tbuckley/cabot-search huggingface dataset:
Management of progressive brain metastases in patients (pts) with relapsed germ-cell tumor (GCT) treated with salvage high-dose chemotherapy (HDCT).
Authors: Jennifer King, Rafat Abonour, Rebecca Hassoun, Sandra K. Althouse, Tareq Salous, Nasser H. Hanna, Lawrence H. Einhorn, Nabil Adra
Journal: Journal of Clinical Oncology (2024)

5036 Background: Previous data confirm that pts with relapsed GCT and progressive brain metastases (mets) can be cured with HDCT and peripheral blood stem cell transplantation (PBSCT) 1 . Still, there is uncertainty with the optimal management sequence of these pts prior to transplant. Here, we describe the management and outcomes of a larger cohort of these pts. Methods: The prospectively maintained Indiana University testicular cancer database was queried for pts with relapsed metastatic GCT who were to undergo HDCT with PBSCT and were noted to have progressive brain mets at time of relapse. Baseline characteristics were summarized. The Kaplan-Meier method was used to analyze progression free survival (PFS) and overall survival (OS). Results: 49 pts met eligibility. Median age was 28.7yrs (16.6-51.5). Primary site was testis in 44 (90.0%), mediastinal in 4 (8.2%), and retroperitoneum in 1 (2.0%). All patients had nonseminomatous disease. Primary tumor predominant histology was choriocarcinoma (34.7%), embryonal (32.7%), mixed (18.4%), teratoma (6.1%), yolk sac tumor (4.1%), and seminoma (2.0%). IGCCCG risk at diagnosis was poor in 91.8%, intermediate in 2.1%, and good in 6.1%. 24 pts (49%) were platinum refractory at HDCT. 17 pts (34.7%) had brain mets at diagnosis; the rest developed at relapse. The table lists pt characteristics. 26 pts (53.1%) went straight to HDCT without localized treatment to progressive brain mets. 8 (16.3%) underwent craniotomy and 8 (16.3%) had radiation prior to HDCT. 3 of the pts who had radiation had stereotactic radiosurgery (SRS); 5 had whole brain radiotherapy (WBRT). 7 pts (14.3%) underwent craniotomy then radiation prior to HDCT. 5 pts (15.2%) were symptomatic from progressing brain mets at HDCT. 1 of these had mild visual symptoms and went straight to HDCT. 1 pt began having headaches the day before HDCT and given proximity to initiation, HDCT was continued. The other 3 symptomatic pts had previously failed localized treatment for brain mets. 22 pts (44.9%) progressed after HDCT. At a median follow-up of 3.8 yrs (0.6-14.8), 16 pts (32.7%) were alive with no evidence of disease, 10 (20.4%) were alive with disease, 20 (40.8%) died of disease, and 3 (6.1%) died of other causes. 2-yr PFS was 43.9%; 2-yr OS was 73.2%. Conclusions: Pts with relapsed GCT with progressive brain mets can be cured with HDCT with PBSCT. Management of progressive brain mets should be individualized for each pt, taking into account extent of brain mets and presence of symptoms. Reference: 1. Kalra M, et al. Cancer.2020; 126(6): 1202-1207.[Table: see text]
Patient-reported outcomes (PROs) for rezvilutamide versus bicalutamide in combination with androgen-deprivation therapy (ADT) in high-volume, metastatic, hormone-sensitive prostate cancer (mHSPC): An analysis of the CHART randomized, open-label, phase 3 trial.
Authors: Ding-Wei Ye, Shusuan Jiang, Hong Luo, Fangjian Zhou, Dalin He, Lulin Ma, Hongqian Guo, Chaozhao Liang, Tie Chong, Jun Jiang, Zhiwen Chen, Yong Wang, Qing Zou, Ye Tian, Jun Xiao, Jian Huang, Jinchao Chen, Xinfeng Yang, Jianpo Lian, Wenliang Wang
Journal: Journal of Clinical Oncology (2024)

5048 Background: In the CHART trial, rezvilutamide plus ADT significantly improved radiographic PFS and OS compared with bicalutamide plus ADT in patients with high-volume mHSPC (Gu et al., Lancet Oncol 2022). Here, we report the PRO results from the CHART trial. Methods: Eligible patients were men ≥18 years old with high-volume mHSPC and without previous chemotherapy or other localized treatment for prostate cancer. Patients were randomly assigned (1:1) to receive ADT plus either rezvilutamide (240 mg) or bicalutamide (50 mg) orally once daily. PROs were exploratory endpoints and were assessed in all randomized patients by using the Brief Pain Inventory-Short Form (BPI-SF) and Functional Assessment of Cancer Therapy-Prostate (FACT-P). PROs were collected within 7 days prior to the first dose, on Day 1 of each cycle (28 days) in Cycles 2–12, once every 2 cycles in Cycles 13–36, once every 4 cycles afterwards, and on Day 30 after the last dose. Results: Between Jun 28, 2018, and Aug 6, 2020, a total of 654 patients were randomly assigned to receive either rezvilutamide plus ADT (n=326) or bicalutamide plus ADT (n=328). The data cutoff for this PRO analysis was Feb 28, 2022, and the median follow-up was 29.3 months (IQR 21.0–33.3). Baseline pain scores and functional status scores were comparable between the two study groups. The median time to progression of pain (both intensity and interference) was not reached in either group. The 25th percentile for the time to average pain progression was 25.8 months (95% CI 14.8–31.4) in the rezvilutamide plus ADT group and 11.7 months (95% CI 8.7–22.1) in the bicalutamide plus ADT group (HR 0.79, 95% CI 0.58–1.08; p=0.133). Patients in the rezvilutamide group exhibited a longer time to pain interference progression compared to the bicalutamide group (25th percentile, 20.2 months [95% CI 12.9–31.3] vs 10.2 months [95% CI 7.4–11.1]; HR 0.70 [95% CI 0.52–0.93]; p=0.015). Regarding functional status, the time to deterioration of the FACT-P total score was prolonged in the rezvilutamide plus ADT group compared to the bicalutamide plus ADT group (25th percentile, 12.8 months [95% CI 7.4–20.3] vs 6.0 months [95% CI 4.6–9.2]; HR 0.66, 95% CI 0.50–0.86; p=0.002). Additionally, the rezvilutamide plus ADT group exhibited delayed deterioration in all FACT-P subscale scores compared to the bicalutamide plus ADT group. Conclusions: Rezvilutamide plus ADT demonstrated superiority over bicalutamide plus ADT in delaying pain progression and functional status deterioration in high-volume mHSPC. Clinical trial information: NCT03520478 .
Clinical utility of transcriptomic signatures to identify androgen receptor and neuroendocrine signaling in prostate cancer.
Authors: Yu-Wei Chen, Joanne Xiu, Kelsey Anne Poorman, Charles J. Ryan, Brady Gilg, Matthew James Oberley, George W. Sledge, Himisha Beltran, Rana R. McKay
Journal: Journal of Clinical Oncology (2024)

5015 Background: Neuroendocrine prostate cancer (NEPC) is a relatively androgen receptor (AR)-independent and aggressive variant of PC that can arise from adenocarcinoma with varied degrees of adenocarcinoma and high-grade neuroendocrine histologic features seen during its progression. This study evaluated the clinical and molecular features of histologic subtypes of prostate tumors (adenocarcinoma, NEPC, mixed adeno-NE) based on previously validated AR signaling and NEPC transcriptomic signatures of PC. Methods: Whole exome (WES) and whole transcriptome sequencing (WTS) were performed on PC tumors. Molecular subsets were defined by AR signaling signature [AR score positive (+) vs negative (-)] and NEPC gene signature [NE score positive (+) vs negative (-)]. The prevalence of key molecular alterations (RB1, TP53, PTEN, AR, FANC, SLFN11 expression) were investigated. Genes encoding cell surface antigens with potential therapeutic implications were described across signature groups. Overall survival (OS) was obtained from claims data and analyzed with Kaplan-Meier estimator. Results: A total of 4,476 prostate tumors were analyzed in this study including: 3,623 prostate adenocarcinoma, 56 NEPC, and 25 tumors with mixed adeno-NE. Tissue from 2,641 (67%) tumors were collected from prostate and 1,326 (33%) were metastatic tumors [lymph node (14%), bone (9%), liver (7%), lung (2%), CNS (2%)]. The four AR/NEPC signature-defined subtypes were AR+/NE+ (N=649, 14%), AR+/NE- (N=1614, 36%), AR-/NE+ (N=875, 20%), and AR-/NE- (N=1358, 30%). AR+/NE- was most common in prostate (39%), LN (42%) and lung metastasis (35%); AR-/NE+ was most common in bone (34%) and liver metastasis (43%); AR-/NE- was most common in CNS metastasis. The most common gene alterations in each molecular subtype are defined in Table. AR-/NE+ tumors had the lowest mRNA expression of FOLH1(PSMA), STEAP1, TACSTD2 (Trop-2), CD276 (B7-H3), and PSCA among the four groups. DLL3 expression was higher among NE+ subtypes. FOLH1 and PSCA expression were higher among NE- subtypes. The median OS (months) was longer in NE- than NE+ subtypes [AR+/NE- (78.3), AR-/NE- (78.7) vs AR+/NE+ (70.7), AR-/NE+ (69.1)]. In the platinum-treated subgroup (N=146), the median OS was numerically longer among tumors with SLFN11 overexpression (17.6 vs 12.0) although this was not statistically significant (p-value: 0.99). Conclusions: Molecularly distinct subtypes of PC can be further characterized by AR signaling signature, NEPC gene expression signature, and co-occurring molecular alterations. The phase II biomarker-driven PREDICT trial will integrate the above signatures/molecular alterations to allocate treatment regimens in metastatic castration-resistant PC. [Table: see text]
Health-related quality of life (HRQOL) results from PRESTO (AFT-19), a phase 3 randomized trial of intensification of androgen blockade in patients with high-risk biochemically relapsed castration sensitive prostate cancer.
Authors: Ronald C. Chen, Gina L. Mazza, Briant Fruth, Han Xiao, Joel Picus, Mary Ellen Taplin, Tanya B. Dorff, Leonard Joseph Appleman, Douglas Jay Weckstein, Akash Patnaik, Alan Haruo Bryce, Daniel Shevrin, James L. Mohler, Daniel M. Anderson, Arpit Rao, Alan Tan, Charles J. Ryan, Scott Eggener, Michael J. Morris, Rahul Raj Aggarwal
Journal: Journal of Clinical Oncology (2024)

5006 Background: The PRESTO trial (NCT03009981) showed that in patients with biochemically relapsed prostate cancer following radical prostatectomy with a PSA doubling time of ≤ 9 months and without evidence of metastatic disease by conventional imaging, intensified androgen receptor blockade for 52 weeks (androgen deprivation therapy [ADT] plus apalutamide [Apa], or ADT plus Apa and abiraterone acetate [Abi] plus prednisone) prolonged PSA progression-free survival compared to ADT alone (Aggarwal et al, JCO 2024). Here we report the HRQOL results. Methods: HRQOL measures included the Hot Flash Related Daily Interference Scale (HFRDIS), Expanded Prostate Cancer Index Composite (EPIC)-26 Sexual domain, PROMIS Fatigue Short Form and EQ-5D-5L, which assesses overall HRQOL in the 504 randomized patients. Published minimally important difference thresholds for these HRQOL measures are: HFRDIS 1.66 points, EPIC Sexual 10-12, PROMIS Fatigue 3-5, and EQ-5D-5L 0.06. General linear mixed modeling was used to estimate between-arm mean differences in HRQOL according to an intent-to-treat approach. Results: Mean changes from baseline to end of treatment (EOT) for each arm and for each HRQOL measure are summarized in Table. No statistically significant mean difference was reported between intensified androgen receptor blockade (Arm B, Arm C) vs ADT alone (Arm A) in any HRQOL measure. Further, numerical differences across arms for all HRQOL measures are below published minimally clinically important difference thresholds. Conclusions: Intensified androgen receptor blockade with Apa or Apa/Abi added to 52 weeks of ADT improves PSA progression-free survival without negatively affecting HRQOL. These HRQOL results add further support to intensification of androgen blockade in patients with high-risk biochemically recurrent prostate cancer. Clinical trial information: NCT03009981 . [Table: see text]
Comparison of outcomes with docetaxel or ARPI combination therapy for metastatic hormone-sensitive prostate cancer (mHSPC) by volume of disease.
Authors: Martin W. Schoen, Ruth Douglas Etzioni, Suhong Luo, Danielle Candelieri, Nicholas Fedele, Priya Baxi, Carley Pickett, Forest Riekhof, Kara Ingram, Krishny Karunanandaa, Srinivas Govindan, Nina Cheranda, Eric Marshall Knoche, Robert Bruce Montgomery
Journal: Journal of Clinical Oncology (2024)

5092 Background: Combination therapy has improved treatment of metastatic hormone sensitive prostate cancer (mHSPC). Doublets include androgen deprivation therapy (ADT) plus docetaxel (DOC) or the androgen receptor pathway inhibitors (ARPIs) abiraterone, enzalutamide, apalutamide, or darolutamide. There have been no large clinical trials that compare DOC to ARPIs in mHSPC. This study evaluates overall survival and time to castration-resistance in patients with de novo (synchronous) mHSPC in the Veterans Health Administration treated with combination therapy. Methods: Veterans were identified with initial diagnosis of ‘distant’ prostate cancer. All veterans had ADT initiated within 4 months of diagnosis and followed until September 2023. First combination therapy with DOC from 7/2016-6/2021 or ARPI from 7/2017-6/2021 were included if initiated within 4 months after ADT. Volume of disease was determined from chart review and castration-resistance (mCRPC) by a combination of natural language processing and administrative data. Real-world progression-free survival (rwPFS) was determined as time to mCRPC or death. Kaplan-Meier time to event analyses and Cox proportional hazard modeling with age, Black race, Charlson comorbidity index, prostate specific antigen, body mass index, and weight change in the year prior was used for analyses. Results: 1,226 patients with de novo mHSPC were identified with median age of 71.5 years and 349 (28.6%) were Black. High volume disease was identified in 929 (76.0%) and low volume in 293 (24.0%). DOC was used in 341 (27.9%) and ARPIs in 881 (72.1%). Veterans with high volume disease had shorter overall survival (OS) than low volume (23.8 vs. 64.1 months, p&lt;0.001). Overall, there was no difference in OS between DOC and ARPI (36.4 vs. 38.9 months, p=0.68), however DOC was associated with a shorter rwPFS (16.5 vs 22.1 months, p&lt;0.001). In high volume disease, there was no difference in OS between DOC and ARPI (33.8 vs. 32.5 months, p=0.68), however DOC was associated with a shorter rwPFS (14.9 vs 19.2 months, p=0.002). In a multivariable model of patients with high volume disease, there was no difference in OS observed between initial treatment with DOC and ARPIs (aHR 0.83, 95% CI 0.69-1.00). Conclusions: In veterans with de novo mHSPC, no difference in OS were observed between combination treatment with DOC or ARPI in patients with low or high-volume mHSPC. ARPIs were associated with longer progression free survival. Due to a lack of clinical trials comparing DOC and ARPI therapy, these data may guide selection of combination therapy for mHSPC.[Table: see text]
Efficacy of first line (1L) poly ADP-ribose polymerase inhibitors (PARPi) in combination with androgen pathway inhibitors (API) by homologous recombination repair (HRR) genes in metastatic castration-resistant prostate cancer (mCRPC): A living meta-analysis.
Authors: Arifa Bibi, Syed Arsalan Ahmed Naqvi, Muhammad Ali Khan, Ammad Raina, Kaneez Zahra Rubab Khakwani, Jacob Orme, Daniel S Childs, Adam McLain Kase, Sylvan C. Baca, Oliver Sartor, Parminder Singh, Alan Haruo Bryce, Irbaz Bin Riaz
Journal: Journal of Clinical Oncology (2024)

e17059 Background: It is unclear if patients with different HRR gene-mutated mCRPC derive consistent benefit from treatment with PARPi and API combination. Approval labels for PARPi+API are inconsistent across regulatory bodies in the US (Food and Drug Administration, FDA) and Europe (European Medical Agency, EMA), adding to confusion among practicing clinicians. Therefore, we aimed to assess the differential efficacy of PARP+API therapy by different genes using up-to-date trial evidence. Methods: We maintain a living meta-analysis on mCRPC treatments that is updated when new data becomes available. Here, we report data from phase III randomized control trials (RCTs) assessing PARPi+API in 1L mCRPC. The outcomes of interest included radiographic progression-free survival (rPFS) and overall survival (OS). Hazard ratios (HR) for rPFS and OS by different genes were summarized using random effects meta-analysis via inverse variance approach. Results: We have screened 27376 references since the inception of this living review. Here, we report data from three trials (15 references) with a total of 1618 patients. Frequently reported HRR gene mutations in the included trials were BRCA2 (35%), ATM (21%), CDK12 (12.2%), CHEK2 (12.2%), BRCA1 (4.6%), and PALB2 (3.4%). In terms of rPFS, statistical benefit was observed in BRCA (0.28; 95% CI: 0.13-0.59) and CDK12 (0.58; 95% CI: 0.35-0.95) subgroups, whereas no statistically significant benefit was seen in PALB2 (0.53; 95% CI: 0.21-1.32), ATM (0.93; 95% CI, 0.57-1.53), and CHEK2 (0.92; 95% CI: 0.53-1.61) subgroups. For OS, benefit was observed in BRCA (0.47; 95%CI: 0.31-0.71) subgroup. While not statistically significant, a signal of meaningful OS benefit was observed in PALB2 (0.33; 95%CI: 0.10-1.16) but no OS benefit was observed in ATM (0.97; 95% CI: 0.57-1.67), CDK12 (0.80; 95% CI: 0.36-1.78), and CHEK2 (0.81; 95% CI: 0.37-1.75) subgroups. Conclusions: Current results show that mCRPC patients with BRCA and CDK12 alterations had delayed disease progression with PARPi+API as 1L therapy. BRCA mutations are also associated with improved OS, while patients with CHEK2 and ATM derived no significant benefit with PARPi+API combination. [Table: see text]
The Emerging Field of Cardioimmunology: Past, Present and Foreseeable Future
Authors: Douglas L. Mann
Journal: Circulation Research (2024)

Over the past 30 years, the field of cardioimmunology has moved from being dismissed as a field that was chasing an epiphenomenon of little biological consequence to a scientific discipline that is providing important new insights into the immunologic basis for hypertension, atherosclerosis, myocarditis, pericarditis, autoimmune heart disease, and heart failure. In this article, we will review the conceptual insights and technical breakthroughs that have allowed the field to move forward, as well as the clinical trials in the cardioimmunology space, to provide a historical context for the articles that will appear in the compendium that is focused on the interface between cardioimmunology, myocardial function, and disease.
Interim analysis of clinical data and reasons for initiating relugolix on a cohort of US patients: The OPTYX study.
Authors: Daniel Eidelberg Spratt, Rana R. McKay, Ashley Ross, Benjamin H Lowentritt, Scott C Flanders, Yajun Emily Zhu, Susana Nolley, Agnes Hong, Sergio C Gatoulis, Tanya B. Dorff
Journal: Journal of Clinical Oncology (2024)

e17072 Background: Relugolix is an oral GnRH receptor antagonist indicated for advanced prostate cancer treatment. The OPTYX study is prospectively collecting clinical and patient outcomes data from US patients initiating relugolix in routine care settings to evaluate the long-term outcomes of relugolix therapy. An interim analysis of key baseline variables, reasons for starting relugolix therapy and treatment patterns is presented. Methods: The multi-center observational OPTYX study aims to enroll 1,000 patients with prostate cancer starting relugolix therapy. The current study population includes diverse disease states, treatment circumstances (eg, monotherapy, combination therapy, or intermittent therapy) and clinical settings representative of real-world patterns of care. Baseline demographics, clinical characteristics, reasons for initiating treatment, and treatment patterns from Oct 2022 to Oct 2023 are described. Results: As of October 2023, 394 men were enrolled in the OPTYX study and received relugolix with a median treatment duration of 114 days. The median age was 71 years; 78.7% of patients self-reported as White, 14.2% as Black. Enrollment occurred through Urology, Oncology and Radiation Oncology practices. Most patients (61.2%) had baseline PSA &lt;20 ng/ml. Mean (SD) baseline testosterone was 317.7 (238.5) ng/dL. At baseline, 15.2% of patients had received prior radiotherapy and 20.0% had prior androgen deprivation therapy. Known distant metastases were found in 24.6% of patients. A total of 135 patients (34.3%) received relugolix in combination with other therapies (Table). Top 3 reasons physicians prescribed relugolix were oral instead of injection (40.6%), rapid testosterone suppression (37.6%) and safety (25.1%), while patient reasons were physician recommendation (74.6%), oral instead of injection (35.5%) and safety (8.9%). In 10.7% of patients who discontinued therapy for any reason, 3.3% completed the planned regimen while 3.6% discontinued due to adverse events. No new serious safety signals have been identified. Conclusions: The OPYTX study is evaluating real-world experience with relugolix, including diverse disease states, practice settings and physician specialties. More than a third of patients and physicians favored oral versus injectable formulation, and more than a third used relugolix in combination with other therapies. There was low unplanned discontinuation of relugolix at data cut-off. Clinical trial information: NCT05467176 . [Table: see text]
Health-related quality of life and pain in a phase 3 study of [<sup>177</sup>Lu]Lu-PSMA-617 in taxane-naïve patients with metastatic castration-resistant prostate cancer (PSMAfore).
Authors: Karim Fizazi, Michael J. Morris, Neal D. Shore, Kim N. Chi, Michael Crosby, Johann S. De Bono, Ken Herrmann, Guilhem Roubaud, James Nagarajah, Mark T. Fleming, Brian E. Lewis, Luke Nordquist, Daniel Castellano, Natalie Carnahan, Samson Ghebremariam, Marianna Hertelendi, Oliver Sartor
Journal: Journal of Clinical Oncology (2024)

5003 Background: [ 177 Lu]Lu-PSMA-617 ( 177 Lu-PSMA-617) prolonged radiographic progression-free survival vs change of androgen receptor pathway inhibitor (ARPI) in taxane-naïve patients with metastatic castration-resistant prostate cancer (mCRPC) in PSMAfore (NCT04689828). We now present health-related quality of life (HRQoL) and pain outcomes at second interim analysis. Methods: Eligible patients had mCRPC, were candidates for change of ARPI after progression on one prior ARPI, and had ≥1 PSMA-positive and no exclusionary PSMA-negative metastatic lesions by [ 68 Ga]Ga-PSMA-11 PET/CT. Ineligible patients were candidates for PARP inhibition or had received prior systemic radiotherapy, immunotherapy or chemotherapy. Patients were randomized 1:1 to open-label 177 Lu-PSMA-617 (7.4 GBq/6 weeks; 6 cycles) or ARPI change (abiraterone/enzalutamide). Patients with confirmed radiographic progression on ARPI change could cross over to 177 Lu-PSMA-617. Secondary endpoints included time to worsening (TTW) in self-reported HRQoL (FACT-P, EQ-5D-5L) and pain (BPI-SF), defined as a composite of score worsening (prespecified thresholds), clinical progression (including new anti-cancer treatment) or death. Post hoc analyses of TTW in FACT-P and BPI-SF excluded clinical progression and death. The study was not powered for these endpoints and type I error was not controlled. Results: We randomized 468 patients (234/arm) with a median age of 72 years (range, 43–94). Median duration of exposure was 8.4 months for 177 Lu-PSMA-617 and 6.5 months for ARPI change. 177 Lu-PSMA-617 delayed TTW in FACT-P, EQ-5D-5L and BPI-SF scales and subscales vs ARPI change (Table). Results were similar in non-composite analyses. Incidence of grade ≥3 adverse events (AEs), serious AEs and AEs leading to discontinuation for 177 Lu-PSMA-617 and ARPI change were 34% vs 44%, 20% vs 28% and 5.7% vs 5.2%, respectively. Conclusions: 177 Lu-PSMA-617 delayed TTW in self-reported pain and HRQoL vs change of ARPI in taxane-naïve patients with PSMA-positive mCRPC. Clinical trial information: NCT04689828 . [Table: see text]