappa Naveen S. , Cagiannos Ilias , Hamilton Robert James , Ferrario Cristiano , Fernandes Ricardo , Danielson Brita , Saad Fred , Hotte Sebastien J. , Brenner Darren R. , Cheung Winson Y. , Boyne Devon J. , Chan Katherine , Osborne Brendan , Zardan Anousheh , Malone Shawn
Published: March 2023

76

Background: In recent years, treatment intensification beyond androgen deprivation therapy (ADT) with several novel therapies have shown survival benefit in patients with metastatic castration-sensitive prostate cancer (mCSPC). Given the rapidly evolving landscape in mCSPC treatment, there is a need to better understand how treatment strategies fit in real-world clinical practice and are combined/sequenced with other available therapies. Methods: Using electronic medical records and administrative data, a population-based retrospective cohort study was conducted. Patients aged ≥18 years of age who were newly diagnosed with de novo mCSPC and initiated ADT post-diagnosis between 2010 to 2020 in Alberta, Canada, were included. Treatment intensification was defined as the receipt of apalutamide, abiraterone acetate, enzalutamide, or chemotherapy (e.g. docetaxel) within 180 days of ADT initiation. Results: A total of 2,515 de novo mCSPC were identified during study period with 2,098 (83%) patients initiating ADT post-diagnosis. Of those, 525 (25%) received intensification beyond ADT. The percentage of patients who were intensified was 3% in 2010-2013 and gradually increased to 67% in 2020. Between 2014-2017, docetaxel was the most common therapy for intensification, but its use decreased considerably in 2018-2020 with abiraterone acetate, apalutamide and enzalutamide becoming increasingly available in the mCSPC setting. Upon progression, 46% and 22% in the intensified group versus 38% and 13% in the ADT-alone group initiated one and two-lines of subsequent therapies respectively. Abiraterone acetate and enzalutamide were the most common subsequent therapy for both the intensified (32% and 31% respectively) and the ADT-alone (56% and 38% respectively) groups. Docetaxel (24%) was used as subsequent therapy among mCSPC patients who were intensified with oral systemic agents. In multivariable logistic regression analyses of patients diagnosed in 2014-2020, significant predictors of intensification were younger age at diagnosis, lower Charlson comorbidity index, greater number of metastatic sites, shorter time to ADT initiation, referral to a specialists/cancer centres, surgery or radiation prior to ADT, and more recent year of diagnosis (all p<0.05). Conclusions: In Alberta, Canada, there has been a considerable increase in the utilization of ADT intensification therapies that correspond with the timing of clinical trial data and approvals of novel agents. Early referral to specialists/cancer centres is warranted to intensify mCSPC treatment beyond ADT and to improve patients’ outcomes. [Table: see text]
Management disparities in metastatic castrate-sensitive prostate cancer (mCSPC).
Authors: Mar Nataliya , Kaakour Dalia
Published: March 2023

79

Background: Recent approvals in management of high-volume mCSPC offer major improvements in patient outcomes. Triplet therapy combining androgen deprivation therapy (ADT) with docetaxel (D) and novel hormonal therapy (NHT) is the new standard of care in this patient population. Patients ineligible for triplet therapy should receive doublet therapy with ADT plus D or NHT based on category 1 evidence. Multiple retrospective datasets examining the “real-world” mCSPC treatment landscape note significant underutilization of therapies beyond ADT and discordance with treatment guidelines. Methods: A 15-question survey to assess management patterns was electronically distributed to various mCSPC providers in California and Washington. Results: A total of 40 responses were received, with 62.5% identifying as medical oncologists (MO), 20.0% as urologists, 5.0% as radiation oncologists, and 12.5% as advanced practitioners/other. Out of physician responders, 48.6% were academic and 51.4% were community-based. When treating newly diagnosed fit mCSPC patients, 20.0% would prescribe triplet therapy, 42.5% ADT/NHT, 5.0% ADT/D, 5.0% ADT/bicalutamide, 0% ADT alone, 10.0% other therapies, and 17.5% would refer out for therapies beyond ADT. When comparing academic versus community oncologists, 66.7% versus 0% would prescribe triplet therapy, while 22.2% versus 68.8% would prescribe ADT/NHT. Some perceived barriers to following mCSPC treatment guidelines included difficulty keeping up with rapidly evolving data/too many treatment options in 27.5%, insurance coverage concerns in 22.5%, difficulty obtaining early referrals for these therapies in 12.5%, patient factors in 10.0%, and toxicity concerns in 2.5%. When making referrals to MO, 37.5% of non-MO responders would do so at development of mCSPC and 6.3% at mCRPC. Conversely, 24.2% of MO perceived receiving referrals at development of mCSPC and 33.3% at mCRPC. Patterns of ordering genomic testing are listed, with biggest perceived barriers being cost, inadequate access to sequencing platforms and genetic counselors, lack of confidence in counseling about results, and patient refusal. Upon progression from mCSPC to mCRPC, ordering of repeat tumor biopsies would occur “sometimes” by 40.0% of providers, “rarely” by 20.0%, and “never” by 20.0%. Conclusions: Multiple provider disparities when managing mCSPC patients still exist. Our survey demonstrated higher compliance with treatment guidelines than in previous retrospective datasets, possibly due to higher proportion of academic providers. Increased provider awareness of genomic testing recommendations is also needed. [Table: see text]
Association of intermittent vs continuous androgen deprivation therapy with cardiovascular disease and endocrine/metabolic disorders in patients with metastatic prostate cancer.
Authors: Morgans Alicia K. , Ebrahimi Ramin , Bobbili Priyanka J. , Nwokeji Esmond , Gandhi Raj , Desai Raj , Horvath Krisztina , Ryan Michael , Hanson Sarah , Duh Mei Sheng , Preston Mark A.
Published: March 2023

82

Background: There is mixed evidence on the risks of cardiovascular disease (CVD) and endocrine/metabolic disorders associated with long-term intermittent and continuous androgen deprivation therapy (iADT and cADT, respectively) for metastatic prostate cancer (mPC). This study examined these risks in patients (pts) with mPC receiving iADT vs cADT in the US. Methods: This was a retrospective cohort study of SEER-Medicare pts with mPC initiating ADT (2010–2017), with ≥36 months of continuous insurance coverage, unless death occurred, who did not receive chemotherapy or a second-generation anti-androgen during follow-up. iADT and cADT cohorts were defined by treatment patterns and gaps in therapy. Comorbidities and clinical events were identified using ICD-9/10-CM codes. Outcomes examined were major adverse cardiovascular events (MACE [myocardial infarction (MI), stroke, cardiomyopathy/heart failure (HF), pulmonary embolism (PE), ischemic heart disease (IHD), or all-cause mortality]) and endocrine/metabolic events (diabetes, hypercholesterolemia, bone fractures, or osteoporosis). Inverse probability of treatment weighting (IPTW) was used to adjust for differences between cohorts; weighted Cox models were used to estimate the hazard ratio (HR) of the outcomes. Subgroup analyses examined pts by CVD history; a sensitivity analysis was performed restricting the definition of MACE to include CVD-related mortality as a component, i.e., MACESA (MI, stroke, cardiomyopathy/HF, PE, IHD, or CVD-related mortality). Results: 2234 pts with mPC were included; 478 (21%) received iADT and 1756 (79%) cADT. Median follow-up time was 27 and 13 months, and time on ADT (excluding gaps for iADT pts) was 24 and 19 months for the iADT and cADT cohorts, respectively. Deaths occurred in 39% of iADT pts vs 55% of cADT pts; PC was the most common cause of death in both cohorts. In adjusted analyses, pts receiving cADT had a higher risk of MACE vs iADT. No differences in risk of endocrine/metabolic events were observed. Subgroup analysis showed that baseline history of CVD did not alter the results for MACE. Sensitivity analysis results showed no difference in risk of MACESA between pts receiving cADT vs iADT. Conclusions: Pts with mPC receiving cADT had a higher risk of MACE (including all-cause mortality), and no difference in risk of endocrine/metabolic events, compared with those receiving iADT. When MACE was restricted to include CVD-related mortality, there was no difference in risk between cohorts. [Table: see text]
Multicenter population-level analysis of systemic therapy use in metastatic or recurrent prostate cancer.
Authors: Mohamed Heba , Kim Grace , Macphail Corin , Bhuiyan Ishmam , Sidhu Taylor , Emami Amir , Huang Longlong , Sun Shaun Zheng , Tyldesley Scott , Ko Jenny J.
Published: March 2023

89

Background: Treatment (tx) options for metastatic prostate cancer (mPC) have advanced significantly. There is a need for data in prescribing patterns and real-world survival outcomes of new therapeutics. Methods: We conducted chart review on all consecutive patients (pts) diagnosed with any stage of PC between 2016-2017 in British Columbia, and only included pts with de novo metastasis or later recurrence. We performed descriptive statistics, univariate and multivariate analysis to examine overall survival (OS). Results: This study included 796 pts with either de novo metastatic (n=554, 69.6%) or recurrent PC (N=242; 30.4 %); 743 (93.3%) had metastasis by time of cutoff (Sep 1, 2022). Median age at diagnosis of mPC in all patients was 73 (range 45-98). 790 (99.2%) started ADT. 263 (35.4%) had additional line of tx started with ADT at mCSPC; 309 (38.8%) had 1st line tx started at mCRPC. 149 pts (18.7%) had testing for homologous repair defects (21 positive). Radiotherapy (RT) to prostate for mPC were given to 93 (11.6%). 307 (38.6%) received 1 line of tx; 181 (22.7%), 2; 128 (16.1%), 3 or more. 432 (54.3%) received >=1 androgen receptor-axis-targeted therapies (ARAT). At cutoff, 474 (59.5%) died; most (n=400; 84.4%) died of prostate cancer. Pts who only stayed on ADT or who stayed on 1 additional tx had better OS than who had more than 1 line (NR vs. 55.5m vs. 21.0m, p=0.03). Similarly, pts who required no ARAT or stayed on 1 ARAT had longer OS than patients who had more than 1 ARAT (NR vs. 48.5m vs. 22.5m, p=0.009). No statistical difference in OS was seen between pts who had chemotx vs none, or pts on trial vs none. None of age, PSA at metastatsis, Gleason score, ADT type, RT to prostate or number of systemic tx were identified as an independent factor affecting OS on multivariate analysis. Pts with comorbidities (hypertension, CHF, diabetes, seizure, prior stroke, CAD or dementia) received abiraterone/prednisone, enzalutamide or apalutamide at a similar rate. Conclusions: Our multicenter data show low uptake of early treatment intensification in pts with mPC. Similar to other real-world data to date, pts who required less switch to another systemic tx were associated with better OS. Different ARATs were prescribed despite potential side effects at a similar rate to pts with major comorbidities.
Neoadjuvant platinum-based chemotherapy for clinically node-positive penile squamous cell carcinoma: An international, multicenter, real-world study.
Authors: Rose Kyle M. , Sanchez Darren , Mustasam Arfa , Sandstrom Reagan , Marchetti Kathryn , Zacharias Niki Marie , Pagliaro Lance C. , Alifrangis Constantine , Moses Kelvin A. , Albersen Maarten , Roussel Eduard , Master Viraj A. , Nazha Bassel , Zhuang Tony , Montgomery Jeffrey S. , Protzel Chris , Machado Marcos Tobias , Spiess Philippe E. , Pettaway Curtis Alvin , Chahoud Jad
Published: March 2023

9

Background: The efficacy of neoadjuvant platinum-based chemotherapy (NAPC) in penile squamous cell carcinoma (PSCC) was provided by small clinical trials, leaving clinicians with scant evidence-based guidance. Thus, we aimed to analyze real-world outcomes of patients with PSCC who received NAPC prior to surgical resection. Methods: Patients from 9 tertiary care centers who had undergone NAPC prior surgical resection for PSCC were included with locally advanced (cTany, cN+), non-metastatic (M0) disease. The primary and secondary outcomes were overall survival (OS) and progression-free survival (PFS), Response was determined via best overall response measured with RECIST 1.1 criteria. Results: 167 patients were included, 137 (84%), of which received TIP prior to surgical resection. Ninety-two (55%) patients died during follow up, and the mean follow up for survivors was 57 months. The median OS was 42 months, while the median PFS was 17 months. The table details the response rates to NAPC, the associated survival, and Cox Proportional Hazards Modelling of OS and PFS. Predictors for OS and RFS included lymphovascular invasion, positive number of lymph nodes, extranodal extension, downstaging, best overall response, and ypN status. Figure 1 demonstrates OS outcomes by RECIST best response after chemotherapy, presence of downstaging after NAPC, ypN stage, and presence of extranodal extension. Conclusions: Upfront NAPC is effective in patients with lymph node metastases from penile carcinoma. Unsurprisingly, patients who demonstrated a robust response to therapy had improved survival outcomes compared to those who had not—as measured by RECIST criteria, tumor downstaging, pN staging, and presence of extranodal extension. This study represents the largest conglomeration of multi-institutional penile carcinoma patients treated with NAPC, and provides further supportive data for multimodal therapy for advanced penile cancer patients while prospective clinical trials complete accrual. [Table: see text]
Radium-223 for mCRPC, a real-world experience study from 7 Galician medical centers.
Authors: Anido Herranz Urbano , Fernandez Calvo Ovidio , Martinez Breijo Sara , Fernández Núñez Natalia , Nogareda Seoane Zulema , Garrido Pumar Miguel , Casas Javier , Muñiz Garcia Gloria , Portela Pereira Paula , Gomez Caamaño Antonio , Pérez Fentes Daniel , Santomé Lucía , Huidobro Vence Gerardo , Molina Díaz Aurea , Medina Ana , Ruiz Bañobre Juan , Vázquez Estévez Sergio
Published: March 2023

96

Background: Radium-223 represents an option for symptomatic metastatic castration-resistant prostate cancer (mCRPC) after demonstrated an overall survival improvement in the ALSYMPCA trial. Radium-223 real-life experiences are scarce, particularly after the results of the ERA-223 trial. To describe Radium-223 outcomes in real life practice, and specifically those related with bone health, sequence of treatment, and prognostic factors. Methods: Multicenter retrospective study of a cohort of 143 patients with mCRPC treated with Radium-223 in either the second line or third line of therapy or beyond in the context of routine clinical practice between 11 March 2013 and 26 July 2022, in seven Galician hospitals. Survival estimates were calculated by the Kaplan-Meier method, and groups were compared with the log-rank test. The Cox proportional hazards regression model was used to evaluate factors independently associated with OS. Between March 11, 2013, and July 26, 2022, 143 patients were enrolled from 5 Galician hospitals. With a median follow-up of 9.68 months. All patients signed an informed consent form agreeing to participate in this observational study, that was approved by the Galician Ethics Committee, registration code 2018/282. Results: Baseline patient and disease characteristics are summarized. Median follow-up was 9.68 months. Median overall survival (OS) was 12 months (95% CI 9.7 – 16.0). Best OS outcomes were achieved in second and third line, 18 months (95% CI 12.0 – 26.0) and 9.4 months (95% CI 8.0 – 12.0) months, respectively. Among those baseline clinic-analytical factors analyzed, only alkaline phosphatase level >354 UI/L was correlated with a worse OS (HR 2.56 (95% CI 1.39 – 4.72; p=0.003) and the number of cycles of Radium-223 received (HR 0.63 (95% CI 0.54 – 0.73; p<0.001) were prognostic factors for Radium-223. Importantly, ninety-nine of patients (80%) were treated with bone-targeted therapy for bone metastases with no OS differences (p=0.66). Conclusions: In our study, Radium-223 efficacy was consistent with previously reported. Best efficacy was achieved in the second or third line of therapy, independently of docetaxel use. Patients with high baseline alkaline phosphatase had worse OS. Few patients presented skeletal-related events, which could be explained by an adequate use of bone-targeted therapy (zoledronic acid or denosumab). [Table: see text]
Real world (rw) homologous recombination repair (HRR) gene mutation testing trends in patients (pts) with metastatic castrate-resistant prostate cancer (mCRPC) in the United States (US).
Authors: Barata Pedro C. , Montgomery Rachel , Last Matthew , Gillespie-Akar Liane , Nazari Jonathan , Arondekar Bhakti , Niyazov Alexander
Published: March 2023

98

Background: Previous research suggests that HRR mutations may have prognostic value in mCRPC. Additionally, HRR mutations are therapeutically relevant and can inform treatment decisions. Limited information is available on HRR mutation testing rates in the US. This study assessed rw HRR testing patterns in pts with mCRPC in the US and described characteristics associated with HRR testing. Methods: Retrospective data from pts with mCRPC initiating first line (1L) treatment between 2014 – 2021 was obtained from the nationwide Flatiron Health electronic health record-derived de-identified database. Pt demographic and clinical characteristics were summarized descriptively across subgroups by HRR gene testing status (tested vs not tested). A multivariable logistic regression model was used to assess factors associated with receiving HRR testing, and included covariates for demographic, clinical, and treatment characteristics. Results: A total of n=8,166 pts with mCRPC receiving 1L treatment were identified. The mean age of the cohort was 72.9 (standard deviation (SD) 8.1) years. Overall, 2,122/8,166 (26%) were known to have received HRR mutation testing. Pts who did not receive HRR testing were older compared to HRR tested pts (mean age 73.7 (SD 8.5) vs 70.6 (SD 7.5) years). A higher proportion of HRR tested were receiving treatments from an academic medical center vs community practice (14.5% vs. 7.7%). Multivariable logistic regression indicated age > 65 (vs < 65 years), Black race (vs White), being treated in the community (vs academic), and having de novo metastatic disease (vs recurrent) were associated with a statistically significant lower odds of HRR mutation testing. In contrast, a higher socioeconomic status and being diagnosed with mCRPC after 2018 were associated with a statistically significant increased odds of HRR mutation testing. Conclusions: In this rw study, a minority of US pts with mCRPC received HRR mutation testing. Disparities in HRR mutation testing exist, and focused efforts to increase HRR testing should be developed, especially among Black pts, pts with lower socioeconomic status, pts treated in the community setting, and pts > 65 years of age. [Table: see text]
CYCLONE 3: A phase 3, randomized, double-blind, placebo-controlled study of abemaciclib in combination with abiraterone plus prednisone in men with high-risk, metastatic, hormone-sensitive prostate cancer (mHSPC).
Authors: Smith Matthew Raymond , Matsubara Nobuaki , McKay Rana R. , Piulats Josep M. , Todenhöfer Tilman , Zhang Tian , Fasnacht Nicolas , Sherwood Sarah , Johnston Erica L. , Schaverien Clare , Lithio Andrew , Nacerddine Karim , Agarwal Neeraj
Published: March 2023

TPS289

Background: Landmark trials have established a survival benefit for novel hormonal agents (NHA) added to androgen deprivation therapy (ADT) for mHSPC. Yet, there is a significant medical need to expand therapeutic options, especially for pts with high-risk mHSPC who experience poorer outcomes. Abemaciclib is an oral selective inhibitor of cyclin-dependent kinase 4 and 6 (CDK4 & 6) dosed on a continuous schedule, approved for the treatment of node-positive high-risk early-stage and advanced or metastatic HR+, HER2- breast cancer. Analogous to the estrogen receptor signaling pathway in breast cancer, there is evidence that the androgen receptor axis activates CDK4 & 6 to sustain prostate cancer cell proliferation, and upregulation of cyclin D1 is a potential mechanism of resistance to NHA therapy. In preclinical models, abemaciclib induces cell cycle arrest and inhibition of prostate tumor growth. Methods: CYCLONE 3 (NCT05288166) is a global, randomized, double-blind, placebo-controlled study evaluating the addition of abemaciclib to abiraterone+prednisone (AP) in pts with high-risk mHSPC. Approximately 900 pts with high-risk mHSPC defined by ≥4 bone metastasis and/or visceral disease will be randomised in a 1:1 ratio to the AP + abemaciclib or AP + placebo arm. Up to 3 months of ADT prior to randomization is permitted; prior D for mHSPC will be excluded per planned protocol amendment. Pts who have not undergone orchiectomy will continue ADT. Stratification factors are de novo mHSPC and visceral metastases. Primary endpoint is investigator-assessed radiographic progression-free survival (rPFS). Key secondary endpoints include rPFS assessed by blinded independent central review, castration-resistant prostate cancer-free survival, overall survival, time to pain progression, safety and pharmacokinetics. Enrollment is open at approximately 270 sites across 25 countries. Clinical trial information: NCT05288166 .
A prospective phase II trial of pembrolizumab plus lenvatinib in advanced adrenal cortical carcinoma after failure of platinum- and mitotane-based chemotherapy (ACCOMPLISH).
Authors: Park Inkeun , Kwon Minsuk , Park Kwonoh , Park Se Hoon , Park Joo-Hwan , Shin Sang Joon , Shim Hyun-Jeong , Yun Tak , Lee Jae-Lyun , Lee Hyo Jin , Choi Wonyoung
Published: March 2023

TPS3

Background: Adrenal cortical carcinoma (ACC) is a very rare cancer with poor prognosis. For advanced ACC, systemic treatment options are limited. There has been only one randomized phase III clinical trial in which etoposide, doxorubicin, cisplatin, and mitotane (EDP-M) achieved statistically significant improvement in terms of objective response rate (ORR) and progression-free survival (PFS). However, after failure of EDP-M regimen, no universally accepted treatment option exists. In human ACC sample, vascular endothelial growth factor (VEGF) and VEGF receptor-2 (VEGFR-2) expression were higher than adrenal adenoma, and 10-20% of tumor cells and 70% of tumor infiltrating monocyte are PD-L1 positive. In retrospective review of cabozantinib in advanced ACC, cabozantinib demonstrated 19% of ORR and 16.2 weeks of median PFS. Also, in phase II clinical trial of pembrolizumab in advanced ACC, ORR of 14-23% were shown. Considering synergism of VEGFR tyrosine kinase inhibitors (TKIs) and immune check point inhibitors (ICIs) in other cancers, combination of VEGFR TKI and ICI is an attractive approach in advanced ACC. Methods: This is an open-label,single-arm,multi-center,investigator-initiated phase II trial of lenvatinib plus pembrolizumab in patients with advanced ACC who failed previous platinum and mitotane therapy (NCT 05036434). Using Simon’s optimal two-stage design, 10 patients will be enrolled initially in the first stage. If at least 2 or more patients achieve complete response or partial response, the trial will continue until enrollment of a total of 30 patients. Patients will receive 200 mg of pembrolizumab every 3 weeks intravenously and 20 mg of daily lenvatinib orally until disease progression, intolerable toxicity, or patients’ withdrawal of consent. Key eligibility criteria are age ≥ 19 years, ECOG PS 0-1, biopsy-proven ACC, disease progression despite cisplatin- and mitotane-based chemotherapy, measurable disease according to RECIST v1.1, no uncontrolled hypertension, adequate kidney, liver, and bone marrow function. Primary endpoint is ORR, and secondary endpoints include PFS, safety profile, overall survival, duration of response. Exploratory evaluation of tumor genomics and immune microenvironment by whole exome sequencing, single-cell RNA sequencing, and T cell receptor sequencing in correlation with response will be performed. Enrollment began in June 2022 and projected enrollment goal is 3 years. Clinical trial information: NCT05036434 .
P3BEP (ANZUP 1302): An international randomized phase 3 trial of accelerated versus standard BEP chemotherapy for male and female adults and children with intermediate- and poor-risk metastatic germ cell tumours (GCTs).
Authors: Zebic Danka , Stockler Martin R. , Martin Andrew James , Pashankar Farzana D. , Tran Ben , Mazhar Danish , Huddart Robert A , Wheater Matthew , Walpole Euan Thomas , Dunwoodie Elaine , Feldman Darren R. , Birtle Alison Jane , Stevanovic Amanda Gwendolyn , Wyld David , Hanning Fritha J. , Grimison Peter S. ,   Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP)
Published: March 2023

TPS431

Background: Bleomycin, etoposide, and cisplatin (BEP) given 3-weekly x 4 remains standard 1st line chemotherapy for intermediate or poor risk metastatic GCT. Accelerating standard regimens by shortening the cycle length to 2-weekly improved cure rates in other cancers. P3BEP will determine effects of accelerated versus standard BEP in this setting. This is a first international, randomized trial of chemotherapy for intermediate and poor-risk metastatic GCT to include adults and children of both sexes. Methods: This open label, randomized, phase 3 trial is conducted seamlessly in 2-stages. The primary endpoint for stage I (n=150) was complete response (CR); and for stage 2 (n=500) is progression free survival at 2 years (PFS2y). These sample sizes provide >80% power with a two-sided type I error rate of 5% to detect an absolute improvement of 25% in the CR rate (stage 1) and of 7% in the PFS2y (stage 2). The target population is males and females aged 11 to 45 with intermediate-or poor-risk metastatic GCT of the testis, ovary, retroperitoneum, or mediastinum. Participants are randomized (1:1) to 4 cycles of standard BEP (q3w) or accelerated-BEP (q2w) with cisplatin 20mg/m2 D1-5, etoposide 100mg/m2 D1-5, bleomycin 30 KIU weekly x 12, and pegylated G-CSF D6 or filgrastim daily. Study assessments occur at 30 days after completing chemotherapy, 6 months from randomization, and after completion of all post-chemotherapy treatments (e.g. surgery). Tumour and baseline blood samples are collected for translational substudies. Progress: As of Sept 2022, 226 participants have been recruited from 24 ANZ sites, 17 UK sites (led by Cambridge Clinical Trials Unit), and 149 USA sites (led by Children’s Oncology Group). The first planned interim analysis for safety (n=76) identified no safety concerns. Stage I analysis (n=150) showed sufficiently favorable results with no futility concerns, supporting ongoing trial recruitment. Clinical trial information: NCT02582697 .
Trial in progress: PRESTIGE—Primary retroperitoneal lymph node dissection (RPLND) for clinical stage II (CSII) testicular germ cell tumour (TGCT) and its impact on health-related quality of life (HRQoL) compared to chemotherapy or radiotherapy.
Authors: Conduit Ciara , Lewin Jeremy Howard , Liow Elizabeth Chien Hern , Dhillon Haryana M. , Hong Wei , De Abreu Lourenço Richard , Lawrentschuk Nathan , Thomas Benjamin , Grimison Peter S. , Ahmadi Nariman , Sengupta Shomik , Tran Ben
Published: March 2023

TPS433

Background: As cure rates for patients with advanced TGCT improve, there is increasing focus on quality of survival. Increasingly, primary RPLND is being used as an alternative to chemotherapy (and radiotherapy) as primary treatment for selected individuals, due to the development of low morbidity surgical techniques (robot-assisted and extraperitoneal approaches), and recognition of acute and long-term toxicity of chemotherapy and radiotherapy. We hypothesise that primary RPLND compared to chemotherapy and radiotherapy will have less detrimental impact on HRQoL with comparable oncological outcomes. Methods: PRESTIGE is a prospective cohort study among adults with histologically confirmed advanced TGCT planned for primary RPLND, chemotherapy or radiotherapy. Eligible patients may have de novo advanced disease, or relapse within two- (NSGCT) or three-years (seminoma) following orchidectomy, without prior chemotherapy or radiotherapy (including adjuvant), and able to complete HRQoL questionnaires in English. See table for cohort-specific eligibility. Surgical approach (modality, template, adjuvant chemotherapy), chemotherapy regimen and radiotherapy dose will be administered at physician discretion and captured in Australia’s national multi-centre TGCT registry, iTestis, with clinical data in follow-up. Participants will complete HRQoL questionnaires focusing on physical, social, emotional, and functional domains commencing prior to treatment and continuing for 24 months. Questionnaires include EORTC QLQ-C30, EORTC QLQ-TC26, Brief Male Sexual Function Inventory and specific questions focusing on retrograde ejaculation and fertility. Patients undergoing RPLND will also have miR-371 evaluation pre-operatively and serially for 12 months after surgery. The primary outcome is change in EORTC QLQ-C30 global health status over 24 months for participants undergoing primary RPLND. Key secondary outcomes are changes in HRQoL, patterns of recurrence, surgical complications, retrograde ejaculation, and infertility. A sample size of 90 participants (30 for RPLND, 60 for chemotherapy) provides >80% power to detect a mean difference of 28% in global health status at 0.05 significance favouring RPLND. Up to 30 individuals receiving radiotherapy may also be enrolled. The first site was activated 4-Aug-22; 2 of 3 study sites are active and 5 out of a planned 120 (4%) participants have enrolled. [Table: see text]
Phase 2 clinical study evaluating the efficacy and safety of disitamab vedotin with or without pembrolizumab in patients with HER2-expressing urothelial carcinoma (RC48G001).
Authors: Powles Thomas , Yu Evan Y. , Iyer Gopa , Campbell Matthew T , Loriot Yohann , De Santis Maria , O'Donnell Peter H. , Burgess Earle F , Necchi Andrea , Krieger Laurence E. M. , Matsubara Nobuaki , Koshkin Vadim S , Zhang Wei , Ichimaru Mari , Galsky Matt D.
Published: March 2023

TPS594

Background: Urothelial carcinoma (UC) is the 10th most diagnosed cancer worldwide, and nearly 50% of patients cannot tolerate the current first-line (1L) standard of care. There is a need to improve outcomes in 1L and later lines of therapy. HER2 is overexpressed in UC and may be associated with poor outcomes. Despite this, no HER2-directed therapies are currently approved for UC. Disitamab vedotin (DV; RC48-ADC) is an investigational antibody-drug conjugate comprising a novel HER2-directed monoclonal antibody, disitamab, conjugated to monomethyl auristatin E (MMAE) via a protease-cleavable mc-vc linker. DV elicits antitumor activity through multimodal mechanisms of action including MMAE-mediated direct cytotoxicity, bystander effect, and immunogenic cell death. Methods: RC48G001 (NCT04879329) is a phase 2, multi-cohort, open-label, multicenter trial to evaluate DV in patients with HER2-expressing locally advanced/metastatic UC (LA/mUC). Patients are enrolled in 3 cohorts based on prior treatment and tumor HER2 expression by immunohistochemistry (IHC) and gene amplification (via in situ hybridization [ISH]), assessed centrally. Cohorts A and B are enrolling patients who have received prior systemic therapy (1 or 2 lines, including platinum-containing chemotherapy) and whose tumors are HER2-positive (IHC 3+, or 2+ and ISH-positive) or HER2-low (IHC 2+ and ISH-negative, or IHC 1+), respectively. Cohort C is enrolling 1L treatment-naive patients in the LA/mUC setting, whose tumors have HER2-positive or HER2-low expression. Cohorts A and B will evaluate DV as monotherapy (intravenous [IV] administration, once every 2 weeks [Q2W]). Cohort C will evaluate DV (IV, Q2W) +/– pembrolizumab (IV, Day 1 of each 6-week cycle). Patients in all cohorts must have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and an Eastern Cooperative Oncology Group Performance Status of 0–1 in Cohorts A and B, and 0–2 in Cohort C. The primary endpoint is confirmed objective response rate (cORR) per blinded independent central review (BICR). Secondary endpoints include cORR by investigator assessment, overall survival, duration of response, progression-free survival, disease control rate per RECIST v1.1 by BICR and investigator, safety, and pharmacokinetic parameters. Enrollment for all cohorts is ongoing in North America and Europe, and planned in Latin America, Asia-Pacific, and Israel. Clinical trial information: NCT04879329 .
Optimal treatment by invoking biologic clusters in renal cell carcinoma (OPTIC RCC).
Authors: Chen Yu-Wei , Beckermann Katy , Haake Scott Mattox , Reddy Anupama , Shyr Yu , Atkins Michael B. , Mar Nataliya , Ornstein Moshe Chaim , Pal Sumanta Monty , Zhang Tian , Rathmell Wendy Kimryn , Rini Brian I.
Published: March 2023

TPS742

Background: The first-line treatment for metastatic clear cell renal cell carcinoma (mccRCC) includes an immuno-oncology (IO) based combination. The current standard regimens include a PD-1 inhibitor plus either (1) an anti-CTLA-4 inhibitor (IO/IO), or (2) an anti-vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI) (IO/TKI). Currently, there is no level 1 evidence to guide physician’s choice between an IO/IO versus IO/TKI combination. The phase III IMmotion 151 trial performed RNA-seq from 823 ccRCC tumors and established seven biologically distinct gene expression clusters of ccRCC (Motzer and Rini et al., Cancer Cell 2020). The seven clusters showed differential responses to immune checkpoint inhibitor and may serve as a predictive biomarker to select frontline treatment. Methods: This trial is a phase II, multicenter study using the established biologic clusters to assign patients with mccRCC to either an IO/IO (ipilimumab/nivolumab) or an IO/TKI (nivolumab/cabozantinib) regimen. Patients diagnosed with mccRCC without prior systemic therapy (including in the neoadjuvant or adjuvant setting) and at least one measurable lesion as defined by RECIST 1.1 are eligible for enrollment. RNA-seq will be performed on metastatic tumor specimens and used to assign tumor clusters. Patients with cluster 1/2 tumors will be assigned to the nivolumab/cabozantinib arm; patients with cluster 4/5 tumors will be assigned to the ipilimumab/nivolumab arm. Cluster 3/6/7 will be excluded. The primary endpoint is overall response rate (ORR) per RECIST 1.1. The hypothesis is that use of tumor clusters to assign front-line therapy to either nivolumab/cabozantinib or ipilimumab/nivolumab will lead to a 20% greater ORR compared to unselected historical controls in CheckMate 9ER (ORR: 55%) or CheckMate 214 (ORR: 40%). This trial adopts Simon’s MiniMax two-stage design (power: 80%, one-sided α: 0.1). For the nivolumab/cabozantinib arm, stage I will enroll 12 eligible patients. If there are 7 or more responders in the first 12 patients, the trial will continue for stage II to enroll additional 14 patients (total n=26). The primary endpoint will be met if there are 18 or more responders (ORR ≥75%). For the ipilimumab/nivolumab arm, stage I will enroll 16 eligible patients. If there are 7 or more responders in the first 16 patients, the trial will continue for stage II to enroll additional 12 patients (total n=28). The primary endpoint will be met if there are 15 or more responders (ORR ≥60%). Key secondary endpoints include progression-free survival (PFS), depth of response>80%, and rate of immune-related adverse events (irAEs). This trial is funded by the Department of Defense Kidney Cancer Research Program Clinical Trial Award (W81XWH-22-1-1033) (NCT05361720). Clinical trial information: NCT05361720 .
A phase II study of nivolumab with ipilimumab and cabozantinib in patients with untreated renal cell carcinoma brain metastases.
Authors: Wang Jianbo , Campbell Matthew T , Shah Amishi Yogesh , Goswami Sangeeta , Msaouel Pavlos , Alhalabi Omar , Hahn Andrew Warren , Kovitz Craig A. , Jana Bagi RP , Araujo John C. , Gao Jianjun , Zurita Amado J. , Jonasch Eric , Corn Paul Gettys , Tannir Nizar M.
Published: March 2023

TPS745

Background: A SEER analysis from 2010 to 2013 demonstrated that the incidence of brain metastases(mets) at the diagnosis of renal cell carcinoma(RCC) is 1.51%, and around 12% of patients(pts) with advanced RCC (aRCC) also had mets to the brain. Brain mets confer a poor prognosis. Local management strategies for brain mets from RCC include surgical resection, stereotactic radiosurgery and whole brain radiation therapy. Although systemic therapies including tyrosine kinase inhibitors and immune checkpoint inhibitors have been explored in aRCC pts with brain mets, prospective data is lacking. Cabozantinib is a potent small molecule inhibitor of multiple tyrosine kinases that was approved by FDA for pts with aRCC alone or in combination with nivolumab. Cabozantinib has demonstrated activity in patients with intracranial tumors. A phase III trial (COSMIC-313) recently evaluated cabozantinib in combination with nivolumab and ipilimumab compared to nivolumab plus ipilimumab and demonstrated significantly improved progression-free survival (PFS) in previously untreated pts with aRCC. The combination was found to be safe as frontline systemic treatment. The role of this combination in patients with aRCC with brain mets remains undefined. As such, we propose a study to assess the safety and efficacy of cabozantinib in combination with nivolumab/ipilimumab in RCC pts with untreated brain mets. We believe the results from this trial could provide additional treatment options for pts with RCC brain mets who are typically excluded from clinical trials. Methods: This is a phase II study to assess the safety and efficacy of the combination of nivolumab with ipilimumab and cabozantinib in pts with untreated brain mets from RCC until disease progression or intolerable toxicities or patient withdrawal. Planned accrual is 40 pts. Pts will be treated with nivolumab (3mg/kg) and ipilimumab (1mg/kg) IV every 3 weeks for 4 doses and cabozantinib 40mg daily. Then pts will be treated with nivolumab 480mg IV Q 4 weeks and cabozantinib 40mg daily until progression or intolerable toxicities or patient’s withdrawal. A lead-in group of 6 pts will be closely monitored for dose limiting toxicities(DLT). If stopping criteria (>3 patients develop DLTs) is met, then treatment will be switched to nivolumab plus cabozantinib omitting ipilimumab. The primary objective is intracranial progression free survival(PFS). Secondary objectives include intracranial safety, objective response rate (intracranial + extracranial) by modified RECIST v1.1 and RECIST v1.1, extracranial PFS and overall survival. This phase II trial is currently enrolling pts. Clinical trial information: NCT05048212 .
Mortality in Acromegaly Diagnosed in Older Individuals in Spain Is Higher in Women Compared to the General Spanish Population
Authors: Biagetti Betina , Iglesias Pedro , Villar-Taibo Rocío , Moure María-Dolores , Paja Miguel , Araujo-Castro Marta , Ares Jessica , Álvarez-Escola Cristina , Vicente Almudena , Guivernau Èlia Álvarez , Novoa-Testa Iria , Perez Fernando Guerrero , Cámara Rosa , Lecumberri Beatriz , Gómez Carlos García , Bernabéu Ignacio , Manjón Laura , Gaztambide Sonia , Cordido Fernando , Webb Susan M , Menéndez-Torre Edelmiro Luis , Díez Juan J , Simó Rafael , Puig-Domingo Manel
Published: March 2023

Context

There are no data on mortality of acromegaly diagnosed in older individuals.

Objective

This work aimed to compare clinical characteristics, growth hormone–related comorbidities, therapeutic approaches, and mortality rate of patients diagnosed before or after 2010 and to assess overall mortality rate compared with the general Spanish population.

Methods

A retrospective evaluation was conducted among Spanish tertiary care centers of 118 patients diagnosed with acromegaly at age 65 or older. Kaplan-Meier curves were constructed to trace survival, and Cox proportional hazard models were used to assess the risk factors associated with mortality. We also compared mortality with that of the Spanish population by using age- and sex-adjusted standardized mortality ratios (SMRs).

Results

No differences were found in first-line treatment or biochemical control, between both periods except for faster biochemical control after 2010. Twenty-nine (24.6%) patients died, without differences between groups, and had a median of follow-up 8.6 years (103, [72.3] months). Overall SMR was 1.02 (95% CI, 0.57-1.54), (0.60; 95% CI, 0.35-1.06) for men and (1.80; 95% CI, 1.07-2.94) for women. The most common cause of death was cardiovascular disease (CVD).

Conclusion

The mortality in patients with acromegaly diagnosed in older individuals was no different between both periods, and there was no overall SMR difference compared with the general Spanish population. However, the SMR was higher in women. As CVD is the leading cause of mortality, it seems advisable to initiate an intense CVD protective treatment as soon as acromegaly is diagnosed, particularly in women, in addition to tight acromegaly control to prevent excess mortality.