bluuebunny/crossref_metadata_2025_split huggingface dataset:
The effect of ACEi/ARB on survival outcome of patients with mCRPC treated with abiraterone.
Authors: Zhao Junliang , Cai Xinyang , Yang Zhenyu , Long Xingbo , Zhang Tianyou , Zhao Diwei , Li Yuanwei , Zhou Fangjian , Wang Jun , Li Yonghong 
Published: June 2024

5071 Background: Androgen deprivation therapy (ADT), such as Abiraterone Acetate (AA), has emerged as a standard treatment for metastatic prostate cancer (mPCa). However, long-term ADT treatment may increase the incidence of cardiovascular adverse events, such as hypertension, which are a common cause of death in patients receiving ADT. Therefore, it is crucial to select appropriate antihypertensive drugs that effectively manage blood pressure and improve overall survival (OS) in these patients. Methods: This study conducted a secondary analysis of the COU-AA-301 and COU-AA-302 trials, which were multicenter double-blind randomized controlled trials (RCTs) to evaluate the efficacy of AA in combination with prednisone and ADT compared to prednisone plus ADT alone in patients with metastatic castration-resistant prostate cancer (mCRPC). Patients were retrospectively assessed and stratified based on the concurrent medication including angiotensin converting enzyme inhibitors/angiotensin receptor blockers (ACEi/ARB) or not. OS and progression-free survival (PFS) were assessed using the Kaplan-Meier method and log-rank test. Multivariable Cox regression analysis was performed to determine the independent correlation of ACEi/ARBs with OS and PFS. Statistical significance was defined as P<0.05. Results: In COU-AA-301, the use of ACEi/ARB medications showed a significant association with improved OS (16.4 vs. 14.2 months, p<0.001) and PFS (3.1 vs. 2.9 months, p=0.002) in AA arm. After adjusting for baseline factors, ACEi/ARB medications were still found to reduce the risk of death (HR 0.72, 95% CI 0.56-0.91) and disease progression (HR 0.81, 95% CI 0.69-0.96). Similarly, in COU-AA-302, ACEi/ARB medications were associated with prolonged OS (37.4 vs. 31.9 months, p=0.003) and PFS (20.3 vs. 14.7 months, p=0.002) in AA arm. By adjusting for baseline factors, ACEi/ARB medications remained significantly associated with lower risk of death (HR 0.70, 95% CI 0.56-0.88) and disease progression (HR 0.70, 95% CI 0.55-0.88). In the placebo group, ACEi/ARB medications demonstrated improved OS only in COU-AA-301 (13.7 vs. 10.6 months, p=0.021). However, this trend did not reach statistical significance after adjusting for baseline factors (HR 0.76, 95% CI 0.55-1.03). Furthermore, the use of ACEi/ARB medications did not confer any PFS benefits in COU-AA-301 and failed to show both PFS and OS benefits in COU-AA-302. Conclusions: The use of ACEi/ARB medications has shown promise in improving OS and PFS in mCRPC patients treated with AAP. However, it is important to acknowledge the inherent limitations of post-hoc analysis, and therefore, further validation through prospective clinical trials is warranted.
PROact: A prospective phase II study to evaluate olaparib plus abiraterone and prednisone combination therapy in patients with metastatic hormone sensitive prostate cancer with HRR gene mutation.
Authors: Zhuang Junlong , Zhang Shun , Zhang Xuyu , Qiu Xuefeng , Guo Hongqian 
Published: June 2024

5082 Background: Approximately 10% - 15% of patients with metastatic hormone sensitive prostate cancer (mHSPC) harbor loss-of-function mutations in homologous recombination repair (HRR) genes. Although olaparib plus abiraterone and prednisone has significantly prolonged overall survival in metastatic castration resistant prostate cancer patients, there is a lack of evidence regarding the efficacy and safety of this combination therapy in patient with mHSPC. Here, we report the interim analysis results of PROact study, the first phase Ⅱ trial to evaluate the effects of olaparib plus abiraterone and prednisone in mHSPC patients with HRR gene mutation. Methods: This was a single center, single arm, phase Ⅱ trial ( NCT05167175 ) conducted in male patients with mHSPC who had at least one HRR gene mutation ( BRCA1, BRCA2, ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD 51C, RAD51Dand RAD54L) as determined by tissue-NGS. Patients were administered olaparib 300 mg BID plus abiraterone 1000 mg QD and prednisone 5 mg QD. Previous treatment with new hormonal agent (NHA) was not allowed. The primary endpoint was 1-year radiographic progression-free survival (rPFS) rate per PCWG3-modified RECIST 1.1 by investigator assessment. The secondary endpoint included prostate-specific antigen (PSA) response rate, objective response rate (ORR), and adverse events. Results: Between May 19, 2022 and Dec 8, 2023, a total of 30 patients were enrolled and administered combination therapy. All the patients had de novo mHSPC, and the median age was 68 (range 49-85), with a median PSA of 166 ng/mL at baseline. A total of 7 HRR mutations were identified, included BRCA2 (n=11), CDK12 (n=8), ATM(n=6), PALB2 (n=2), CHEK2 (n=2), RAD51B (n=2) and RAD51D (n=1). As of Jan 29, 2024, the median follow-up was 7.1 months. In the 30 patients who had PSA response evaluated, PSA50 response rate achieved 100% (30/30), and the PSA90 response rate was 96.7%(29/30). In the 12 patients who had RECIST assessment, the objective response rate was 91.7% (11/12). Two achieved complete response, nine obtained partial response, and one had stable disease. The treatment was well tolerated, with 7(23.3%) patients experienced ≥grade 3 treatment-related adverse events (TRAEs). Common TRAE was anemia. Conclusions: This was the first trial to show efficacy and an acceptable safety profile of olaparib plus abiraterone and prednisone in mHSPC patients with HRR mutation. Data of primary endpoint of 1-year rPFS will be reported in the due time. Clinical trial information: NCT05167175 .
Whole exome correlates in metastatic hormone sensitive prostate cancer (mHSPC): Results from E3805 CHAARTED.
Authors: Hamid Anis , Vergara Matias , Park Jihye , Chinsky Tyler M , Aldubayan Saud , Grist Emily , Attard Gerhardt , Van Allen Eliezer Mendel , Sweeney Christopher 
Published: June 2024

5088 Background: The landscape and clinical impact of genomic variants in mHSPC are incompletely understood. We have shown that deleterious germline BRCA2 alterations (alts) associate with shorter time to castration resistant prostate cancer (TTCRPC) on androgen deprivation therapy (ADT), but not on ADT plus docetaxel (ADT+D) (ASCO 2023). Somatic variation from tissue of patients (pts) with mHSPC is not well characterized and may influence therapeutic outcomes. Methods: We performed whole exome sequencing of HSPC specimens obtained at initial diagnosis and germline DNA from whole blood from pts in the CHAARTED trial (NCT00309985) of ADT vs ADT+D. Somatic single nucleotide variants (SNV) and allele-specific copy number alts (CNAs) were identified, including estimation of tumor mutational burden (TMB) and copy number burden (CNB). Prognostic effects were evaluated in both arms. Loss of selected tumor suppressor genes was defined by monoallelic or biallelic loss. TTCRPC and overall survival (OS) were estimated by Kaplan-Meier method. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) were estimated by Cox models. Results: After quality control, 68 tumor-normal cases were analyzed. The majority of pts had synchronous (51.5%) and high volume (58.8%) disease. Most frequent somatic SNVs were TP53 (33.8%), PTEN (7.4%), PIK3CA (5.9%) and SPOP (5.9%). AR amplification was uncommon (4.4%), however frequent MYC gain (60.3%) was seen as well as monoallelic deletion of NKX3-1, TP53, PTEN and BRCA2. Whole genome doubling occurred in 14.7%. Median TMB and CNB were 4.7 mut/Mb and 9.1%, respectively. CNB was elevated in synchronous (p=0.01) and high volume (p=0.046) disease. CNB greater than median was associated with shorter TTCRPC in the overall cohort (HR 2.06, 95%CI 1.13-3.75, p=0.015) and ADT+D arm (HR 2.98, 95%CI 1.17-7.58, p=0.016). The effect in the overall cohort was reduced after adjustment for volume and presentation (HR 1.72, p=0.091). A compounding effect of PTEN and TP53 alts was seen in the ADT arm where median TTCRPC for wild-type (WT), 1-gene hit, 2-gene hit was 19.6 mos, 8.5 mos, 6.3 mos, respectively. The median OS of WT vs 1-hit/2-hit loss was 47.1 mos vs 26.8 mos (HR 2.05, 95% CI 0.90-4.68, p=0.087). Similar differences in TTCRP and OS by PTEN/ TP53 status were not observed with ADT+D. Conclusions: The genomic landscape of mHSPC is characterized by frequent alts in putative drivers known to be enriched in mCRPC (Table). We observed a low rate of genomic instability and AR amplification/mutation similar to non-metastatic HSPC. Concordant with the STAMPEDE trial, greater CNB confers a higher risk of progression. Combined tumor suppressor gene alts associate with prognosis in mHSPC, which may differ by therapy intensification. [Table: see text]
A phase II trial of enzalutamide (Enz) with 5-alpha reductase inhibitors (5-ARI) as an androgen deprivation therapy (ADT)–sparing approach for older men with castration-sensitive prostate cancer (CSPC).
Authors: Kilari Deepak , Kadambi Sindhuja G , Baran Andrea M. , Zittel Jason , Burfeind John D. , Messing Edward M. , Van Veldhuizen Peter J. , Bylow Kathryn A. , Sahasrabudhe Deepak M. , Mohile Supriya Gupta , Fung Chunkit 
Published: June 2024

5089 Background: Older men with prostate cancer who have aging-related conditions are at high risk for adverse events (AEs) from ADT. 5-ARI inhibit the conversion of testosterone to dihydrotesterone and could be synergistic with Enz. In this phase II study, we evaluated Enz and Dutasteride (Dut) or Finasteride (Fin) in lieu of ADT for older men with CSPC who are at risk of AEs from ADT. Methods: Eligible patients were ≥65 years (y); deemed “not fit” by geriatric assessment (GA) or at high risk for side effects from ADT as determined by the treating physician; had metastatic (M1) or non-metastatic (M0) CSPC with a PSA doubling time ≤9 months and testosterone >50ng/dl. Enz 160 mg daily and Dut 0.5mg daily or Fin 5mg daily were administered until disease progression per Prostate Cancer Clinical Trials Working Group 2 guidelines. The primary study endpoint is PSA progression free survival (PFS). Key secondary endpoints include time to PSA nadir, absolute PSA nadir and evaluation of safety and toxicity of study treatments per CTCAE V4.0. Results: 43 men enrolled in the study. At study entry, subjects had the following baseline characteristics: median age was 78 y (range 66-94); 93% had ECOG 0-1; 63% had M1 CSPC with 30% of them having high volume disease per CHAARTED criteria; 23% had Gleason ≥ 8 CSPC; median PSA was 11.4 ng/ml (2-145), and median testosterone level was 342 ng/dl (56-639). Baseline GA at study entry showed that 18.6% had Instrumental Activity of Daily Living impairment; 9.8% had recent falls; 52.4% had Short Physical Performance Battery impairment; 40.5% had Older American Resources and Services (OARS) physical health and 31% had OARS medical social support impairments; 11.6% had Geriatric Depression Scale impairments; 65.9% had either Blessed Orientation-Memory-Concentration or Montreal Cognitive Assessment impairments; and 34.9% had Vulnerable Elders Survey-13 impairments. At a median follow-up of 5.9 y, 23 pts (53%) remained on study treatment and the median PSA PFS has not been reached for the entire group. The median time to PSA nadir was 8.1 months, with median PSA nadir at 0.02 ng/ml (range 0-2.75) and 98% having ≥90% PSA decline. The five most common any grade AE was fatigue (88%), gynecomastia (72%), hot flashes (42%), hypertension (40%), and falls (37%). No subject had treatment-related Grade 4 or 5 AEs. Four (9.3%) subjects withdrew treatment, 21% held treatments and 30.2% reduced dose of treatment due to AEs. Conclusions: The combination treatment with Enz and Dut/Fin appears to have clinical efficacy for older patients with CSPC who are at high risk for AEs from ADT. Clinical trial information: NCT02213107 .
Intensification of ADT with enzalutamide in high-risk patients with biochemical relapse following radical prostatectomy undergoing salvage radiation: Initial results from RTOG 3506 (STEEL).
Authors: Posadas Edwin Melencio , Gay Hiram Alberto , Rodgers Joseph P , Morgan Todd Matthew , Xiao Ying , Yu James , Michalski Jeff M. , Bouchard Myriam , Desai Neil B , Funk Ryan , Boike Thomas Pence , Jurgens Donald James , Wong Anthony C. , Shen Xinglei , Miyawaki Lloyd T , Bland Christopher S , Hairston John , Sandler Howard M. , Pugh Stephanie L , Feng Felix Y 
Published: June 2024

5101 Background: Patients with high-risk features who experience biochemical relapse (BCR) after radical prostatectomy (RP) benefit from the addition of androgen deprivation therapy (ADT) to salvage radiotherapy (SRT). We hypothesized that intensification of androgen receptor (AR) blockade with enzalutamide would improve SRT outcomes for high-risk patients. Methods: Post prostatectomy prostate cancer patients who have had BCR (PSA ≥ 0.2 ng/mL) with at least 1 high-risk feature (Gleason 8-10, seminal vesicle invasion, pN1, persistent PSA >0.1 ng/mL after RP, and PSA ≥ 0.7 ng/mL) were eligible. Patients were randomized 1:1 to 24 months of ADT with an LHRH analog (LHRHa) or intensified ADT comprised of LHRHa + enzalutamide. The primary endpoint was progression free survival (PFS) with progression defined as PSA ≥ 0.05 ng/mL or initiation of new therapy following SRT. The target accrual of 170 patients provided 80% power to detect a HR=0.65 using a one-sided logrank test with a type I error of 0.10. Results: Between April 2019 and August 2022, 188 patients were enrolled. The patient characteristics were well balanced between the two arms. Median age was 64 years. Nodal involvement (pN1), pT3a-b, and Gleason 9 were noted in 22%, 77%, and 52% of patients, respectively. Over 70% had > 1 aggressive feature. Median follow-up time at the time of this report was 15.8 months. Prostatic fossa and pelvic SRT were mandatory. Para-aortic radiotherapy (RT), and lymph node and prostatic fossa lesion RT boosts were left at the discretion of the radiation oncologist. PFS favored the enzalutamide-intensified arm (HR=0.72, 80% confidence interval [CI]:0.56-0.94, one-sided p=0.14). Grade 3 adverse events (AEs) related to treatment in the standard versus enzalutamide arms were 11 vs. 23%, while Grade 4 AEs were 4% vs. 1%, respectively. The most common AEs (all grades, >15%) included hot flashes, fatigue, diarrhea, and decreased lymphocytes. The grade 3+ AEs (>3%) included decreased lymphocytes and hypertension. The largest differences (>7%) in AEs included insomnia, decreased lymphocytes. Diarrhea was less frequent with enzalutamide (40% vs 54%). Conclusions: The addition of enzalutamide to standard ADT did not meaningfully increase toxicity. While there was a trend toward PFS benefit from intensification, it has not yet met statistical significance. Updates on PFS and other clinical endpoints including quality of life will be reported with longer follow-up. Clinical trial information: NCT03809000 .
Efficacy and safety of cadonilimab plus anti-EGFR monoclonal antibody as de-chemotherapy regimen in persistent, recurrent, or metastatic gynecologic cancer.
Authors: Zhang Qiying , Liu Zi , Zhang Jing , Wang Fei , Fan Shi , Wang Juan , Wang Tao , Su Jin 
Published: June 2024

5538 Background: Cadonilimab, an anti-PD-1/CTLA4 bi-specific antibody, and Nimotuzumab, an anti-EGFR monoclonal antibody, have demonstrated effectiveness in treating persistent, recurrent, or metastatic (P/R/M) cervical cancer individually. However, the exploration of combined bi-specific immunotherapy and anti-EGFR target therapy remains unexplored in P/R/M gynecological cancer. Methods: This open-label, prospective single-arm phase II study (NCT05606263). Eligible participants were P/R/M gynecological cancer patients who declined or couldn’t tolerate chemotherapy, or had failed first-line or subsequent treatments, irrespective of PD-L1 status. Patients received Cadonilimab at 6 mg/kg plus Nimotuzumab at a dose of 400 mg every two weeks. The primary endpoint included safety and objective response rate (ORR), with secondary endpoints comprising progression-free survival (PFS) and overall survival (OS). Results: From July 2022 to February 2024, twenty-nine P/R/M gynecological cancer patients received at least one dose of cadonilimab plus Nimotuzumab, including 22 (75.9%) with cervical cancer, 4 (13.8%) with endometrial carcinoma, and 3 (10.3%) with vulva cancer. The median age was 60 years (range: 39–80 years). Reasons for participating in this clinical trial included refusal of chemotherapy (7/29), inability to tolerate chemotherapy (7/29), and failure of first-line or subsequent lines of systemic therapy (15/29). Among them, 5 patients progressed after PD-1/PD-L1 treatment. After a median follow-up of 6 months (range: 1–18), the best response was observed in 17 patients, with 3 achieving complete response (CR) and 14 partial response (PR). Notably 2 patients relapsed after PD-1 treatment. The ORR was 58.6% (95% CI, 39.7–77.7). Additionally 6 patients achieved stable disease (SD), while 6 patients experienced disease progression. The median PFS and OS were not reached, but the 6-month PFS rate was 58.1% (95% CI, 35.5–75.2), and the 6-month OS rate was 76.5% (95% CI, 54.6–88.8). Adverse events (AEs) were generally manageable and tolerable (Grade 1-2), including hypothyroidism (13.8%), immune-mediated hepatitis (13.8%), rash maculo-papular (6.9%), thrombocytopenia (6.9%) and nephritis (3.4%). Conclusions: To the best of our knowledge, this represents the inaugural clinical report on the de-chemotherapy regimen of Cadonilimab plus Nimotuzumab for P/R/M gynecological cancer. The combination exhibited a promising tumor response rate (58.6%), surpassing the 32.3% observed with Cadonilimab alone, and demonstrated a manageable safety profile. These findings suggest the potential of bi-specific immunotherapy coupled with anti-EGFR target therapy especially in patients who are resistant to chemotherapy or intolerant to it, even in cases where single- specific immunotherapy has previously failed. Clinical trial information: NCT05606263 .
Maximizing cervical cancer prevention in safety-net settings of care: Resources from the Federal Cervical Cancer Collaborative for provider and patient engagement.
Authors: Segebrecht Jane , Hendrix Ellen , Chollette Veronica , K. McGee-Avila Jennifer K. , Loukissas Jennifer K. , Tookmanian Elise , Wentzensen Nicolas , Temkin Sarah M. 
Published: June 2024

5542 Background: Uneven administration of cervical cancer prevention, screening, and management, and changing guidelines prompted the Health Resources and Services Administration (HRSA) Office of Women’s Health and federal partners to develop the Federal Cervical Cancer Collaborative (FCCC). The FCCC aims to achieve the vision of the Cancer Moonshot in safety-net settings, reduce disparities in cervical cancer, and bridge the U.S. government’s priorities of cancer research and health care delivery. The FCCC supported: i) a survey of NCI-Designated Cancer Centers on barriers and opportunities that influence how Cancer Centers partner and engage with HRSA-supported and other safety-net settings of care; ii) the development of resources for providers in safety-net settings of care to support equitable cervical cancer prevention, screening, and management; and iii) the development of health communications materials to foster patient engagement for improved access to preventive health services. Methods: From January-February 2022, the FCCC conducted a multiple-choice and open-ended survey of 72.3% of Cancer Centers (n = 47) to identify opportunities to strengthen collaborations with safety-net settings. From February 2022-June 2023, the FCCC convened nine roundtables, with stakeholders across U.S. territories and freely associated states, national organizations, academia, and federal agencies, to inform provider technical assistance and patient outreach materials. Results: Cancer Centers reported patient-level barriers as the most challenging, compared with clinician-level, organizational-level, and systems-level barriers. The most common barriers to management of abnormal cancer screening included: transportation/travel (98%), health literacy (96%), and caregiving responsibilities (95%). The roundtable series informed the development of two resources: a primary care provider toolkit and patient outreach materials to strengthen cervical cancer prevention, screening, and management of abnormal results in safety-net settings of care. Conclusions: Roundtables and survey findings can inform needed structural and public health interventions to overcome patient level barriers and strengthen partnerships between Cancer Centers and safety-net settings. The findings also guide the FCCC’s long-term commitments to support equitable cervical cancer prevention in safety-net settings. The toolkit offers practical tools and guidance to primary care providers to improve quality of care, train staff, and communicate with patients. Patient outreach materials can support patient engagement in care and access to care. Both freely available resources will be used in a national remote tele-mentoring initiative for providers in safety-net settings of care.