bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase II, double-blind, randomized study of salvage radiation therapy (SRT) plus enzalutamide or placebo for high-risk PSA-recurrent prostate cancer after radical prostatectomy: The SALV-ENZA Trial.
Authors: Tran Phuoc T. , Lowe Kathryn , Wang Hao , Tsai Hua-Ling , Song Daniel Y. , Hung Arthur , Hearn Jason W.D. , Lotan Tamara L. , Paller Channing Judith , Markowski Mark Christopher , Denmeade Samuel R. , Carducci Michael Anthony , Eisenberger Mario A. , Orton Matthew , Deville Curtiland , Liauw Stanley L. , Heath Elisabeth I. , Desai Neil B , Beer Tomasz M. , Antonarakis Emmanuel S. 
Published: June 2022

5012 Background: We sought to investigate whether enzalutamide (ENZA) treatment, without androgen deprivation therapy, increases freedom-from-PSA-progression (FFPP) when combined with salvage radiation therapy (SRT) in men with recurrent prostate cancer post-radical prostatectomy (RP). Methods: Men with biochemically recurrent prostate cancer after RP were enrolled into a randomized, double-blind, phase II, placebo-controlled, multicenter study of SRT + placebo vs SRT + ENZA. The randomization (1:1) was stratified by center, surgical margin status (R0 vs R1), PSA prior to salvage treatment (PSA ≥0.5 vs < 0.5 ng/mL), and pathologic Gleason sum (7 vs 8-10) using a minimization algorithm. Following randomization, patients received either placebo or ENZA 160 mg PO once daily for 6 months. Following 2 months of study drug therapy, external beam radiotherapy to 66.6-70.2 Gy was administered to the prostate bed (no pelvic nodes). The primary endpoint was FFPP. The trial design was powered for a HR 0.44 FFPP benefit with intended enrollment of 96 subjects and was closed as planned to enrollment on March 2020 short of that goal. Secondary endpoints were time to local recurrence (LR) within the radiation field, metastasis‐free survival (MFS), and safety as determined by frequency and severity of adverse events (AEs). Results: A total of 86 patients were randomized with a median follow-up of 34 (range 0-52) months. The median pre-SRT PSA was 0.3 (range 0.06-4.6) ng/mL, 56/86 (65%) had extra-prostatic disease (pT3), 39/86 (45%) had Gleason Grade Group 4 or higher and 43/96 (50%) had positive surgical margins. Trial arms were well balanced. FFPP was significantly improved with ENZA vs placebo, for example 2-year FFPP was 87.1% vs 68.1%, respectively, and overall with a HR 0.40 [95% confidence interval (CI), 0.17-0.92, p-value = 0.026]. Subgroup analyses demonstrate differential benefit (p-value of interaction = 0.031) of ENZA in men with pT3 (HR 0.19, 95%CI 0.05-0.67) vs pT2 disease (HR 1.29, 95%CI 0.34-4.81). There were insufficient secondary endpoint events for analysis. The most common adverse events were grade 1-2 fatigue (13% ENZA vs 9%) and urinary frequency (6 % ENZA vs 8%). Conclusions: SRT plus ENZA monotherapy for men with PSA recurrent high-risk prostate cancer following RP is safe and delays PSA progression relative to SRT alone. The impact of ENZA on distant metastasis or survival is unknown at this time. Additional molecular biomarker analyses are being pursued. Clinical trial information: NCT02203695.
Racial concordance and trust in health communications: A randomized trial of videos about prostate cancer.
Authors: Loeb Stacy , Ravenell Joseph , Gomez Scarlett Lin , Borno Hala , Siu Katherine , Sanchez Nolasco Tatiana , Byrne Nataliya , Wilson Godfrey , Griffith Derek , Crocker Rob , Sherman Robert , Langford Aisha 
Published: June 2022

5014 Background: Black men have a significantly higher risk of prostate cancer and more aggressive disease compared to White men. The Internet is a popular source of health information and is commonly used by Black adults. However, Black adults are underrepresented in online content about prostate cancer. Given that medical mistrust is greater among Black compared to White adults, this study sought to evaluate the association between racial representation in online content about prostate cancer and trust in the content. A secondary objective was to identify additional attributes that influence trust in online content. Methods: This was a randomized trial of 2904 U.S. adults age ≥40. Participants were randomly assigned to view one of 8 different online videos. Videos used an equivalent script about either prostate cancer screening or clinical trials presented by one of 4 different presenters: Black physician, Black patient, White physician, or White patient. The primary outcome of the study was trust in the information using a Likert scale. Logistic regression models were applied to compare trust in the videos, based upon the characteristics of the speaker and topic of the video. Results: Study participants were 1703 (59%) Black and 1201 (41%) White adults. Black adults were 1.5 times more likely to trust a Black presenter compared to a White presenter (p<0.001). For White adults, no significant difference in trust was identified between Black or White presenters (p=0.21). For both Black and White adults, a physician presenting the information was more trusted than a patient, and videos discussing screening were more likely to be trusted than those discussing clinical trials (Table). Conclusions: Racial concordance is significantly associated with trust in prostate cancer information among Black adults. Additionally, health information is considered more trustworthy when delivered by a physician. These results highlight the importance of physicians in disseminating health information to the public, and of increasing racial diversity among healthcare providers. They also suggest an ongoing need for public education about clinical trials to prioritize issues of mistrust and distrust. [Table: see text]
BRCAAWAY: A randomized phase 2 trial of abiraterone, olaparib, or abiraterone + olaparib in patients with metastatic castration-resistant prostate cancer (mCRPC) with DNA repair defects.
Authors: Hussain Maha H. A. , Kocherginsky Masha , Agarwal Neeraj , Zhang Jingsong , Adra Nabil , Paller Channing Judith , Picus Joel , Reichert Zachery R , Szmulewitz Russell Zelig , Tagawa Scott T. , Whang Young E. , Dreicer Robert , Kuzel Timothy , Bazzi Latifa , Gerke Travis A. , Daignault-Newton Stephanie , Chinnaiyan Arul , Antonarakis Emmanuel S. 
Published: June 2022

5018 Background: The PARP-inhibitor olaparib is approved for mCRPC patients (pts) with deleterious germline or somatic homologous recombination repair gene mutations (HRRm). PARP1 interacts with androgen signaling, and castration-resistant tumor cells exhibit increased PARP1 activity. Preclinically PARP1-inhibition synergizes with androgen receptor (AR) targeted therapy. BRCAAway is a biomarker selected, randomized, open-label, multicenter phase 2 trial evaluating efficacy of targeting AR vs PARP vs combination in first line mCRPC patients with germline and/or somatic HRRm in BRCA1, BRCA2, or ATM. Methods: Eligible mCRPC pts underwent tumor next generation sequencing and germline testing. Pts with inactivating BRCA1, BRCA2 and/or ATM alterations were randomized 1:1:1 to Arm 1 abiraterone (1000 mg daily) + prednisone (5mg bid) (Abi/pred), Arm 2 olaparib (300 mg bid) or Arm 3 olaparib + Abi/pred. The primary end point is progression-free survival (PFS) analyzed using Kaplan-Meier estimates and Cox regression. Secondary endpoints include measurable disease response rate (RR) by RECIST, PSA-RR, undetectable PSA (≤ 0.2 ng/ml) and toxicity. Arms 1 and 2 pts were allowed to cross over at progression. Pts with other HRRm were treated with olaparib; Arm 4 (ongoing). Results: 161 pts were registered and had NGS testing; 60 pts were randomized to Arms 1-3; to date 59 are evaluable for toxicity and 53 are evaluable for PFS. Baseline median age 67 (range 42-85) years; 54 pts were White, 6 were Black; sites of disease: bone only (n=31), soft tissue only (n=18), bone and soft tissue (n=10); median PSA 14.61 ng/ml (range 0.15-4036.8). Mutational status: BRCA1 only n = 2, BRCA2 only n = 39, ATM only n = 8, and > 1 HRRm n = 11. 34 pts had germline and 26 had somatic mutations. Median (range) follow-up time: 8.3 (0.8, 33.3), 12.2 (2.7, 21.8) and 16.8 (2.9, 41.7) months in Arms 1, 2 and 3. 43 pts had treatment-related adverse events; most common were fatigue (23 pts; 1 Grade (G) 3, 22 G1/2), nausea (17 pts, G1/2), and anemia (9 pts, 2 G3, 7 G1/2). ≥50% PSA decline was 79%, 67%, and 85% of pts in Arms 1, 2, and 3, respectively. Median PSA nadir (ng/mL) (95% CI) Arms 1-3: 2.17 (0.44, 49.27), 3.10 (0.83, 12.01), and 0.50 (0.10, 2.13), respectively. Undetectable PSA, median PFS, and 12-month PFS by Arm are listed in the table. Conclusions: In mCRPC pts with inactivating BRCA1, BRCA2 and/or ATM alterations Abi/pred + olaparib was well tolerated and resulted in longer PFS and better PSA response vs either agent alone. Clinical trial information: NCT03012321. [Table: see text]
Gene-by-gene analysis in the MAGNITUDE study of niraparib (NIRA) with abiraterone acetate and prednisone (AAP) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) and homologous recombination repair (HRR) gene alterations.
Authors: Sandhu Shahneen , Attard Gerhardt , Olmos David , Efstathiou Eleni , Castro Elena , Rathkopf Dana E. , Smith Matthew Raymond , Roubaud Guilhem , Small Eric Jay , Gomes Andrea Juliana , Saad Marniza , Tural Deniz , Thomas Shibu , Urtishak Karen , Gormley Michael , Mason Gary , Diorio Brooke , Wang George C. , Lopez-Gitlitz Angela , Chi Kim N. 
Published: June 2022

5020 Background: NIRA + AAP significantly improved outcomes in pts with mCRPC and HRR gene alterations in the Phase 3 MAGNTUDE study. There is a paucity of data supporting use of PARP inhibitors in pts with HRR gene alterations other than BRCA1/2. We report on the efficacy of NIRA + AAP in pts with mCRPC and a qualifying single gene HRR alteration other than BRCA1/2. Methods: A pre-specified analysis was undertaken of the primary endpoint (radiographic progression-free survival [rPFS] by BICR), secondary endpoints (time to cytotoxic chemotherapy [TCC], time to symptomatic progression [TSP], overall survival [OS]), as well as time to PSA progression (TPSA) and overall response rate (ORR) across 186 pts (91 randomized to NIRA + AAP, 95 to PBO + AAP) with an alteration in the ATM, BRIP1, CDK12, CHEK2, FANCA, HDAC2, or PALB2 gene (excluding cooccurring alterations) . This analysis of individual alterations was not powered for formal statistical inference. Given the rarity of some alterations, groups based on functional similarity are also presented. Results: (Table). Pts with PALB2 or CHEK2 alterations had consistent improvement across all endpoints. In pts with ATM alterations benefit was observed in TCC, TSP, TPSA and ORR. There was benefit only in TPSA and ORR for pts with CDK12 alterations. When combined into functional groups, pts with an alteration in the HRR-Fanconi pathway ( BRIP1, FANCA, and PALB2) as well as pts with a HRR associated alteration ( CHEK2 or HDAC2) showed improvement in all endpoints. Conclusions: These data support the overall conclusions of the MAGNITUDE primary analysis and support benefit of NIRA + AAP in pts with HRR mutations beyond BRCA1/2. Clinical trial information: NCT03748641. [Table: see text]
The association of germline HSD3B1 genotype with outcomes in metastatic hormone-sensitive prostate cancer (mHSPC) treated with androgen deprivation therapy (ADT) with or without enzalutamide (ENZA) [ARCHES].
Authors: Sharifi Nima , Azad Arun , Patel Mona , Hearn Jason W.D. , Wozniak Michele , Zohren Fabian , Sugg Jennifer , Haas Gabriel P. , Stenzl Arnulf , Armstrong Andrew J. 
Published: June 2022

5022 Background: A common missense-encoding germline polymorphism in HSD3B1(1245A→C) stabilizes the 3βHSD1 enzyme and increases the rate-limiting step for metabolic flux from adrenal precursors to potent androgens. This adrenal-permissive HSD3B1(1245C) allele mechanistically drives more rapid progression after ADT in nonmetastatic and low-volume (LV) mHSPC. It is unknown whether upfront treatment with ENZA could improve these poor outcomes. We sought to determine the association between the HSD3B1 genotype and outcomes in ARCHES, a randomized, placebo (PBO)-controlled, phase 3 global study of ADT with ENZA or PBO in mHSPC. Overall, 31.3% of men on placebo crossed over to ENZA prior to progression. Methods: Germline DNA from 660 men (243 LV and 417 high volume [HV]) in ARCHES was genotyped for HSD3B1. Radiographic progression-free survival (rPFS), prostate-specific antigen (PSA) outcomes, and overall survival (OS) were compared between men who inherited 0 (adrenal restrictive) vs. 1–2 copies of the HSD3B1(1245C) allele (adrenal permissive) using log-rank tests, Kaplan-Meier estimates, and Cox proportional hazards models for hazard ratios (HRs). Results: In ARCHES, 340 and 320 men had the adrenal-restrictive and adrenal-permissive HSD3B1 genotype, respectively. The adrenal-permissive genotype was not associated with worse rPFS, time to PSA progression (TTPP), or OS. Cox model HRs for death in the adrenal-permissive compared with adrenal-restrictive men in the ENZA + ADT and PBO + ADT arms were 1.21 (95% confidence interval [CI] 0.84, 1.74) and 1.48 (95% CI 0.98, 2.25), respectively. Three-year OS was 82% and 73% in men treated with ENZA + ADT with restrictive vs. permissive genotypes, respectively, and 68% and 70% in men treated with PBO + ADT. ENZA significantly improved rPFS, TTPP, and OS, irrespective of genotype. HRs for ENZA + ADT vs. PBO + ADT in models adjusted for genotype were: rPFS, 0.64 (p < 0.001); TTPP, 0.27 (p < 0.001), and OS, 0.62 (p < 0.001). Of OS events in the HSD3B1-genotyped men, 48 (23%) and 163 (77%) deaths occurred in the LV and HV groups, respectively. Conclusions: In men with mHSPC, ENZA improved OS, rPFS, and TTPP over PBO + ADT, irrespective of HSD3B1 genotype. Survival analysis of HSD3B1-genotyped men in this study is largely driven by men with HV disease. The analysis of men with LV disease was limited by the small number of events. Clinical trial information: NCT02677896.
Management of residual nonretroperitoneal disease in nonseminomatous germ-cell tumors (NSGCT).
Authors: King Jennifer , Kesler Kenneth , Ashkar Ryan , Althouse Sandra K. , Hanna Nasser H. , Einhorn Lawrence H. , Adra Nabil 
Published: June 2022

5034 Background: The management of NSGCT patients (pts) with post-chemotherapy residual non-retroperitoneal disease (RP) remains unsettled. Decisions for surveillance vs surgical resection are commonly steered by pathology from retroperitoneal lymph node dissection (RPLND). Data is limited in pts who do not require RPLND (normal or normalized RP post-chemo). Methods: The prospectively maintained Indiana University testicular cancer database was queried for pts with metastatic NSGCT who completed first-line chemotherapy and had residual extra-RP disease without residual RP disease. Pts with post-chemo non-RP surgical resection were included. Results: 134 pts met eligibility. Median age at diagnosis was 28.6 (range, 16.2-51.5). Primary tumor predominant histology was embryonal (35.1%), mixed (25.4%), seminoma (2.2%), yolk sac (9.7%), choriocarcinoma (15.7%), teratoma (11.2%). 76 pts (56.7%) had teratoma in the primary tumor. Metastatic sites at diagnosis were RP (15.7%), mediastinal LN (8.2%), lung (28.4%), liver (11.2%), bone (6.7%), brain (21.6%). Those with RP mets at diagnosis had normalization of RP nodes after chemo. IGCCCG risk was good in 57, intermediate in 21, and poor in 56 pts. Median pre-chemo AFP was 66 (0.9-467,000). hCG was 960.5 (0.5-1,300,000). First-line chemo was BEPX4 in 68, BEPx3 in 29, EPX4 in 10, VIPX4 in 9, and other in 18 pts. All pts had surgical resection of non-RP disease. None had RPLND. 84 pts had lung nodule resection, 16 had mediastinal LN, 8 had cervical LN, 5 had liver, 6 had bone, and 20 had brain met resection. Of the 76 pts with teratomatous elements in the orchiectomy, 41 (53.9%) had teratoma and 24 (31.6%) had non-teratoma GCT in post-chemo non-RP surgical specimens. Of the 58 pts without teratoma in the orchiectomy, 9 (15.5%) had teratoma and 34 (58.6%) had non-teratoma GCT in the non-RP surgical resection specimens. Teratoma in the orchiectomy was a predictor of non-RP teratoma (Fisher’s exact test P<0.0001). Conclusions: The presence of teratoma in orchiectomy predicts teratoma in residual post-chemo non-RP disease in pts who do not undergo RPLND. The absence of teratoma in orchiectomy should not preclude resection of residual non-RP disease given a subset of patients had persistent GCT. [Table: see text]
Anti-EGFR antibody plus anti-PD-1 antibody and chemotherapy as a neoadjuvant regimen for patients with locally-advanced penile squamous cell carcinoma: A prospective, single-arm, single-center, phase II clinical trial.
Authors: An Xin , Yan Ru , Guo Shengjie , Xue Ting , Ma Huali , Chen Meiting , Zhou Fangjian , Yao Kai , Dong Pei , Zhang Zhiling , Liu Zhuowei , Shi Yanxia , Han Hui 
Published: June 2022

5037 Background: Advanced penile squamous cell carcinoma (PSCC) is a rare disease with a poor prognosis. We performed a monocentric, Simon’s two-stage phase II study to evaluate the efficacy and safety of PD-1 blockade plus anti-EGFR target therapy and chemotherapy as neoadjuvant therapy in patients with locally advanced PSCC. We previously reported promising results in the first stage. The enrollment of the second stage had been completed by January 2022, herein we reported the updated results. Methods: Patients with chemotherapy-naive, locally-advanced PSCC (cT4 or cTxN3M0) were enrolled. The neoadjuvant regimen consists of anti–PD-1 antibody toripalimab, anti–EGFR antibody nimotuzumab, and chemotherapy (albumin-bound paclitaxel plus cisplatin and ifosfamide). Curative surgery was performed following a maximum of four cycles of treatment. The primary endpoint is the pathological complete response (pCR) rate. Secondary endpoints include overall response rate (ORR), relapse-free survival (RFS), overall survival (OS), and treatment-related adverse events (TRAEs). Results: A total of 29 patients were enrolled in two stages, with a median age of 57 (range 31-71) years. Till January 2022, 21 patients had completed the neoadjuvant treatment, 17 (81%) achieved an objective response, (CR 5, PR 12), 2 had SD, and 2 showed PD. Among 18 patients who underwent radical surgery, 11 showed no residual tumor on histopathology, with a pCR rate of 61.1% (11/18). The median follow-up time was 10.6 months. Two patients with PD died from disease, and 2 patients who experienced disease relapsed after radical surgery, in which 1 with SD, and 1 with PR. No relapse was observed among patients with pCR. The survival data are still immature. No unexpected toxicities and treatment-related death were recorded. Five out of 21 (23.8%) patients experienced grade 3 or 4 TRAEs. Grade 3 neutropenia occurred in 3 (14.3%) patients with 10 used G-CSF prophylaxis. No febrile neutropenia occurred. Other grades 3 toxicities included 1 case of peripheral sensory neuropathy and 1 anemia. The most common grade 1/2 TRAEs were alopecia (100%), decreased appetite (85.7%), nausea (71.4%), peripheral sensory neuropathy (66.7%), anemia (66.7%), neutropenia (33.3%), and infusion-related reactions (28.6%). The most common immune-related adverse events (IRAEs) were grade 1/2 hypothyroidism (19.0%), and grade 1 hyperthyroidism (4.8%). No severe IRAEs including pneumonitis, colitis, and myocarditis were observed. Conclusions: The triple combination is a provoking safe and efficacious neoadjuvant regimen for patients with advanced PSCC. Clinical trial information: NCT04475016.
Molecular correlates of high B7-H3-expressing metastatic castrate-resistant prostate cancers (mCRPC) via exome, transcriptome, and epigenome analyses.
Authors: Shi Xiaolei , Day Abderrahman , Bergom Hannah E. , Tape Sydney , Baca Sylvan , Ryan Charles J. , Zorko Nick , Antonarakis Emmanuel S. , Hwang Justin 
Published: June 2022

5045 Background: mCRPC is a lethal condition with limited effective treatment options. B7-H3, a transmembrane protein of the B7 checkpoint superfamily is overexpressed in prostate cancer (PC) and is associated with poor prognosis. While several novel approaches target B7-H3 in prostate cancer, lack of knowledge about the molecular features and regulatory mechanisms of B7-H3 expression in mCRPC prevents the optimal design of these interventions. We aimed to characterize B7-H3 in mCRPC with the purpose to reveal the roles of B7-H3 in mCRPC pathogenesis, and stratify the patient population optimal for B7-H3–targeted therapies. Methods: We conducted bioinformatic interrogations at genome-scale on whole-exome and whole-transcriptome sequencing (WES, WTS) data from SU2C/PCF (n = 209, mCRPC), SUWC (n = 101, mCRPC) and GTEx (n = 246, benign prostate tissue). We developed and utilized novel machine learning (ML) algorithms to examine the association of B7-H3 with other key PC pathways. We examined the genetic and epigenetic regulation of B7-H3 by CHIP-seq. We also performed single-cell mRNA sequencing (scRNA-seq) analysis on one patient before and after treatment with the AR inhibitor, enzalutamide. We utilized both Gene Set Enrichment Analysis (GSEA) and our ML approaches to identify enriched signaling pathways in high B7-H3–expressing mCRPC. Results: Expression of B7-H3 was significantly elevated in mCRPC compared to benign prostate tissues, and was distinctive from other B7 family members. High B7-H3 expression was significantly associated with ERG fusions, AR-V7 variant, and increased FOXA1 and androgen receptor (AR) mRNA expression. At gene-level analysis, our ML algorithm suggested that B7-H3 shared similar gene networks as AR and its co-regulators, HOXB13, and FOXA1. CHIP-seq analysis revealed that the distal enhancers of B7-H3 in mCRPC were hyperactive (based on enhanced H3K27Ac marks) relative to primary tumors. Notably, these B7-H3 enhancers were bound by HOXB13, FOXA1 and AR in mCRPC samples. Our scRNA-seq analysis of one patient resistant to enzalutamide showed increased number of B7-H3-expressing cells. Based on integrated GSEA and ML analyses on WTS data, B7-H3 was positively associated with TGF-beta signaling, an enzalutamide resistance pathway. Conclusions: In mCRPC, we found B7-H3 overexpression as compared to other B7 family members. The association of B7-H3-high expression and certain genomic alterations may stratify mCRPC patients for B7-H3–targeted therapy. Further, B7-H3 exhibited regulation by AR, HOXB13 and FOXA1, at the B7-H3 enhancers. The activating epigenetic modification at the distal enhancers represents another potential marker to examine B7-H3 expression in tumors. Altogether, our study indicates that B7-H3 is a critical target in mCRPC patients, including those resistant to enzalutamide.