bluuebunny/crossref_metadata_2025_split huggingface dataset:
Interim results from a phase 1/2 study of HPN328, a tri-specific, half-life (T1/2) extended DLL3-targeting T-cell engager, in patients (pts) with neuroendocrine prostate cancer (NEPC) and other neuroendocrine neoplasms (NEN).
Authors: Beltran Himisha , Dowlati Afshin , Jain Prantesh , Johnson Melissa Lynne , Sanborn Rachel E. , Thompson Jonathan Robert , Mamdani Hirva , Schenk Erin L. , Aggarwal Rahul Raj , Sankar Kamya , Gramza Ann W. , Anand Banmeet S , Choudhury Noura J. 
Published: January 2024

121 Background: HPN328 is a delta-like canonical Notch ligand 3 (DLL3)-targeting T-cell engager. HPN328 has 3 binding domains including anti-DLL3 for target engagement, anti-albumin for T1/2 extension, and anti-CD3 for T cell engagement and activation. HPN328 treatment resulted in robust and specific anti-tumor activity in preclinical in vitro and in vivo DLL3-expressing NEPC models. Methods: Patients (pts) with relapsed/refractory, metastatic NEPC, small cell lung cancer (SCLC) and other NEN associated with DLL3 expression are eligible. Verification of DLL3 expression is required for NEN other than SCLC or NEPC for eligibility. Primary objectives are safety, maximum tolerated dose (MTD), recommended dose(s) for expansion (RDE) determination, and pharmacokinetics (PK). Secondary objectives are immunogenicity and efficacy. HPN328 is administered IV weekly or biweekly with a priming dose preceding the target dose in higher dose cohorts. Adverse events (AEs) are graded (G) by CTCAE 5.0, and ASTCT for cytokine release syndrome (CRS). Results: As of 21Aug23, 66 pts received HPN328 as a single agent at target doses of 0.015-24 mg across 14 dose escalation cohorts. Ten (10) pts had NEPC and 2 had small cell bladder cancer (SCBC). The remainder were SCLC or other NEN. Median number of prior regimens for all patients was 2 (1-6). Treatment is ongoing in 29 pts, with 3 from early escalation cohorts on study for more than a year. Treatment-related AEs in >10% of pts included CRS (52%), fatigue (35%), dysgeusia (33%), nausea (17%), vomiting and diarrhea (14% each), decreased appetite (12%), and pyrexia (11%). Nearly all CRS occurred after the initial priming dose and not with subsequent infusions. The most common ≥ G3 events were neutropenia (9%) and pneumonia and anemia (5% each). G3 CRS was a dose-limiting toxicity (DLT) in 2 pts at a priming dose of 2 mg; subsequent target dose escalation continued to 24 mg with a priming dose of 1 mg and no further DLTs of CRS; MTD at the target dose has not been reached. The 2 SCBC patients had confirmed partial responses (PR). Of the 10 NEPC patients, 3 of 6 with at least one imaging study had unconfirmed PRs. HPN328 exhibited linear PK with dose-proportional increases in exposure and a median T1/2 of 71 hrs. Transient increases in cytokines up to 24 hrs post-dose and T-cell activation were observed. Conclusions: HPN328 is well tolerated and clinically active. MTD determination, dose escalation, and dose optimization are ongoing. Updated safety and efficacy results including recently enrolled NEPC and SCBC pts will be presented. Clinical trial information: NCT04471727 .
Differential treatment effect on overall survival (OS) based on early prostate-specific antigen (PSA) response in metastatic hormone-sensitive prostate cancer (mHSPC): A secondary analysis of TITAN trial.
Authors: Roy Soumyajit , Malone Shawn , Sun Yilun , Wallis Christopher J.D. , Kishan Amar Upadhyaya , Morgan Scott C. , Gebrael Georges , Swami Umang , Jia Angela , Brown Jason R , Saad Fred , Agarwal Neeraj , Spratt Daniel Eidelberg 
Published: January 2024

126 Background: Early PSA response has been found to be associated with improved outcome in mHSPC patients treated with androgen deprivation therapy (ADT) plus androgen receptor pathway inhibitors (ARPI). However, it is unknown if the treatment effect on OS varies based on early PSA response in these patients. Methods: We performed a secondary analysis of TITAN study in which men with mHSPC were randomly assigned to ADT plus placebo vs. ADT plus apalutamide (ADT+APA). To compare the association of OS with early PSA response, defined as achieving a PSA nadir of ≤0.2 ng/mL at ≤6 months of randomization, between two arms, we applied multivariable Cox regression model on a landmark population with an interaction term between the treatment arm and PSA response. Adjusted OS were calculated. Confounders were chosen based on their association with PSA response and OS. Results: Overall, 1049 patients were eligible with 526 in the ADT arm and 523 in the ADT+APA arm. Approximately 24% (125/526) patients in the ADT arm and 62% (323/523) patients in the ADT+APA arm achieved early PSA nadir. On landmark analysis, ADT+APA was associated with improved OS among those with an early PSA nadir (HR: 0.66; 95% CI: 0.44-1.00) but no improvement in OS among those without an early PSA nadir (HR: 1.15 [0.87-1.46]) with differential treatment effect between groups stratified by early PSA nadir by 6 months (p=0.03). Adjusted 4-year OS for patients who reached PSA nadir was 66% (95% CI: 56-75) in the ADT alone arm and 78% [74-83] in the ADT+APA arm while for patients who did not reach PSA nadir, adjusted 4-year OS was 46% [41-52] and 47% [40-54] in the ADT alone and ADT+APA arm, respectively. Numbers needed to treat (NNT) was 7.8 (95% CI: 6 to 15) for the overall landmark population, 7.7 [5 to 36] for patients with PSA nadir by 6 months, and 55 [10 to -4] for those without PSA nadir, respectively. Conclusions: In this exploratory analysis of TITAN study, early PSA nadir at or before 6 months was associated with superior OS in both treatment arms. However, there was evidence of differential treatment effect on OS based on early PSA nadir with no beneficial effect from ADT+APA in those who did not reach early PSA nadir. Patients with lack of early PSA nadir had inferior and similar OS in both treatment groups. Further investigation is needed to determine how to best manage patients treated with doublet therapy without an early PSA response.
(ARTO trial-NCT03449719): Role of local treatment after progression in patients with castrate-resistant prostate cancer undergoing first-line abiraterone treatment.
Authors: Francolini Giulio , Di Cataldo Vanessa , Detti Beatrice , Garlatti Pietro , Caini Saverio , Bruni Alessio , Ingrosso Gianluca , D'Angelillo Rolando Maria , Alitto Anna Rita , Augugliaro Matteo , Triggiani Luca , Parisi Silvana , Facchini Gaetano , Banini Marco , Simontacchi Gabriele , Desideri Isacco , Meattini Icro , Valicenti Richard K. , Livi Lorenzo 
Published: January 2024

130 Background: ARTO (NCT03449719) is a multicentre, randomized phase II trial testing the benefit of concomitant stereotactic body radiation therapy (SBRT) and abiraterone acetate (AA)+ prednisone administration in oligometastatic Castrate Resistant Prostate Cancer (CRPC) patients. Results already showed significant benefit in terms of biochemical response and Progression Free Survival (PFS) in the experimental arm. To explore role of local treatment throughout the whole clinical history of these patients, here is reported a subgroup analysis focusing on impact of treatment (SBRT vs second line systemic therapy) after progression. Methods: Patients affected by oligometastatic CRPC (</= 3 non-visceral metastatic lesions) were enrolled in the trial and randomized 1:1 to receive either AA+ prednisone alone (control arm) or associated with concomitant SBRT on all sites of disease (treatment arm). PFS2 was defined as time between first progression event and second progression, death or last follow up. Cox regression analysis was performed to compare PFS2 in patients treated with SBRT on oligo-progressive metastatic sites vs patients undergoing second line systemic therapy (primarily taxane chemotherapy). Results: One hundred fifty-seven patients were enrolled in ARTO trial. At last follow up (August 2023), 77 patients progressed after abiraterone+ prednisone treatment (23 vs 54 in the experimental vs control arm, respectively). Of these, 14 received best supportive care and were excluded from the analysis, 23 underwent SBRT on oligo-progressive metastatic sites (17 and 6 originally randomized to the experimental vs control arm, respectively), 40 were treated with second line systemic treatment. A second progression event was detected in 14 patients. Median PFS 2 was 10 months (95% CI 10-17) and 10 months (95% CI 7-12) for patients undergoing SBRT vs second line treatment, respectively (HR 1.26, 95% CI 0.33-4.75, p 0.73). Conclusions: When oligoprogressive status is detected, SBRT may achieve similar benefit if compared to second line systemic treatment. These data, in the context of a randomized trial with positive results for primary endpoints, suggest that repeated SBRT may be a viable treatment option in selected patients. Clinical trial information: NCT03449719 .
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 B. , Michalski Jeff M. , Bouchard Myriam , Desai Neil B , Funk Ryan , Boike Thomas , Jurgens Donald James , Wong Anthony C. , Shen Xinglei , Miyawaki Lloyd T , Bland Christopher S , Hairston John C , Sandler Howard M. , Pugh Stephanie L , Feng Felix Y 
Published: January 2024

131 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 .
Oral cyclophosphamide (Cyc) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC): A retrospective cohort from a tertiary public cancer center in Brazil.
Authors: Ricucci Shinkado Yumi , Pineda Labanda Diana Del Cisne , Polho Gabriel Berlingieri , Alves Contado Gustavo , Crusoé Nathália de Souza Del Rey , Horita Vivian , Resende Martins João Carlos , Fialho de Freitas Guilherme , Muniz David Queiroz Borges , Mota Jose Mauricio 
Published: January 2024

150 Background: Oral Cyc is an active treatment for mCRPC, although largely unused in current clinical practice due to the rise of more effective options and no evidence of survival benefit. Real-world data on its use in developing countries is still scarce. Methods: We reviewed our institutional database to identify mCRPC pts who received oral Cyc. Medical charts were analyzed to extract clinical data. PSA50 response was determined as the proportion of patients achieving a prostate specific antigen (PSA) declines ≥50%. Radiographic responses and progression were evaluated by Prostate Cancer Working Group 3. Survival estimates used the Kaplan-Meier method and correlations were made with the Chi-square test for categorical variables. Results: From January 2011 to January 2023, 287 pts received oral Cyc. Most patients (>96%) received 100 mg once daily 3 weeks on/1 week off. Median age was 64.3 years (interquartile range [IQR] 35.8-85.3). 63.1% had metastatic de novo disease, 57.1% had Gleason ≥8, and 5.9% had visceral metastasis. 78.1% received two or more previous lines of treatment, and most pts (73.5%) had docetaxel previously. Any PSA decline was observed in 36.0%, and 15.0% had a PSA50 response. Median time for a PSA50 response was 2.7 months (IQR 1.3-3.8). Radiographic overall response rate was 24.2%. Median time on treatment was 2.53 months (IQR 0.40-51.9). Median time to PSA, clinical, or radiological progression among responders was 6.9 months (IQR 0.7-51.9), but 16.6% (n=7) had responses lasting for ≥12 months. Permanent treatment discontinuation due to toxicity occurred in 14.1%, and 8.0% were hospitalized due to adverse events. Table shows the association between baseline factors with PSA50 response. Correlative biomarker studies are ongoing and will be presented. Conclusions: Metronomic oral Cyc can benefit a small proportion of patients with mCRPC in a scenario of limited healthcare resources. [Table: see text]
Radiographic progression without PSA progression in metastatic hormone-sensitive prostate cancer (mHSPC): A retrospective analysis from the ENZAMET trial (ANZUP 1304).
Authors: Davis Ian D. , Martin Andrew James , Zielinski Robert Richard , Thomson Alastair , Tan Thean Hsiang , Sandhu Shahneen , Reaume M. Neil , Pook David William , Parnis Francis , North Scott A. , Marx Gavin M. , McCaffrey John , McDermott Raymond S. , Inderjeeth Andrisha Jade , Horvath Lisa , Frydenberg Mark , Chowdhury Simon , Chi Kim N. , Stockler Martin R. , Sweeney Christopher ,   The Australian and New Zealand Urogenital and Prostate Cancer Trials Group
Published: January 2024

151 Background: ENZAMET randomized 1125 participants with mHSPC to compare enzalutamide (ENZA) versus a standard non-steroidal anti-androgen (NSAA) and demonstrated superior progression-free survival and overall survival (PFS and OS) with ENZA. Radiographic progression in the absence of prior/concurrent PSA progression (rProg1st) is an emerging biomarker of poor clinical outcomes. We sought to determine the frequency of rProg1st, and correlate the impact of enzalutamide on transitions between disease states for the ENZAMET cohort. Methods: The ENZAMET dataset was analyzed using a multi-state Cox proportional hazards regression model that partitioned the clinical experience of participants (pts) into 4 states: (1) Evt-Free (event-free), (2) rProg1st (radiologic progression recorded without prior/concurrent evidence of confirmed PSA progression), (3) OtherProg (All Other type of clinical progression events (PSA and treatment switch, excluding death), (4) Death. Results: Radiographic progression was recorded in 388/1125 (34%) pts. Radiographic progression without confirmed prior/concurrent PSA progression per protocol was recorded in 114/1125 (10%) with similar proportions in those assigned ENZA 55/114 (48%) vs NSAA 59/114 (52%). Baseline characteristics of the 114 pts with rProg1st were similar to the other pts in ENZAMET, and were similar in the ENZA and NSAA groups (Table 1). Compared with NSAA, ENZA delayed both rProg1st (HR 0.66, 95%CI: 0.46 to 0.96, p=0.03) and OtherProg (HR 0.37, 95%CI: 0.31 to 0.44, p<0.001). 5-year OS rates were 24% (95%CI: 18-34) in the rProg1st group versus 42% (95%CI: 38-47) in the OtherProg group. Of those who had not progressed (495/1125) with a median follow-up of 68 months, 8% had died of causes other than prostate cancer. As previously reported ENZA prolonged overall survival in the whole trial cohort (N=1125, HR 0·70, 95%CI 0·58 to 0·84, p<0·0001). Conclusions: Participants who had radiographic progression without prior/concurrent PSA progression had worse overall survival whether assigned NSAA or enzalutamide. Enzalutamide reduced the hazards for, and delayed the times to, rProg1st and OtherProg. There were no baseline characteristics that helped identify these pts upfront; we plan molecular biological analyses to help identify this unique group earlier. Clinical trial information: NCT02446405 . [Table: see text]
Predicting abiraterone efficacy in advanced prostate cancer: Insights from marker of proliferation Ki-67.
Authors: Zhao Fengnian , Zhao Jinge , Shi Yifu , Wei Xinyuan , Chen Ni , Shen Pengfei , Zeng Hao 
Published: January 2024

176 Background: The marker of proliferation Ki-67 (KI67) is a well-known biomarker reflecting cell proliferation activity and was reported to be associated with the treatment efficacy of chemotherapy in different tumors. However, it is unknown whether KI67 also has a role in predicting the efficacy of the next-generation hormone therapies, e.g., abiraterone, for patients with prostate cancer (PCa). Methods: Clinicopathological data of 144 men with metastatic PCa who received abiraterone therapy were retrospectively collected. The KI67 positivity was examined by immunohistochemistry (IHC) using the prostate biopsy specimen. The predictive value of KI67 and other factors on the therapeutic efficacy of abiraterone treatment was explored. Kaplan-Meier curve and COX regression analysis were used for survival analysis. The endpoints were PSA progression-free survival (PSA-PFS) and radiographic progression-free survival (rPFS) according to the PCWG3 criteria. Results: Among the 144 included patients, 82 (56.9%) and 62 (43.1%), respectively, received abiraterone therapy at metastatic hormone-sensitive (mHSPC) and castration-resistant PCa (mCRPC) stage. The median KI67 positivity was 20% for the total cohort (interquartile range: 10%-30%). When taken as a continuous variable, KI67 positivity was adversely related to both PSA-PFS (HR, 95%CI: 1.02, 1.01-1.03, P=0.001) and rPFS (HR, 95%CI: 1.02, 1.02-1.03, P=0.001) of the abiraterone therapy, while was not associated with PSA response. The results of multivariate COX regression analysis implied that, after adjusting by mHSPC/mCRPC stage, ISUP grading, pain score, visceral metastasis, and metastatic burden, KI67 was still an independent predictor of PSA-PFS (HR, 95%CI: 1.02, 1.01-1.03, P=0.001) and rPFS (HR, 95%CI: 1.02, 1.01-1.03, P=0.008) of the abiraterone therapy. Moreover, when patients were divided into two groups with high and low KI67, using cutoffs of 10%, 20%, and 30%, KI67 remained a significant predictor of both PSA-PFS (HR: 1.67, 1.91, 2.29; P value: 0.052, 0.004, <0.001) and rPFS (HR: 1.54, 1.83, 1.88; P value: 0.119, 0.008, 0.008) of the abiraterone treatment. Subgroup analysis based on whether patients received abiraterone at mHSPC or mCRPC stage suggested that KI67 30% (median PSA-PFS: 11.4- vs. 27.6-Mo, P<0.001; median rPFS: 16.6- vs. 33.6-Mo, P=0.001) was the optimal cutoff to maximize patient prognostic differentiation for the mHSPC cohort, while KI67 20% (median PSA-PFS: 6.9- vs. 14.9-Mo, P=0.033; median rPFS: 10.1- vs. 16.5-Mo, P=0.030) was the optimal cutoff for the mCRPC cohort. Conclusions: Our study revealed that KI67 positivity in prostate biopsy specimens was a robust predictor of abiraterone efficacy for patients with advanced PCa. Further validation using datasets from other centers is needed to strengthen the findings of our work.
Effect of combined treatment with sipuleucel-T and IL-15 on tumor control, tumor-infiltrating immune effectors, and key mediators of immunoresistance in a preclinical prostate cancer model.
Authors: Pachynski Russell Kent , Saeed Muhammad Azeem , Peng Bo , Van Tine Brian Andrew , Sheikh Nadeem Anwar , Fehniger Todd A. 
Published: January 2024

177 Background: Sipuleucel-T (sip-T) is an autologous therapeutic vaccine produced using a tumor antigen-cytokine fusion protein, and the only FDA approved cellular immunotherapy for metastatic castration-resistant prostate cancer (mCRPC) patients. Sip-T significantly improves overall survival (OS), but has limited impact on PSA and radiographic responses. Here, we present the first high dimensional analysis of the sip-T product; we used a preclinical model of human prostate cancer to show the effects of IL-15 on anti-tumor efficacy, tumor infiltration of effector cells, and reversal of immunosuppressive mediators. Methods: We performed a comprehensive assessment of the sip-T product collected from prostate cancer patients using mass cytometry (CyTOF). Control and IL-15 stimulated sip-T were evaluated, and changes in leukocyte subsets as well as markers of activation and exhaustion were identified. Using a preclinical mouse model of human prostate cancer, we examined the effects of IL-15 treatment on sip-T. CyTOF, flow cytometry, RNAseq, and qPCR were used to evaluate the effects of IL-15 on sip-T phenotype, function, and in vitro and in vivo efficacy. Results: CyTOF analysis revealed that CD3+ T cells constituted the highest proportion of sip-T, followed by B-cells, natural killer (NK) cells, NKT, and monocytes, with only a small percentage of dendritic cells. Following sip-T stimulation with IL-15, a significant expansion and activation of CD8+ T-cell and NK cell populations was seen. Co-culture of sip-T with IL-15 and control or prostate-relevant antigens showed significant activation and expansion of CD8 T and NKT cells in an antigen-specific manner, with significantly increased tumor cytotoxicity and evidence of antigen spread. IL-15 treatment combined with sip-T in a preclinical mouse model showed significant suppression of tumor growth compared to sip-T alone, with increased tumor-infiltrating lymphocytes (TIL). A significant increase in interferon (IFN)-γ producing CD8+ T and NKT cells within the tumor microenvironment was seen in the IL-15 group. Tumor transcriptomic analyses revealed IL-15 treatment was able to reverse immunoresistance, with significant decreases in PD-L1, CTLA, TIGIT, B7-H3, and others compared to sip-T alone. Conclusions: This is the first study to evaluate the sip-T product using CyTOF, and the first pre-clinical in vivo prostate tumor modeling of sip-T. IL-15 treatment significantly enhances anti-tumor efficacy, effector immune cell activation and tumor infiltration, and reverses key mediators of immune suppression. Studies with modified IL-15 cytokines are ongoing and will be presented.