bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase II trial of stereotactic ablative radiation (SAbR) for oligoprogressive kidney cancer.
Authors: Hannan Raquibul , Christensen Michael , Garant Aurelie , Hammers Hans J. , Arafat Waddah , Courtney Kevin Dale , Bowman Isaac Alex , Cole Suzanne , Sher David , Ahn Chul , Timmerman Robert D. , Brugarolas James 
Published: June 2021

4564 Background: Metastatic renal cell carcinoma (mRCC) patients on systemic therapy may experience oligoprogression. SAbR has been demonstrated to be safe and is associated with high local control rates in mRCC. In this prospective phase II single arm trial, we investigated SAbR to control oligoprogressive mRCC. Methods: Patients with mRCC who demonstrated response to systemic therapy with subsequent radiographic evidence of three or fewer sites of progression were treated with SAbR to all progressive sites. Systemic therapy was held during SAbR at the discretion of the treating oncologist. Follow-up included radiographic imaging at three-month intervals. Sequential SAbR for continued oligoprogression was allowed. The primary objective was extension of ongoing systemic therapy by >6 months in 40% of the patients. Progression was defined by any of these 3 criteria: (1) local failure at a radiated site; (2) progression ineligible for additional SAbR (>3 sites) or involving >30% of metastasis; or (3) progression as clinically determined by treating physicians. An exact binomial test was used to test the probability of postponing systemic therapy. Secondary endpoints focused on overall survival (OS), local control (LC) rates, toxicity, and health-related quality of life (QOL). Results: The trial completed accrual with enrollment of 20 patients who received SAbR to a total of 36 sites. At enrollment four, twelve, three, and one patients were on first, second, third, and fourth line of systemic therapy, respectively. Eleven were on immunotherapy and nine on a tyrosine-kinase inhibitor. Three patients required repeat SAbR to a new site for sequential disease control. At a median follow-up of 8.3 months (interquartile range 3.9 – 15.1), SAbR extended the duration of the ongoing systemic therapy by >6 months in 12 out of 17 patients (70.6%, 95% CI: 48.9%-92.3%). Thirteen out of 20 patients progressed with a median PFS of 8.7 months (95% CI: 3.2-12.4). Five patients died and the OS did not reach the median. LC was 36/36 (100%). Treatment related grade 1 and grade 2 toxicity was experienced by three and one patient, respectively; no grade 3 toxicities were reported. When compared to baseline, no significant decline in QOL was detected. Conclusions: SAbR extended PFS of ongoing systemic by >6 months in oligoprogressive patients with mRCC. SAbR was safe and did not adversely affect QOL. These data support further evaluation of SAbR for oligoproressive mRCC in a prospective randomized setting. Clinical trial information: NCT03696277.
Survival trends of men and women with metastatic clear cell renal cell carcinoma.
Authors: Grigg Claud , Trufan Sally , Clark Peter E , Riggs Stephen Boyd , Zhu Jason , Matulay Justin T. , Raghavan Derek , Burgess Earle F 
Published: June 2021

4566 Background: Clear cell renal cell carcinoma (ccRCC) is nearly twice as common in men as in women, and women with non-metastatic RCC have a better prognosis than men. The etiology for these disparities is not known, though sex-specific differences in risk factor prevalence and tumor biology have been reported. The differential impact of systemic therapies, including tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs), on prognosis in women and men with metastatic ccRCC is not defined. Methods: Clinicopathologic features and survival of patients with clinical stage IV ccRCC were obtained from the National Cancer Database (NCDB). Patients were grouped by date of metastatic diagnosis into three eras that correspond to major advances in systemic therapy: 2004-2005 (pre-TKI), 2006-2014 (TKI), and 2015-2016 (ICI). Uni- and multi-variable chi-square, logistic regression, and survival analyses were used for comparisons. Survival differences were assessed using Kaplan-Meier curves. Results: 15,025 male and 7,100 female patients with metastatic ccRCC were identified. Demographic features were similar between cohorts though females were slightly older (median 64.8 vs 62.7 mo, p < 0.0001), more likely to be black (6.5% vs 6.0%, p = 0.0119) or receiving Medicare benefits (46.4% vs 39.9%, p < 0.0001). In the combined cohort, median overall survival (OS) was higher in patients diagnosed in the ICI vs TKI (23.0 vs 16.5 mo) and pre-TKI eras (14.4 mo, log-rank p < 0.0001). Compared with men of the same age groups, OS was inferior for women age 50-64 yr (median 18.4 vs 21.1mo, p = 0.0084) and > 64 yr (15.3 vs 12.6mo, p = 0.0001), but not < 50 yr (20.3 vs 21.7mo, p = 0.6290). In the ICI era, median OS improved by a lesser absolute but similar relative amount for women compared to men (+5.6mo [+39%] and +7.2mo [+41%]), respectively). After controlling for age, race, Charlson-Deyo score, initial treatment modality, and insurance and socioeconomic status, women remained at increased risk of death in both the ICI era (HR 1.12 [95% CI 1.04-1.22], p = 0.004) and the TKI era (HR 1.08 [1.04-1.12], p < 0.001). Conclusions: Women with metastatic ccRCC have a worse prognosis than men which is not explained by demographic differences. This disparity is observed in both the TKI and ICI eras. This finding contrasts with previous studies suggesting women with localized RCC have a favorable prognosis compared with men. Further investigation into the sex-specific biology of metastatic ccRCC is warranted.
Surveillance after complete response in patients with metastatic non-seminomatous germ-cell tumor (NSGCT).
Authors: King Jennifer , Althouse Sandra K. , Cary Clint , Masterson Timothy A. , Foster Richard , Ashkar Ryan , Hanna Nasser H. , Einhorn Lawrence H. , Adra Nabil 
Published: June 2021

5018 Background: The optimal management of patients (pts) with complete response (CR) after first-line chemotherapy remains unsettled with guidelines recommending either surveillance or retroperitoneal LN dissection (RPLND). We present long-term outcomes from a large dataset of pts managed with surveillance after achieving CR to first-line chemotherapy. Methods: The prospectively maintained Indiana University testicular cancer database was queried for pts with metastatic NSGCT treated between 1990-2017 who achieved a CR after first-line chemotherapy. CR was defined as normalization of tumor markers (AFP+hCG) and no residual mass > 1cm. Kaplan-Meier methods were used to analyze progression-free survival (PFS) and overall survival (OS). Results: 388 pts met eligibility and were included in this analysis. Median age at diagnosis was 28.4 (range, 13-61.5). Primary site was testis in 385 pts (99%). Primary tumor predominant histology was embryonal ca (241), mixed (61), seminoma (31), yolk sac tumor (20), choriocarcinoma (10), and teratoma (14). 126 pts (32.5%) had teratoma in the primary tumor. Metastasis sites were retroperitoneum (295), mediastinal LN (15), pulmonary (149), liver (15), bone (7), and brain (6). IGCCCG risk was good in 325, intermediate in 25, and poor in 32 pts. Pre-chemotherapy retroperitoneal LN size was available in 232 pts: < 3cm in 170 and ≥3cm in 62. Median pre-chemo AFP was 10.7 (1-31,000) and hCG was 16.5 (0-595,930). First-line chemo was BEPx3 in 274, BEPx4 in 30, other regimens in 82 pts. With a median follow-up of 3.9 yrs, 34 pts (8.8%) progressed. At most recent follow-up, 363 (93.6%) pts were alive with no evidence of disease and 10 pts (2.6%) died of their disease. The estimated 2-yr PFS was 90.1% (95% CI: 86.2-93%) and 2-yr OS was 97.8% (95% CI: 95.2-99%). The estimated 2-yr PFS by IGCCCG risk category was 90.4% for good vs 90.4% for intermediate vs 86.5% for poor risk (p = 0.23), and the estimated 2-yr OS was 98.6% for good vs 95.5% for intermediate vs 92.9% for poor risk disease respectively (p = 0.002). For the 34 pts who progressed on surveillance, 16 (4%) progressed in the retroperitoneum only. 3 pts had malignant transformation of teratoma to PNET, adenocarcinoma, or other elements. 11 of progressed pts were treated with surgery, 12 were treated with salvage chemo, and 11 were treated with surgery+chemo. At most recent follow up, 21 of progressed pts had NED, 10 had died of disease, and 3 were lost to follow up. Conclusions: Pts with metastatic NSGCT who achieve CR after first-line chemotherapy can be safely observed with surveillance. Most pts who relapse can be salvaged with surgery and/or chemotherapy.
Evaluation of PSA progression after initiation of enzalutamide or abiraterone: Real-world data on metastatic castration-resistant prostate cancer (mCRPC).
Authors: López-Campos Fernando , Lorente David , Llacer Perez Casilda , Ramirez-Backhaus Miguel , Peleteiro Paula , Gomez-Iturriaga Alfonso , Henriquez-López Ivan , Lozano Rebeca , Romero Nuria , Alonso-Gordoa Teresa , Molina-Cerrillo Javier , Navarro-Castellón Joaquin , Castaño Ana , Pelari Lira , Hernández-Corrales Antonio , Morillo Virginia , García Raquel , Ferrer Albiach Carlos , Castro Elena , Olmos David 
Published: June 2021

5024 Background: PSA value is widely used for the monitoring of treatment outcome in mCRPC in the clinical real-world setting. Early PSA changes are not considered in the definition of PSAProg due to the potential for spurious “flare” reactions. We aimed to evaluate the significance of an early PSA increase in mCRPC patients (pts) treated with enzalutamide or abiraterone (Enz/Abi). Methods: We retrospectively evaluated Enz/Abi-treated mCRPC pts from 11 hospitals between 2011-2020. Early PSAProg was defined as a 25% increase in PSA from baseline at 4 (PSAProg4) or 8 (PSAProg8) weeks after treatment initiation. PSA progression at 12 weeks (PSAProg12) was confirmed by a second reading. Uni- and multivariable (MV) Cox regression models were conducted to explore the association of PSAProg and overall survival (OS) in chemotherapy naïve patients treated with Abi or Enz. Interaction tests were conducted to explore differences in the impact of PSA progression on OS in Abi or Enz-treated pts. Results: We analyzed 511 chemotherapy-naïve mCRPC pts treated with Abi (N=391; 76.5%) or Enz (N=120; 23.5%). Median follow-up: 30.2 months. OS was longer in Enz-treated pts (38.1 vs 29m; HR 1.4; p=0.027). 59 (15.1%), 70 (17.9%) and 48 (12.3%) of Abi-treated and 9 (7.5%), 11 (9.2%) and 10 (8.3%) of Enz-treated pts experienced PSAProg4, PSAProg8 and PSAProg12, respectively, although differences were not statistically significant. PSAProg was associated with worse OS at all 3 timepoints only in Abi-treated pts. In Enz-treated pts, PSAProg4 had a large impact on OS, not observed in PSAProg8 or PSAProg12. We observed no significant interaction between agent (Enz/Abi) and PSA progression (Table). Conclusions: PSA progression at 4 weeks after Enz/Abi is significantly associated with shorter OS and may help identify pts not benefitting from Abi/Enz before clinical or radiographic progression. PSA pattern progression and its association with OS might differ depending on the drug used (Enz/Abi). Prospective validation studies are needed.[Table: see text]
Cortisol as biomarker for CYP17 inhibition in mCRPC patients treated with abiraterone acetate.
Authors: Bruin Maaike , van Nuland Merel , Jacobs Bart , Bergman Andre M. , Rosing Hilde , Beijnen Jos H. , Huitema Alwin 
Published: June 2021

5035 Background: Abiraterone acetate is an effective metastatic castration resistant prostate cancer (mCRPC) treatment, however, there is a high variability in response. It inhibits CYP17, thereby preventing the production of androgens. Abiraterone trough concentrations (Cmin) > 8.4 ng/mL have been associated with an increased progression free survival (PFS) (Eur J Cancer. 2017;72:54-61; Prostate Cancer Prostatic Dis. 2020;23(2):244-251). However, plasma levels do not directly provide information on the level of CYP17 inhibition. Ideally, testosterone levels should be measured, but these levels are below the detection limit of available assays. The synthesis of cortisol is also inhibited by abiraterone via CYP17 inhibition and might therefore be a biomarker for CYP17 inhibition. The objective of this study was to investigate if cortisol levels are related to abiraterone levels and to clinical response. Methods: An observational study was performed in mCRPC patients treated with abiraterone acetate. At the outpatient clinic, plasma samples were collected for pharmacokinetic (PK) monitoring at each hospital visit. Reference populations of healthy volunteers and mCRPC patients using enzalutamide were included to investigate the influence of mCRPC and abiraterone treatment on the circadian rhythm of cortisol. Abiraterone and cortisol levels were measured using validated liquid chromatography-mass spectrometry (LC-MS/MS) assays. Clinical (prostate specific antigen (PSA) independent) PFS and PSA response were evaluated. Results: In total, 117 mCRPC patients using abiraterone acetate, 100 mCRPC patients using enzalutamide and 12 healthy volunteers were included. A clear circadian rhythm of cortisol was described in healthy volunteers and unaffected in mCRPC patients using enzalutamide. Contrarily, a circadian rhythm of cortisol could not be identified in mCRPC patients using abiraterone acetate, due to continuous suppression throughout the day. Patients with an abiraterone Cmin > 8.4 ng/mL (n = 77) had a median cortisol concentration of 1.03 ng/mL vs. 2.59 ng/mL in patients with an abiraterone Cmin ≤8.4 ng/mL (n = 40) (p = 0.020). The median cortisol concentration in PSA responders (n = 63) was 1.02 ng/mL vs. 2.59 ng/mL for PSA non responders (n = 54) (p = 0.037). Patients in the highest cortisol tertile ( > 3.03 ng/mL) had a median PFS of 3.7 months (n = 39) vs. 13.8 months in patients with cortisol levels ≤3.03 ng/mL (n = 78) (p = 0.007). The median PFS was 16.3 months in patients with an abiraterone Cmin > 8.4 ng/mL and cortisol concentration < 3.03 ng/ml vs. 5.3 months in patients with an abiraterone Cmin > 8.4 ng/mL and cortisol concentration > 3.03 ng/ml (p = 0.02). Conclusions: This study demonstrates that cortisol levels are of additional value to abiraterone concentrations as a marker for abiraterone acetate efficacy. This might help be helpful to assess efficacy of abiraterone treatment.
Differential responses to taxanes and PARP inhibitors (PARPi) in ATM- versus BRCA2-mutated metastatic castrate-resistant prostate cancer (mCRPC) patients (pts).
Authors: Su Christopher T , Nizialek Emily , Berchuck Jacob E , Vlachostergios Panagiotis J. , Ashkar Ryan , Sokolova Alexandra , Barata Pedro C. , Aggarwal Rahul Raj , McClure Heather , Nafissi Nellie , Bryce Alan Haruo , Sartor A. Oliver , Cheng Heather H. , Adra Nabil , Sternberg Cora N. , Taplin Mary-Ellen , Cieslik Marcin , Antonarakis Emmanuel S. , Alva Ajjai Shivaram 
Published: June 2021

5040 Background: PARPi have shown promise in mCRPC pts with mutations in DNA repair, but ATM- and BRCA2-altered pts may respond differently to PARPi. We hypothesized that differences may also exist for taxane therapy, aiding in treatment sequencing decisions. Methods: mCRPC pts (N = 137) with deleterious ATM or BRCA2 mutations who received taxanes, PARPi, or both were identified from 8 US academic centers. Demographic, treatment, and survival data were collected. Kaplan-Meier analyses were performed for time-to-treatment-discontinuation (TTD), as well as overall survival (OS), from time of first taxane or PARPi therapy. Cox hazard ratio (HR) regression analyses were performed, adjusting for Gleason sum (≤7 vs. 8-10). For OS, receipt of subsequent therapies following first taxane or PARPi was also included as a covariate. Results: 50 ATM- and 87 BRCA2-mutated pts were identified. 40/50 (80%) of ATM-mutated pts received taxane only or taxane prior to PARPi, while 10/50 (20%) received PARPi only or PARPi prior to taxane. ATM-mutated pts showed a trend towards longer TTD when taxane was given first vs PARPi given first (P = 0.08, adjusted HR for taxane treatment 0.50 [95% CI: 0.24–1.08]). Considering all pts who received taxane first, ATM-mutated pts had longer TTD than BRCA2-mutated pts who received taxane first ( P= 0.04, adjusted HR for ATM 0.61 [CI: 0.37–0.99]). Among ATM-mutated pts, OS was longer in those receiving taxane first ( P= 0.06, adjusted HR for taxane treatment 0.33 [CI: 0.10–1.05]). Among BRCA2-mutated pts, 43/87 (49%) received taxane first and 44/87 (51%) received PARPi first. BRCA2-mutated pts had longer TTD when PARPi was given first vs taxane given first ( P< 0.0001, adjusted HR for PARPi treatment 0.32 [CI: 0.19–0.56]). Considering all pts who received PARPi first, BRCA2-mutated pts also had longer TTD than ATM-mutated pts who received PARPi first ( P= 0.0031, adjusted HR for BRCA2 0.29 [CI: 0.12–0.66]). There was no significant OS difference in BRCA2-mutated pts regarding which treatment was given first ( P= 0.63, adjusted HR for PARPi treatment 1.18 [CI: 0.59–2.35]). Conclusions: Our data in ATM- and BRCA2-mutated mCRPC pts suggests a trend towards improved clinical outcomes when taxanes are used prior to PARPi in ATM-mutated pts, while the reverse sequence appears to be better for BRCA2-mutated pts.[Table: see text]
Differences in the tumor genomic landscape between African Americans (AA) and Caucasians (CA) advanced prostate cancer (aPC) patients (pts) by comprehensive genomic profiling (CGP) of cell-free DNA (cfDNA).
Authors: Barata Pedro C. , Reisinger Raquel , Bilen Mehmet Asim , Heath Elisabeth I. , Nandagopal Lakshminarayanan , Swami Umang , Kessel Adam , Jaeger Ellen , Wesolowski Sergiusz , Chipman Jonathan , Mack Alleda , Ravindranathan Deepak , Maughan Benjamin L. , Nussenzveig Roberto , Yandell Mark , Kohli Manish , Lilly Michael B. , Sartor A. Oliver , Agarwal Neeraj 
Published: June 2021

5058 Background: Emerging data suggest differences in the tumor genomic profile of AA compared with CA men with aPC. We hypothesized that there will be significant differences in the tumor genomic landscape between AA and Ca pts as detected by cfDNA CGP. Methods: Pts with aPC and available cfDNA CGP by the Guardant (G360) 73 gene panel were included. In addition, G360 74 gene panel was used to identify CDK12 mutation (not detected in 73 gene panel) in an independent cohort of aPC pts. Barnard’s test was used to evaluate the association between genetic mutation and gene. Genomic landscape was also compared by a Bayesian Network (BN) machine learning approach. Results: A total of 552 pts (125 AA, 427 CA) tested by G360 73 gene panel were included. Multiple genomic aberrations were enriched in AA patients (Table). In the independent cohort of 261 aPC patients (AA=106 pts, CA=155 pts) tested by G360 74 gene panel, CDK12 mutation was significant enriched in AA pts. (9.4% vs. 1.9%, p=0.006). Machine learning analysis supported these results, and will be presented at the meeting. Conclusions: These hypothesis generating data suggest significant differences in the tumor genomic profile between AA and CA pts with aPC. Identification of molecular drivers of tumor progression enriched in AA pts may allow development of tailored systemic therapy for these men, and decrease disparities in disease related outcomes. Data need external validation. PB,RR,MAB contributed equally to this work.[Table: see text]
Impact of age on efficacy and safety of relugolix: A subgroup analysis from the randomized, phase 3 hero study versus leuprolide in men with advanced prostate cancer.
Authors: Cookson Michael , Shore Neal D. , George Daniel J. , Akaza Hideyuki , Saltzstein Daniel , Tutrone Ronald F. , Bossi Alberto , Brown Bruce , Selby Bryan , Lu Sophia , Walling Jacqueline M. , TOMBAL Bertrand F. , Saad Fred 
Published: June 2021

5075 Background: In the phase 3 HERO study, the oral GnRH receptor antagonist relugolix demonstrated sustained testosterone suppression superior to that of leuprolide and a comparative 54% decrease in risk of major adverse cardiovascular events. Relugolix was recently approved for use in the US for the treatment of adult patients with advanced prostate cancer. Here, we further characterize the impact of age on the use of relugolix in advanced prostate cancer from the HERO study. Methods: The HERO study was a randomized, open-label, parallel group study evaluating relugolix in men with advanced prostate cancer. Overall, 934 men with advanced prostate cancer underwent 2:1 randomization to receive relugolix 120 mg orally once daily after a single loading dose of 360 mg or leuprolide 3-month injections for 48 weeks. Subgroups analyzed by age were <65 years or ≥65 years and ≤75 years or >75 years. Assessments analyzed included sustained testosterone suppression to castrate levels (<50 ng/dL) from day 29 through 48 weeks, early and profound (<20 ng/dL) castration rates, prostate-specific antigen (PSA) levels, and safety. Testosterone recovery (≥280 ng/dL) was evaluated in 184 patients who enrolled in the testosterone recovery substudy. Results: Of the 930 patients (relugolix:622;leuprolide:308) that received study drug in the HERO study, 173 (18.6%) were <65 years and 757 (81.4%) were ≥65 years of age, while 664 (71.4%) were ≤75 years and 266 (28.6%) were >75 years of age. Across all age subgroups, point estimates for sustained castration rates through 48 weeks for relugolix patients were consistent with the overall estimate of relugolix sustained castration rate observed in the overall population. Differences in sustained castrations rates at week 48 between relugolix and leuprolide groups were similar regardless of the age subgroup (table). The likelihood of testosterone recovery at 90 days after completion of treatment was higher in the relugolix group versus the leuprolide group in all age subgroups: <65 (79.1% vs 16.7%), ≥65 (48.6% vs 0%), ≤75 (60.0% vs 4.0%),and >75 years (40.7% vs 0%). No clinically relevant differences were noted in the incidence or types of adverse events within treatment groups in all the age subgroups analyzed. Conclusions: In this subgroup analysis of the HERO study, relugolix was effective regardless of age, and the benefit/risk profile remained favorable for relugolix compared with leuprolide, consistent with the overall population. Testosterone recovery was higher in the relugolix group than the leuprolide group for all age subgroups analyzed, with higher rates of recovery in younger versus older men. Clinical trial information: NCT03085095. [Table: see text]