bluuebunny/crossref_metadata_2025 huggingface dataset:
Management of progressive brain metastases in patients (pts) with relapsed germ-cell tumor (GCT) treated with salvage high-dose chemotherapy (HDCT).
Authors: King Jennifer , Abonour Rafat , Hassoun Rebecca , Althouse Sandra K. , Salous Tareq , Hanna Nasser H. , Einhorn Lawrence H. , Adra Nabil
Published: June 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]
Survival associated with chemotherapy and prognostic biomarkers in penile cancer at a reference hospital in the Northeast Brazil from 2000 to 2021.
Authors: Soares Joao Paulo Holanda , Cunha Maria do Perpétuo Socorro Saldanha , Hirth Carlos Gustavo , Silva Paulo Goberlânio de Barros
Published: June 2024

5043

Background: Penile cancer is a rare neoplasm worldwide. Despite a higher incidence in the Brazilian Northeast region, data regarding chemotherapy (CHT) treatment of penile cancer in Brazil is scarce. The relationship between markers of immunosuppression in the tumor microenvironment of penile cancer and MDSCs (Myeloid Derived Suppressor Cells) is still poorly understood. Methods: 294 patients affected by Squamous Penile Cancer treated at the Haroldo Juaçaba Hospital (Ceará-Brazil) between 2000 and 2021 (82 underwent chemotherapy: 27 adjuvant, 31 neoadjuvant and 24 palliative ) were retrospectively evaluated due to their clinical and histopathological characteristics and the following immunohistochemical markers: PD-L1, CD8t (intratumoral), CD163t (intratumoral), CD84, HLA-DR II. We sought to correlate these biomarkers to clinical staging, type (neoadjuvant, adjuvant or palliative) and response to CHT, PFS post-Chemotherapy (PFS-CHT), Overall Survival by stage (OS) and OS post-Chemotherapy (OS-CHT). Results: The median age for all patients was 62,9 years (18-103). Partial penile amputation was the most common surgery (74%), followed by inguinal lymphadenectomy (56%). Platinum Doublet was administered in 95% of cases. OS at 5 years for stages I, II, III e IV was 95,3%, 93,6%, 87,4% and 14,8%, respectively. The response rate (RECIST) (PR, SD and PD) in those who underwent Neoadjuvant CT was 29% 22% and 48%, while in the Palliative group was 5%, 11% and 82% respectively. Median OS-CHT was 49 months in the adjuvant, 21 months in neoadjuvant and 12 months in palliative group (p<0.001 adjuvant vs neoadjuvant/palliative); PFS-CHT was 11 months, 4 months and 1 month in the adjuvant, neoadjuvant and palliative group, respectively (p<0.001). In the neoadjuvant group, those who underwent surgery (70%) had a PFS-CHT of 6 months versus 2 months in those who were not operated (p<0.001). In univariate analysis, PFS-CHT was significantly higher in those who had lower expression of CD8t (9 vs 5 months; p=0.02), or CD163t (7 vs 5 months; p=0.043) or CD84 (7 vs 5 months; p =0.043). Conclusions: This is the largest retrospective study on chemotherapy and survival outcomes in Brazil. Patients who underwent surgery and adjuvant CHT had the best prognosis in terms of survival followed by those operated after neoadjuvant CHT. Lower expression CD163t, or CD84 (marker of MDSCs) or CD8t correlated with greater PFS-CHT. These data may help to understand the suppressive microenvironment in penile cancer and response to chemotherapy.
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: Ye Ding-Wei , Jiang Shusuan , Luo Hong , Zhou Fangjian , He Dalin , Ma Lulin , Guo Hongqian , Liang Chaozhao , Chong Tie , Jiang Jun , Chen Zhiwen , Wang Yong , Zou Qing , Tian Ye , Xiao Jun , Huang Jian , Chen Jinchao , Yang Xinfeng , Lian Jianpo , Wang Wenliang
Published: June 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 .
Fractionated docetaxel (D) and radium 223 (Ra223) in metastatic castration-resistant prostate cancer (CRPC): A modular phase I trial.
Authors: Connell Brendan , Hwang Clara , Folefac Edmund , Lawlor Christian , Koethe Benjamin , Mathew Paul
Published: June 2024

5049

Background: Disease progression following novel hormonal therapy in CRPC remains bone-dominant and D-responsive. D + Ra223 would be a logical combination but myelosuppression is dose-limiting. Prior combinations have required a reduction in dose intensity (DI) in both agents. Fractionated schedules of D Q2weekly (DQ2) have comparable activity to D 75mg/m2 Q3weekly with mitigated myelosuppression. We hypothesized that a fractionated schedule of DQ2 with standard Ra223 dosing would be feasible while preserving DI. Methods: Subjects had progressive bone-metastatic CRPC, ECOG PS 0-2, and no bulky visceral disease. Design was phase I, 6+6, dose escalation plus expansion with 28-day cycles. DQ2 was given in a 4-week lead-in, then with Ra223 every 4 weeks. Dose-level (DL) 1: D 40mg/m2; if neutropenia, then 1a: D 40mg/m2 with G-CSF on Day 16, 2a: D 50mg/m2 with G-CSF on Day 16. Up to 6 cycles of the combination were given. Primary objective was the feasibility and maximum tolerated DL explored (MTD). Secondary objectives included PSA response, ORR, PFS, OS, and quality of life. Results: 43 patients (pts) enrolled including 34.9% non-white pts and 76.7% with ≥ 4 bony mets. 8 dropped out during the D lead in (1 each neutropenia, stroke, failure to thrive, anorexia/fatigue, thrombocytopenia, infusion reaction and 2 hospitalized for other reasons). At DL1, 2 of 3 had DLT (both neutropenia). No DLT occurred at DL1a (n=5) or DL2a (n=5). MTD was DL2a. 22 subjects enrolled to expansion cohort at DL2a. Of the 35 pts treated with D + Ra223, adverse events of interest listed in the table. No febrile neutropenia, fractures, or G5 toxicity were seen. 19/35 completed all 6 cycles of combination therapy. PSA50 response was seen in 18 (51.4%) and PSA90 in 9 (25.7%) pts. Of 31 pts with evaluable data, best response (RECIST 1.1) was 1 CR, 5 PR, 23 SD, 2 PD. Median PFS was 50.0 weeks (95% CI: 37.3-86.1) and OS was 86.1 weeks (95% CI: 60.0-130.9). 10 pts progressed exclusively in nodal/visceral metastases compared to 6 in bone only. Quality of life measures remained stable on study. Conclusions: Utilizing a D lead-in strategy, combination DQ2 and Ra223 was feasible and well tolerated, with a favorable PFS and evidence of preferential control of osseous metastases. Dose-intensity for both docetaxel and Ra223 was preserved and comparable to the FDA-approved dose-schedules for each of the single agents. The lead-in design and use of G-CSF contributes significantly to the feasibility. Clinical trial information: NCT03737370 . [Table: see text]
Rapid and deep prostate-specific antigen (PSA) response to apalutamide plus ADT and survival in metastatic castration-sensitive prostate cancer (mCSPC) in real world practice in the US (OASIS Project).
Authors: Maughan Benjamin L. , Liu Yanfang , Mundle Suneel , Wang Xiayi , Karsh Lawrence Ivan
Published: June 2024

5076

Background: Apalutamide (APA) in combination with androgen-deprivation therapy (ADT) is an effective life-prolonging treatment option for mCSPC. Early and deep PSA responses are response indicators in metastatic castration-resistant PC that have been associated with improved clinical outcomes in patients with PC. APA+ADT has been shown to induce early and deep PSA responses. We evaluated correlations between PSA and long term clinical outcomes in adults with mCSPC in real world practice. Methods: This retrospective, observational cohort study used the ConcertAI RWD 360 prostate cancer dataset to evaluate correlations between PSA and long term clinical outcomes in adults with mCSPC who initiated treatment with APA+ADT. All patients with newly diagnosed mCSPC from 1 Jan 2018 to 30 Sept 2022 were enrolled and followed up until 31 Mar 2023. Correlations between time to 50% and 90% declines in PSA (PSA50 and PSA90), and time to undetectable PSA (≤0.2 ng/mL) and 24-month OS were evaluated. Adjusted Hazard ratios (aHRs) were estimated using multivariate Cox proportional hazard models adjusted for age, comorbidities, BMI, baseline PSA. Results: 183patients with mCSPC who initiated APA+ADT treatment and had monthly PSA testing were included in the analysis; mean (SD) age 73 years (8), baseline PSA 34 (81). Mean (SD) duration of follow up was 18 m (10). Overall, 116 patients (63%) reached undetectable PSA over the follow-up period and 24-month OS was 68%. OS was significantly higher when patients achieved undetectable PSA, PSA90 and PSA50 within 3 months after initiating APA+ADT (24-month survival rate, 87%, 84% and 80%, respectively) compared with patients who did not reach these levels during the follow-up period (Table). The aHR was 0.15 (95% CI 0.05–0.47; p<0.001) in patients who reached undetectable PSA within 3 months compared with not yet reached. The aHR was 0.27 (0.12–0.65; p<0.01) in patients with onset of undetectable PSA beyond 3 months compared to not reached. Conclusions: Rapid and deep PSA decline was strongly associated with better overall survivalin patients with mCSPC initiated on APA+ADT.[Table: see text]
Post-progression survival of patients with metastatic hormone-sensitive prostate cancer (mHSPC) who received darolutamide or placebo: Post hoc analysis of ARASENS.
Authors: Grimm Marc-Oliver , Smith Matthew Raymond , Hussain Maha H. A. , Saad Fred , Fizazi Karim , Littleton Natasha , Paracha Noman , Srinivasan Shankar , Verholen Frank , Tombal Bertrand F.
Published: June 2024

5083

Background: Darolutamide (DARO) is a structurally distinct and highly potent androgen receptor pathway inhibitor (ARPI). In ARASENS (NCT02799602), the addition of DARO to androgen-deprivation therapy (ADT) and docetaxel (DOC) significantly reduced the risk of death by 32.5% in patients (pts) with mHSPC, despite most placebo (PBO) pts (75.6%) receiving subsequent therapy. DARO also delayed time to progression to metastatic castration-resistant prostate cancer (mCRPC; median, not reached vs 19.1 months for PBO), resulting in a longer time in mHSPC, which is associated with improved quality of life vs mCRPC. We report post-progression subsequent anticancer therapies and related survival from ARASENS. Methods: Pts with mHSPC were randomized 1:1 to DARO 600 mg twice daily or PBO in addition to ADT + DOC. After treatment discontinuation, pts entered active and long-term survival follow-up periods during which assessments included subsequent therapies and survival outcomes. Post-progression survival was defined as time from first subsequent therapy to death using Kaplan-Meier estimates. Results: Of 1305 treated pts (DARO n=651; PBO n=654), 315 receiving DARO and 495 receiving PBO entered follow-up. Of these, 57% (n=179) and 76% (n=374), respectively, received subsequent therapy; abiraterone and enzalutamide were the most frequent first subsequent therapy (Table). In the DARO arm, 90% of first subsequent therapies were ARPI or chemotherapy. Minimal difference was observed in post-progression survival between subsequent therapies, suggesting subsequent therapy with another ARPI does not provide further survival benefit vs non-ARPI options (mainly chemotherapy). In contrast, in the PBO arm where the majority (78%) received first subsequent therapy with an ARPI, a survival benefit was observed vs non-ARPI subsequent therapies (median, 23.0 vs 13.5 months). Conclusions: DARO+ADT+DOC increased overall survival vs PBO+ADT+DOC and also delayed time to progression to mCRPC. DARO pts had similar survival with all post-progression therapies. Pts receiving PBO+ADT+DOC quickly progressed to mCRPC and treatment with an ARPI in ARPI-naïve pts improved survival. Clinical trial information: NCT02799602 . [Table: see text]
EMBARK post hoc analysis of sexual activity (SA) patient-reported outcomes (PROs) in patients (pts) who were sexually active or interested in sex at baseline (BL).
Authors: Freedland Stephen J. , Mulhall John , Gleave Martin , De Giorgi Ugo , Rannikko Antti , Saad Fred , Ramirez-Backhaus Miguel , Ivanova Jasmina I. , Nasr Anchen F. , Ganguli Arijit , Kral Pavol , Reisman Arlene , Shore Neal D.
Published: June 2024

5084

Background: In EMBARK (NCT02319837), enzalutamide (ENZ) + leuprolide (L) or ENZ (ENZ mono) delayed metastasis-free survival vs placebo (P) + L while maintaining high quality of life (QoL) in high-risk biochemically recurrent nonmetastatic hormone-sensitive prostate cancer. SA (a composite score from European Organization for Research and Treatment [Tx] of Cancer QoL Questionnaire-Prostate 25 [QLQ-PR25]) was better preserved with ENZ mono vs P + L with no difference between ENZ + L vs P + L. To better understand effect on SA in relevant subgroups, we examined SA in pts who were sexually active or interested in sex at BL. Methods: QoL was assessed (BL, every 12 weeks) until metastasis/death. Cox regression was used to examine time to confirmed deterioration (TTCD) (confirmed at next visit) defined by one category change for sexual interest, activity, satisfaction, erectile function, and feeling like a man using QLQ-PR25 and FACT-P items (Table).Intent-to-treat analysis was applied. Results: Among pts interested in sex (n=694) or sexually active (n=437) at BL, TTCD in QLQ-PR25 SA domain, items 50 (interest), 51 (activity), GS7 (satisfaction), and BL5 (erectile function) were significantly delayed with ENZ mono vs P + L. In contrast, TTCD in BL5 (erectile function) was shorter with ENZ + L vs. P + L (Table). Conclusions: Among pts who were interested in sex or sexually active at BL, ENZ mono better preserved SA vs P + L in terms of SA domain, interest, activity, satisfaction, and maintaining erection. Adding ENZ to L had no impact on interest, activity, or satisfaction but may adversely affect erectile function, though differences in the median TTCD were clinically non-significant (0.06 months [1.8 days] and 0.09 months [2.7 days] in pts interested in sex and sexually active at BL, respectively). Clinical trial information: NCT02319837 . [Table: see text]
Comparison of outcomes with docetaxel or ARPI combination therapy for metastatic hormone-sensitive prostate cancer (mHSPC) by volume of disease.
Authors: Schoen Martin W. , Etzioni Ruth Douglas , Luo Suhong , Candelieri Danielle , Fedele Nicholas , Baxi Priya , Pickett Carley , Riekhof Forest , Ingram Kara , Karunanandaa Krishny , Govindan Srinivas , Cheranda Nina , Knoche Eric Marshall , Montgomery Robert Bruce
Published: June 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<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<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]
Immunologic effects of B cell depletion on T cells in high-risk prostate cancer.
Authors: Kim Sangwoo Shawn , Murtadha Jamillah , Miyauchi Sayuri , Ryan Stephen T , Zhang Jing , Pittman Emily , Messer Karen , Karin Michael , Kane Christopher J. , Shabaik Ahmed , Howell Stephen B. , Jamieson Christina , Sharabi Andrew
Published: June 2024

5096

Background: High-risk prostate cancer (HR-PCa) remains one of the leading causes of cancer-related death. Previous studies reported that a high density of immunosuppressive B cells in HR-PCa resection specimens was found to correlate with biochemical failure. In this context, a single arm prospective study assessing neoadjuvant rituximab, an anti-CD20 monoclonal antibody used to deplete B cells, was previously conducted on patients with HR-PCa eligible for radical prostatectomy (“PROTUX”). Here, we performed deep TCR sequencing to elucidate the impact of B cell depletion on T cells in prostate cancer patients. Methods: A single arm study enrolled patients with HR-PCa to receive neoadjuvant rituximab prior to radical prostatectomy (NCT: 01804712). Patients were treated with rituximab 375 mg/m2 once weekly for 4 treatments followed by prostatectomy within 14 days of the final treatment of rituximab. A matched cohort of patients with HR-PCa who underwent prostatectomy without any prior therapy were used as controls. Specimens from 14 patients were retrieved and genomic DNA was isolated using a QIAamp DNA FFPE Advanced UNG kit. TCR sequencing was performed with Adaptive Biotechnologies using the Ultradeep TCRB v4b assay. Data were then analyzed using the Adaptive immunoSEQ Analyzer. Groups were compared using a Mann-Whitney U test. Statistical analysis and graphing were done in Prism 10 and R. Results: We observed that patients treated with rituximab had higher TCRb productive clonality (0.080 vs 0.026, p = 0.03). Strikingly, the calculated number of T cells present in prostatectomy samples was significantly greater in patients receiving rituximab compared to controls (1.18 cells/ng DNA input vs 0.10 cells/ng, p = 0.002). Maximum productive frequency and the cumulative frequency of the top 10 clones were not significantly different between the two cohorts. However, we found that the T cells from patients who received rituximab had longer TCRb CDR3 regions (proportion CDR3 ≥16 amino acids of 0.232 vs 0.197, p = 0.007), suggesting a less antigen-experienced phenotype. Conclusions: Using specimens from a clinical trial assessing the use of neoadjuvant rituximab in HR-PCa, we found that B cell depletion can significantly affect T cell infiltration, clonality, and phenotype. Given the increasing appreciation for crosstalk between T cells and B cells in mediating anti-tumor immune responses, these findings suggest a context dependent role of B-cells in patients with HR-PCa. Clinical trial information: NCT01804712 .
Socio-economic disparities in prostate cancer hospitalizations and outcomes across the United States.
Authors: Imeh Michael , Gvajaia Ani , Amaeshi Lemchukwu , Raza Ali , Uwumiro Fidelis
Published: June 2024

5103

Background: Socioeconomic class (SEC), measured by educational attainment, is recognized as a notable factor influencing outcomes in prostate cancer. This study evaluated the effects of income status on the prevalence, treatment, and hospitalization outcomes among men diagnosed with prostate cancer. Methods: The combined 2016–2020 nationwide inpatient sample database was queried for all hospitalizations for a primary diagnosis of prostate cancer using ICD-10-CM codes. Socioeconomic status was defined based on the Agency for Healthcare Research and Quality (AHRQ) median annual income index into the lowest SEC ($1–$49,999), the lower SEC ($50,000–$64,999), the high SEC ($65,000–$85,999), and the highest SEC ($≥86,000). Baseline characteristics were compared using Pearson’s χ2 tests and the Kruskal-Wallis test for nominal and continuous variables. Outcomes of interest were hospitalization rates, treatment, and outcomes (including mortality, complications, and resource utilization). The adjusted odds ratios of the outcomes were assessed using a stepwise multivariable logistic regression, adjusted for age, sex, race, insurance status, illness severity, risk of mortality, and comorbidity burden. This was done using the All Patient Refined Diagnosis Related Groups (APR-DRG) metrics and the Charlson comorbidity index. Results: The study analyzed 244,520 hospitalizations for prostate cancer. The median age of the cohort was 64 years (interquartile range: 59–69 years). Most were white Americans (69.9%) and blacks (16.3%). Approximately 53,550 (21.9%) were in the lowest SEC, 58,196 (23.8%) were in the lower SEC, 61,619 (25.2%) in the high SEC, and 66,803 (27.3%) in the highest SEC. Hospitalizations in the highest SEC were younger than those in the lowest SEC (63.7 vs. 66.5; P<0.001). Hospitalizations in the lowest SEC were correlated with greater mortality (655, 1.2%; AOR: 1.43; 95% CI: 1.22-1.56; P=0.011) compared with those in the highest SEC (475, 0.7%; AOR: 0.86; 95% CI: 0.65-0.97; P<0.001). The highest SEC correlated with higher rates of prostatectomy (2,995, 4.5%; AOR: 1.29; 95% CI: 1.08-1.10; P<0.001), whereas the lowest SEC had lower rates (1,810, 3.4%; AOR: 0.52-0.98; P=0.008). The lower and lowest SECs had higher frequencies of chemotherapy (8.1% and 7.4%, respectively; P for all <0.001). SEC did not correlate with the likelihood of immunotherapy (P = 0.738), radiotherapy (P = 0.073), length of hospital stays (P = 0.283), or mean hospital costs (P = 0.582). Hospitalizations in the higher SECs had lower odds of erectile dysfunction (highest SEC, AOR: 0.83; 95% CI: 0.74-0.93; P = 0.001; and high SEC, AOR: 1.13; 95% CI: 1.02-1.24). Conclusions: Prostate cancer affects the younger demographics of patients with higher SECs. However, hospitalizations in patients with lower SECs present with more advanced disease and result in poorer mortality outcomes than those in patients with higher SECs.
An open label, single arm phase II, multicenter trial of durvalumab and BVAC-C, in patients with HPV 16- or 18-positive cervical cancer and failure of first-line platinum-based chemotherapy (DURBAC).
Authors: Choi Chel Hun , Kim Byoung-Gie , Lee Jeong-Won , Kim Tae-Joong , Lee Yoo-Young , Cho Duck , Park Byoung-Kwan Hun , Song Sang Yong , Kim Dae-Yeon , Kim Kidong , Kim Hee Seung , Lee Jung-Yun , Lim Myong Cheol , Jeon Insu , Song By-yeong , Shin Kwang-Soo , Kim Wuhyun , Kang Chang-Yuil
Published: June 2024

5513

Background: In the phase I/IIa study of HPV positive recurrent cervical carcinoma, BVAC-C, a pioneering B cell- and monocyte-based immunotherapeutic vaccine transfected with recombinant E6/E7 gene of HPV type 16/18, demonstrated favorable tolerability. The ongoing phase 2 clinical trial investigates the potential synergistic effects of combining BVAC-C with durvalumab (MEDI4736), an anti-PD-L1 therapy, to enhance anti-tumor immune responses. Methods: The trial comprises two parts. Part A, utilizing a 3+3 dose-escalation design, assesses BVAC-C combined with 1500 mg durvalumab to establish the maximum tolerated dose (MTD) and recommended dose for Part B. Part B, with an expansion phase involving up to 25 patients, focuses on safety and clinical efficacy, measured by the 6-month progression-free survival (PFS) rate. Part A enrollment commenced in September 2021 across six Korean centers, with 9 participants enrolled and MTD determined by November 2022. 25 patients were enrolled in Part B enrollment was completed with 25 patients by December 2023. Tumor response evaluation follows RECIST 1.1 criteria and iRECIST. The essential eligibility criteria comprise histologically confirmed cervical carcinoma with HPV 16/18 positivity, recurrence following or resistance to a solitary prior first-line platinum-based chemotherapy ± bevacizumab, lack of prior exposure to immune-oncology (IO) drugs, and the presence of measurable disease according to RECIST v1.1. Results: Among 29 patients available for this interim analysis, 6-month PFS-rate was 51% (95% CI 33 – 77). The objective response rate (ORR) was 29.2% (7/24), with 2 complete responses. The disease control rate (DCR) was 66.7% (16/24). With a median follow up of 7 months, the median duration of response (DOR) and PFS were not reached. All evaluated patients exhibited inflammatory cytokine responses (IFN-γ or TNF-α) and robust E6/E7-specific T cell responses following BVAC-C vaccinations. Notably, immune responses correlated with clinical outcomes. The most common treatment-emergent adverse events (TEAEs) were pyrexia and myalgia, mostly grade 1 and manageable. Conclusions: The combination of BVAC-C and durvalumab demonstrates promise as a second-line treatment option with a manageable safety profile for patients with recurrent HPV 16/18 positive cervical cancer. The survival data is scheduled to receive an update during the upcoming ASCO meeting. Further studies are warranted to identify potential biomarkers of treatment response. Clinical trial information: NCT04800978 .
Secondary cytoreduction followed by chemotherapy versus chemotherapy alone in platinum-sensitive relapsed ovarian cancer (SOC-1): A final overall survival analysis of a multicenter, open-label, randomized, phase 3 trial.
Authors: Zang Rongyu , Zhu Jianqing , Liu Jihong , Jiang Rong , Cheng Xi , Chen Yulian , Jia Huixun , Shi Tingyan , Guo Yi , Feng Yanling , Tu Dongsheng , Zhang Yuqin , Huang Xiao , Jiang Shiyang , Gao Wen , Yang Huijuan , Zhang Ping
Published: June 2024

5520

Background: Surgery for platinum-sensitive relapsed ovarian cancer is widely practiced but has contradictory outcomes of survival in previously published studies. Methods: This multicenter, open-label, randomized, phase 3 trial was performed in four primarily academic centers in China. Eligible patients were aged ≥18 years old with platinum-sensitive relapsed ovarian cancer and were predicted to have resectable disease according to the international model (iMODEL) combined with PET-CT, which was reported previously. Overall survival (OS) and progression-free survival were the co-primary end points in hierarchical testing and planned for the final analysis of OS with a two-sided alpha of 0.05, when 209 deaths happened. Results: Between July 19, 2012 and June 3, 2019, 357 patients were enrolled. Patients were randomly assigned to receive surgery (182 pts.) or control (175 pts.). Median follow-up was 82.5 m. The median OS was 58.1 m in the surgery group and 52.1 m in the control group (hazard ratio [HR] for death, 0.80; 95% confidence interval [CI], 0.61 to 1.05; P=0.109). Overall, 61/175 (35%) patients in the control group crossed to surgery in subsequent therapies. A sensitive analysis showed that adjusted HR for death for crossover to surgery was 0.76 (95% CI, 0.58 to 0.99) (Table). When excluding the center with the highest crossover rate, secondary cytoreduction provided a 21.0-m benefit of overall survival over a control therapy. The highest crossover surgery rate was 49% in patients with 4-19 sites of relapse. The hazard ratio for death in patients with 1-19 sites was 0.69 (95% CI, 0.46 to 1.03). Patients with a complete resection had the most favorable outcome, with a median OS of 73 m. Median time to second subsequent therapy was 34.8 m vs 28.1 m (HR 0.68; 0.55-0.87). 24 of 182 (13.2%) patients remained relapse free and alive over 60 m in the surgery group, as compared with 5 of 175 (0.6%) patients in the control group. Conclusions: Secondary cytoreduction did not increase overall survival in the intention-to-treat population but led to a longer duration of overall survival when the crossover effect was taken into consideration. These findings are arguably clinically meaningful and support the efficacy of secondary cytoreduction in specialized centers and selected patients. ClinicalTrial.gov: NCT01611766. Res Sponsor: Shanghai Gynecologic Oncology Group. Clinical trial information: NCT01611766 . [Table: see text]
Unveiling the unique identity of clear-cell endometrial cancer (CCEC): A comprehensive comparative analysis with ovarian counterpart and other endometrial subtypes.
Authors: Blanc-Durand Felix , Ngoi Natalie , Rouleau Etienne , Pautier Patricia , Michels Judith , Ouali Kaïssa , Genestie Catherine , Lim Yi Wan , Lim Diana , Wijaya Silvana Talisa , Leary Alexandra , Tan David Shao Peng
Published: June 2024

5521

Background: Clear cell endometrial cancer (CCEC) is a rare and poorly understood entity, comprising less than 10% of endometrial cancer cases. In contrast, clear-cell ovarian cancer (CCOC) ranks as the second most prevalent subtype among epithelial ovarian cancers. CCOC is distinguished by specific phenotypic and molecular features, coupled with an overall aggressive behavior. CCEC and CCEC both share clinical and pathologic characteristics, suggesting common pathogenesis. This study aims to elucidate the molecular landscape of CCEC, in comparison with CCOC and other EC subtypes (nEC). Methods: We conducted a multicenter, retrospective analysis of CCOC, CCEC and nEC patients from Institut Gustave Roussy in France and National University Cancer Institute in Singapore. All patients underwent comprehensive molecular profiling using the tumor-based FoundationOneCDX panel. Results: This study analyzed 19 patients with CCEC, 81 patients with CCOC and 91 patients with nEC. CCEC exhibited distinct clinical and molecular features compared to CCOC or nEC. CCEC patients were significantly older (mean age 64.6 years) compared to CCOC (53.0 years, p<0.001) and nEC (59.9 years, p<0.001) cohorts. They also presented more frequently with FIGO IV disease (63.2%) versus 16.7% in CCOC patients (p<0.001) and 28.9% in nEC patients (p=0.007). Compared to CCOC, CCEC harbored significantly fewer ARID1A mutations (15.8% vs 54.3%, p=0.004), fewer KRAS mutations (0% vs 19.8%, p=0.035), significantly more TP53 mutations (42.1% vs 13.6%, p=0.008), and higher loss-of-heterozygosity (LOH) scores (10.5% vs 4.5%, p=0.004). Compared to nEC, CCEC exhibited significantly fewer CTNNB1 mutations (0% vs 18.7%, p=0.04), fewer PTEN mutations (5.3% vs 57.1%, p<0.001) and fewer KRAS mutations (0% vs 22.0%, p=0.021). Additionally, CCEC had higher LOH scores (10.5% vs 3.7%, p=0.019), and tended be less frequently associated with microsatellite instability (0% vs 19.3%, p=0.07) compared to nEC. Conclusions: CCEC significantly differs from CCOC and nEC in both clinical and molecular aspects. These findings support the consideration of CCEC as a distinct entity, advocating for a personalized approach that takes into account both the clear-cell aspect and the endometrial cancer molecular stratification.
Nimotuzumab in combination with radiotherapy for elderly patients with locally advanced cervical squamous cell carcinoma: Results from a prospective, multicenter, open-label, single-arm trial.
Authors: Qu Ang , Wang Jun jie , Zhuo Yanhong , Liu Zi , Zhu Hong , Wei Lichun , Sun Xiaoge , Gao Yuhua , Cheng Huijun , Zhao Fengju , Song Yipeng , Wen QingLian , Zhou Xiaohong , Wang Ping , Yang Jialin , Zou Lijuan , Yuan Xiangkun , Wu Dongyue , He Jianli , Zhang Yun Yan
Published: June 2024

5527

Background: Locally advanced cervical squamous cell carcinoma (LACSCC) is associated with poor survival, and elderly patients generally have fewer treatment options due to chemotherapy intolerance. Nimotuzumab is a humanized monoclonal antibody that has demonstrated therapeutic activity in many tumors. We conducted a single-arm trial to investigate the efficacy and safety of combining nimotuzumab and radiotherapy for elderly patients with LACSCC. Methods: In this prospective, multicenter, open-label, and single-arm trial, patients with LACSCC were registered (NCT04976478) and enrolled from Nov 2021 to Jan 2023. All patients were ≥ 65 years old, had ECOG of 0-2, histological diagnosis of cervical squamous cell carcinoma, clinical stage IB3-IVA (FIGO 2018), intolerant to chemotherapy, or refused chemotherapy. The regimen was nimotuzumab (200 mg once in a week for 6 weeks) combined with radiotherapy. The radiotherapy scheme contained intensity-modulated radiotherapy (IMRT)/volumetric intensity-modulated arc therapy (VMAT) with pelvic/extended field irradiation (45-50.4Gy, 1.8-2.0Gy/f, 25-28f), and brachytherapy (HR-CTV D90, 80-85Gy), of which brachytherapy plus external beam radiotherapy was completed in 8 weeks. The primary endpoints were overall survival (OS) and disease-free survival (DFS). Other assessed endpoints were objective response rate (ORR), disease control rate (DCR) and complete response rate (CRR). All adverse events were monitored and recorded. Results: As of Jan 2023, 119 elderly patients have been enrolled and all patients were included in the efficacy and safety analysis. The median follow-up was 16.16 months (95% CI: 13.14-17.45). Nimotuzumab combined with radiotherapy resulted in favorable OS (1 year-OS: 96.03%, 95% CI: 89.75-98.50; 2 year-OS: 90.21%, 95% CI: 78.98-95.60), and DFS (1 year-DFS: 85.71%, 95% CI: 76.98-91.31; 2 year-DFS: 78.31%, 95% CI: 66.67-86.29). The ORR was 89.92%, DCR was 93.28%, and CRR was 52.94%. A total of seven patients died, of which three were due to disease progression and two were of unknown causes. The most common Grade 3-5 adverse events (AEs) mainly included leukopenia (3.36%), anemia (2.52%), and neutropenia (1.68%). None of the patients developed severe AEs or deaths. So far, this trial is still ongoing. Conclusions: Among elderly LACSCC patients, adding nimotuzumab to radiotherapy indicated promising efficacy and appeared to have manageable toxicity. Nimotuzumab plus radiotherapy could represent a novel treatment strategy for this population. Clinical trial information: NCT04976478 .
Use of cell-free DNA from ascites to identify variants and tumour evolution in a cohort of patients with advanced ovarian cancer.
Authors: Werner Bonnita , Powell Elyse , Duggan Jennifer , Cortesi Marilisa , Lee Yeh Chen , Arora Vivek , Athavale Ramanand , Dean Michael , Warton Kristina , Ford Caroline
Published: June 2024

5547

Background: Accurate and clinically relevant molecular profiling is critical in the evolving landscape of precision treatments for ovarian cancer. Malignant ascites, a common manifestation in advanced ovarian cancer, provides easy access to tumour material in the form of cell-free DNA (cfDNA). Ascites fluid is an ideal liquid biopsy to enable molecular profiling and application of precision medicine as an alternative to tissue biopsy. Objectives: We aimed to identify clinically relevant variants in ascites and to examine tumour evolution by comparing matched samples from different points in the disease trajectory. Methods: A unique cohort of sequential ascites-derived cfDNA samples (26 samples from 15 participants, interval range 13-559 days), from people with ovarian cancer (clear cell and high-grade serous, aged 36-82) was collected. These were sequenced with the Illumina TSO-500 assay, along with matched DNA from ascites-derived tumour cells (n=5) and archived FFPE-tissue from surgery (n=5). cfDNA from one patient was additionally analysed with PCR-free sequencing, using an Oxford Nanopore Technology R9.4.1 MinION. Results: cfDNA had similar tumour purity, variant detection and reference alignment as well as improved coverage when compared to FFPE and ascites cell DNA. Somatic ovarian cancer-associated driver mutations were detected in 100% of cfDNA samples at mutation fractions of up to 0.9 MAF. 3 confirmed cases with somatic BRCA1/BRCA2 mutations were identifiable in ascites cfDNA, of these, ascites preceded surgery by 100 days or more in 2 cases, enabling earlier access to tumour tissue and expediting PARP-inhibitor access. Combined analysis of large-scale genomic alterations, loss of heterozygosity and tumour mutation burden identified 6 cases of high genomic instability (including 4 with mutations in BRCA1 and BRCA2). Over sequential ascites samples, changes in copy number profiles were observed and prevalence of subclones shifted by >10% in 6 of 10 participants. Additionally, in one participant, selective deletion of Chr17p13.1 and a chromothripsis-affected Chr8q emerged between interval debulking surgery and disease recurrence, resulting in changes to clinically relevant TP53 and MYC variants over time. No artefactual single-base substitution signatures were observed in cfDNA, though results from 2 of 5 FFPE samples were >20% sequencing artefact. Conclusions: Our work demonstrated the reliability of using cfDNA from ascites for molecular profiling, allowing a liquid biopsy of ovarian cancer when tumour tissue access may be restricted. This approach improves accessibility of tumour material, allowing capture of clinically actionable mutations prior to surgery or upon recurrence, following tumour evolution.
Overall survival (OS) in patients with platinum-sensitive relapsed ovarian cancer (PSROC) treated with olaparib maintenance monotherapy: Update from the L-MOCA trial.
Authors: Gao Qing-lei , Zhu Jianqing , Zhao Weidong , Huang Yi , An Ruifang , Zheng Hong , Qu Pengpeng , Wang Li , Zhou Qi , Wang Danbo , Lou Ge , Wang Jing , Low John , Kong Beihua , Yin Rutie , Lv Weiguo , Liu Jihong , Sun Wei , Zang Rongyu , Ma Ding
Published: June 2024

5559

Background: The open-label, single-arm, L-MOCA trial (NCT03534453) was the first study to demonstrate promising efficacy and tolerability of olaparib maintenance monotherapy in Asian patients with PSROC (median progression-free survival 16.1 months). Here we report the interim OS analysis. Methods: The study enrolled Asian patients with high-grade epithelial PSROC who had received ≥2 prior lines (L) of platinum-based chemotherapy and achieved complete or partial response. Patients were treated with oral olaparib (300 mg) twice daily until disease progression or unacceptable toxicity. A prespecified descriptive analysis of OS, a secondary endpoint, was conducted after approximately 3 years of follow-up. OS was analyzed in the full analysis set (FAS; defined as patients who received olaparib) and in subgroups defined by biomarker status ( BRCAmutation /homologous recombination deficiency (HRD) status) and prior L of anticancer therapy. Results: By the date of data cutoff (16 Nov 2023), the median duration of follow-up was 40.0 months (range 0.5–64.2); 105 (46.9%) deaths occurred. In the FAS (N=224), the median OS was 54.4 months (95% CI 43.8–not evaluable [NE]). Median OS was not reached (NR; 51.9–NE) in the BRCA mutant ( BRCAm) subgroup and 44.3 months (34.8–59.1) in the BRCA wild-type ( BRCAwt) subgroup. In patients who had tumors with HRD, median OS was 59.1 (43.5–NE); among them, patients with HRD BRCAwt showed a median OS of 54.6 months (33.0–NE); in the homologous recombination proficiency (HRP) subgroup, median OS was 37.2 months (28.3–56.1). Adverse events of any grade occurred in 222 (99.1%) patients. The incidence of myelodysplastic syndrome and acute myeloid leukemia remained low (3 [1.3%]). No new safety signals were identified. Conclusions: Olaparib showed promising OS benefit in Asian patients with PSROC, regardless of the BRCA mutation or HRD status, with a well-tolerated safety profile. Clinical trial information: NCT03534453 . [Table: see text]
Beacon: A phase II study of bevacizumab, atezolizumab, and cobimetinib in patients with recurrent, platinum resistant, high grade serous ovarian cancer.
Authors: Manoharan Sathya , Bressel Mathias , James Paige , Ko Yi-An , Hamilton Anne L. , Scott Clare L. , Mileshkin Linda R. , Grossi Marisa , Burdett Nikki , Ananda Sumitra , Desai Jayesh , Rischin Danny , Neeson Paul J. , Bowtell David , Au-Yeung George ,   on behalf of the imCORE Network
Published: June 2024

5565

Background: Platinum resistant high grade serous ovarian cancer (HGSC) is associated with a poor prognosis and limited treatment options. Immune checkpoint inhibitors have failed to show significant impact in treatment of HGSC to date. Bevacizumab (anti-VEGF) and atezolizumab (anti-PDL1) have shown synergy in multiple cancer types. Cobimetinib (MEK inhibitor) may also potentiate immune responses, particularly by altering the tumour microenvironment. We sought to evaluate the efficacy of cobimetinib, bevacizumab and atezolizumab in women with platinum resistant HGSC. Methods: BEACON is a Phase II single arm study of cobimetinib (60mg oral D1-21 q 28-days), bevacizumab (5mg/kg IV q2w) and atezolizumab (840mg IV q2w from Cycle 2) in patients with platinum-resistant recurrent HGSC. Patients continued therapy until progression or unacceptable toxicity. The primary endpoint was overall response rate (ORR) according to RECIST 1.1 at 24 weeks. Secondary endpoints included best overall response (BOR), safety, progression free survival, and response duration. Correlative studies on paired tumor biopsy and blood samples will explore molecular characteristics/subtypes and potential biomarkers of response as exploratory objectives. This study has now completed accrual and we present the 24-week response data, with a data cut off 21st December 2023. Results: Twenty-nine patients were enrolled between September 2018 and June 2023. Median age was 62 years (range 37 - 79) and 97% had received ≥ 2 prior lines of chemotherapy. The median number of cycles received was 3 cycles of atezolizumab and cobimetinib, and 4 cycles of bevacizumab. The ORR at 24 weeks was 21% [95% CI: 8-40], and a further 28% had stable disease as assessed per RECIST. Five patients (17%) have remained on study treatment for ≥ 52 weeks to date, suggesting that in some patients there was durable disease control. In terms of safety, 22 patients (76%) required a dose reduction in cobimetinib, mainly due to gastrointestinal and skin toxicity. Seventeen patients (59%) experienced a ≥Grade 3 treatment related adverse event, most commonly hypertension (6 patients, 21%). Two patients (7%) discontinued all study treatments due to toxicity. Conclusions: Preliminary results from this study show promising efficacy with the combination of atezolizumab, bevacizumab and cobimetinib in platinum resistant HGSC. Duration of response, progression free survival data and translational data exploring molecular characteristics will be presented as data matures. Clinical trial information: NCT03363867 . [Table: see text]