bluuebunny/crossref_metadata_2025_split huggingface dataset:
Preliminary results from a phase 1/2 study of co-stimulatory bispecific PSMAxCD28 antibody REGN5678 in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Stein Mark N. , Zhang Jingsong , Kelly William Kevin , Wise David R , Tsao Kai , Carneiro Benedito A. , Falchook Gerald Steven , Sun Furong , Govindraj Shilpa , Sims Jennifer S , Zhu Min , Seebach Frank A. , Lowy Israel , Thanigaimani Pradeep , Sandigursky Sabina , Miller Elizabeth 
Published: March 2023

154 Background: Pts with mCRPC have a poor prognosis with limited treatment options, including minimal response to immunotherapies. REGN5678 is a first-in-class, full-length anti-PSMAxCD28 bispecific costimulatory antibody designed to target prostate cancer cells and enhance T-cell activation. We report preliminary results from the dose escalation part of a first-in-human, open-label, Phase 1/2 study (NCT03972657) examining REGN5678 in combination with cemiplimab, a PD-1 blocking antibody. Methods: Pts with mCRPC had received ≥2 lines of systemic therapy in the metastatic and/or castration-resistant setting, including ≥1 second-generation anti-androgen. Pts received REGN5678 weekly at dose levels [DL] 0.1–300 mg, initially as monotherapy for 3 weeks, followed by combination with cemiplimab (350 mg Q3W) until progression or toxicity. Primary objectives are safety, tolerability, and pharmacokinetics. Preliminary efficacy measurements include decline in prostate-specific antigen (PSA) from the start of combination treatment and radiographic response from baseline. Results: At the data cutoff (DCO; July 27 2022), 35 pts had been treated. Treatment-emergent adverse events (TEAEs) ≥Grade (G)3 occurred in 54% (19/35) of pts. Cytokine release syndrome occurred in 6 pts (all G1) and there were 2 dose-limiting toxicities (both G3): pain (at 1 mg) and Guillain-Barré syndrome (at 300 mg). 4 pts (11%) experienced a ≥G3 immune-mediated adverse event (imAE; at DLs 30–300 mg). REGN5678 exposure was non-linear over the tested DLs (more than dose proportional). There were minimal signs of efficacy at lower DLs (REGN5678 0.1–10 mg), with only 1/16 pts showing a PSA decline (of 21%). More PSA declines occurred at higher DLs: 1/4 pts at 30 mg (a PSA decline of 100%), 3/8 at 100 mg (>99%, 44%, 22%), and 3/4 at 300 mg (>99%, 99%, 82%). Notably, all ≥G3 imAEs occurred in pts with PSA declines. Among pts with measurable disease and ≥1 on-treatment scan, radiographic response per RECIST 1.1 occurred in 1/3 pts at 30 mg (complete response), 1/4 at 100 mg (unconfirmed partial response [PR]), and 1/1 at 300 mg (PR confirmed after DCO). Conclusions: Preliminary data on REGN5678 plus cemiplimab in pts with mCRPC provide first evidence of clinical activity of a CD28 co-stimulatory bispecific antibody in solid tumors. Clinical activity was observed at DLs 30–300 mg. ≥G3 imAEs occurred in pts with PSA declines, suggesting a possible association. The study is ongoing to determine the maximum tolerated and recommended Phase 2 doses. Clinical trial information: NCT03972657 . [Table: see text]
Phase II trial evaluating olaparib maintenance in patients with metastatic castration resistant prostate cancer (mCRPC) after docetaxel treatment, reaching partial or stable response: SOGUG-IMANOL study.
Authors: Juan FITA Maria Jose , Anido Herranz Urbano , Mendez Vidal Maria Jose , Gironés Regina , Mellado-Gonzalez Begoña , Sepulveda Sánchez José Manuel , Alvarez-Fernandez Carlos , Climent Miguel Ángel , Heras Lucia 
Published: March 2023

168 Background: Prostate cancer is the second most common cancer in men. A number of important systemic therapies have been developed to treat mCRPC and now comprise the current therapeutic landscape. Docetaxel became the first systemic therapy to improve survival in these men in a randomized study demonstrating superiority versus mitoxantrone (18.9 months versus 16.5, p=0,004). But, inexorably, after stopping, disease progresses. Methods: A prospective phase II trial was designed to test Olaparib maintenance efficacy, in terms of progression free survival (PFS), in patients with mCRPC with DNA-repair defects that have achieved partial or complete response after being treated with systemic therapy (at least six cycles of docetaxel). Results: 134 mCRPC patients were included since Feb-2018 to Nov-2020 and were tested for DDR alterations. 19.4% of patients had somatic mutations (30.8% BRCA2, 3.8% BRCA1, 19.2% ATM, 7.7% CHEK2, 7.7% PALB2). 53,8% received Olaparib maintenance treatment, with a median follow-up of 23.3 months. Median age was 73 years. Median basal PSA was 17 ng/dL. 100% were metastatic (14.3% de novo and 85.7% relapsed after primary treatment), 78.6% had bone metastasis, 35.7% visceral and 35.7% adenopathies. 42.9% had previous treatment with abiraterone and 35.7% with enzalutamide. 46.2% received at least 8 cycles of docetaxel. 7.1% achieved a partial response and 92.9% a disease stabilization. Response to Olaparib treatment was 14.3% partial response, 71.4% stabilization and 7.1% disease progression.14.3% had a PSA50 decrease. Median duration of response was 8.27 months. Median PFS was 10.1 months. Median PSA-PFS was 3.5 months. G3/4 adverse events were 21.4% asthenia,14.3% anemia and 7.1% neutropenia. Conclusions: Olaparib maintenance after at least six cycles of docetaxel shows promising activity in mCRPC with DDR alterations, with an acceptable toxicity profile. Our pathogenic mutations percentage (19,4%) is in line with previous publications. Clinical trial information: NCT03434158 .
Phase Ib trial of enzalutamide (Enza) with venetoclax (Ven) in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Perimbeti Stuthi , Jamroze Anmbreen , Attwood Kristopher , Farmer Bailey , Beumer Jan Hendrik , Bies Robert , Levine Ellis Glenn , Kirk Jason , Tang Dean , Chatta Gurkamal S. , Gopalakrishnan Dharmesh 
Published: March 2023

182 Background: Androgen receptor (AR) signaling is critical to prostate cancer (PCa) cell survival and proliferation. Androgen ablation leads to expansion of both AR−/lo and AR+/hi resistant clones in CRPC xenografts. Most current therapies for mCRPC are directed towards AR+/hi cells. BCL-2 is highly up-regulated in CRPC xenografts and human tumors post-Enza. Ven, a selective BCL-2 inhibitor, inhibits Enza resistance in AR−/lo and CRPC models. We hypothesize that co-targeting AR−/lo and AR+/hi clones with Ven and Enza may inhibit Enza resistance in human mCRPC. Methods: This is a phase 1b single center, single arm trial of fixed dose Enza (160mg/d) with escalating doses of Ven in patients with mCRPC that has progressed on multiple lines of prior therapies including antiandrogens to evaluate pharmacokinetics, safety and recommended phase 2 dose. A total of 10 patients were enrolled in the study. Three dose levels of Ven (400mg (DL1), 600mg (DL2), and 800mg (DL3)/d q28d) were evaluated using a 3+3 study design. Kaplan Meier method was used to estimate median overall survival (OS) and time to next systemic therapy (TNST). Results: Median age was 71.3 years and mean duration on treatment was 28.7 weeks (range: 8-140 weeks). On an average, each patient received 3 lines of treatment prior to enrollment(range:1-8). The most frequent treatment related adverse events (TRAEs) (>10%) were mostly grade 1-2 as listed. Grade 3 TRAEs included hypertension (20%), fatigue (10%), and thrombocytopenia (10%). Grade 3 fatigue as DLT was reported in one patient in DL3. Only 1/10 (10%) attained PSA50 response; 4/10 (40%) patients had stable disease and 6/10 (60%) had disease progression as their best radiographic response. Median OS for the study population was 18.8 months (95% CI 5.3-28.2 months) and median TNST was 5.4 months (95% CI 0.9-34.6 months). Conclusions: This phase 1b trial demonstrates an acceptable toxicity profile for the combination of Enza and Ven in refractory mCRPC. PK evaluations and correlative biomarker studies are currently ongoing. Clinical trial information: NCT03751436 . [Table: see text]
Therapeutic potential of plant-derived nanovesicles for neuroendocrine prostate cancer.
Authors: Saini Sharanjot , Sreekumar Amritha , Lee Tae Jin , Sharma Ashok , Simmons Matthew 
Published: March 2023

186 Background: Neuroendocrine prostate cancer (NEPC) is a highly lethal variant of prostate cancer (PCa) that often emerges after androgen receptor (AR)-targeted therapies such as enzalutamide and abiraterone. NEPC arises via trans-differentiation of prostate adenocarcinomas to neuronal lineage, a process referred to as ‘neuroendocrine trans-differentiation’ (NED), wherein prostate cancer cells show an altered expression of lineage markers such as decreased expression of AR and increased expression of neuronal markers. Currently, there is a lack of effective targeted therapies for NEPC. Current treatment options are limited to highly toxic platinum-based drugs. Hence, there is an urgent need to develop novel treatment strategies to treat NEPC. The focused objective of this study is to develop novel, non-toxic therapeutic intervention against NEPC. Towards this, we exploited the potential of plant-derived nanovesicles/extracellular vesicles as a novel therapeutic. Extracellular vesicles (EVs) are lipid-bilayer-delimited particles that are released from almost all types of cells, including plant cells, typically between 30-150 nm in size. Methods: EVs/nanovesicles were isolated from plant-derived sources by ultracentrifugation. Isolated nanovesicles were characterized by Nanoparticle Tracking Analyses and electron microscopy. After characterization, the effects of nanovesicles were tested in NEPC cell lines in vitro. Effects on cell viability and apoptosis were assessed by MTS assay and flow cytometry, respectively. To understand the mechanistic basis of EV induced alterations, next generation RNA sequencing was performed in control vs EV treated NCI-H660 cells on Illumina HiSeq platform. Significant targets were further validated by real time PCR and Western blot analyses. Results: Plant-derived nanovesicles reduced viability and induced apoptosis in NEPC cell lines. Genes involved in ECM-receptor interaction, focal adhesion, proteoglycans in cancer and small cell lung cancer genes were significantly impacted by these vesicles in NEPC cell line. Remarkably, nanovesicles led to significantly attenuated levels of key proneural transcription factors including ASCL1, BRN2 and SOX2. In addition, neuronal markers ENO2 and NCAM1 were downregulated suggesting that treatment with nanovesicles reverse the ‘cardinal’ genetic alterations that drive NEPC. Conclusions: Plant-derived nanovesicles can be employed as a novel treatment modality in neuroendocrine prostate cancer.
Transdermal square-wave testosterone therapy: A pilot trial in metastatic castration-resistant prostate cancer.
Authors: Candelario Nellowe , Nicklawsky Andrew , Graham Laura , Lam Elaine T. , Callihan Eryn , Wacker Michael , Flaig Thomas W. , Kessler Elizabeth R 
Published: March 2023

188 Background: Metastatic castration-resistant prostate cancer (mCRPC) becomes resistant to anti-androgen therapies due to a variety of adaptive mechanisms. Intramuscular bipolar androgen therapy (BAT) which alternates between high and low testosterone (T) levels is therapeutically active in mCRPC and confers sensitivity to second-generation androgen receptor antagonists such as enzalutamide (ENZA). We hypothesized that transdermal T with sustained supraphysiologic T levels would lead to high response rates to ENZA in mCRPC. We also hypothesized Square-wave transdermal T therapy would be a safe alternative to BAT due to the ability to quickly withdraw therapy in the setting of symptoms. Methods: This was an open-label, single-site, phase 2 feasibility trial in men with asymptomatic mCRPC who had not previously received ENZA. Transdermal T was administered at a dose of 100 mg/day for a minimum of 12 weeks and until disease progression. Therapy was then switched to ENZA 160 mg/day until next disease progression. Patients who initially responded to T could receive a second course of transdermal T followed by ENZA, remaining on study until progression on both T and ENZA, or for the 12-month study duration, whichever was sooner. ADT was continued throughout. The primary endpoint of the study was feasibility. T dose was adjusted to achieve T levels between 900-1500 ng/dL. Secondary end points included PSA50 response rate (50% decline in PSA) and safety. Results: Fifteen patients were enrolled. Ten (66.7%) had Gleason >8 disease. Thirteen (86.7%) patients had bone metastases. Median baseline PSA was 11.73 ng/mL. Primary endpoint of feasibility based on patient recruitment and retention was met. The median testosterone level on T was 901.3 ng/dL (Range: 645.2 to 1171.1). Median time on therapy was 15.9 weeks on T and 25.9 weeks on ENZA. PSA50 was 13.3% on initial T therapy and 66.7% after switching to ENZA. Three (20%) patients did not initiate ENZA after T progression. Two desired to avoid androgen-related side effects and 1 initiated chemotherapy. No Grade 3 or higher adverse events (AEs) occurred on T and the most common AEs were weight gain, rash, and nipple sensitivity. Conclusions: Square-wave transdermal T alternating with ENZA is feasible and achieves adequate T levels in the treatment of asymptomatic mCRPC. Given the acceptable safety profile and quick reversibility, transdermal T warrants further exploration, and we have expanded enrollment to include higher risk patient populations. Clinical trial information: NCT03734653 .
Outcomes of systemic treatment in patients with metastatic pheochromocytoma and paraganglioma: A single center retrospective analysis.
Authors: Park Young Gyu , Yoon Shinkyo , Park Inkeun , Lee Jae-Lyun 
Published: March 2023

2 Background: Pheochromocytomas and paragangliomas (PPGLs) are neuroendocrine tumors arising from chromaffin cells of the adrenal medulla or extra-adrenal paraganglia. Although 15-17% of patients develop metastatic disease, there are very limited systemic treatment options. In this study, we aimed to evaluate the treatment landscape and outcome in PPGL patients retrospectively. Methods: Between December 2004 and December 2021, 33 patients were diagnosed with metastatic PPGLs and received systemic treatment at the Department of Oncology, Asan Medical Center, Seoul, South Korea. Metastatic PPGLs included a locally advanced unresectable disease, initially metastatic disease, and recurrent disease. Systemic treatment involves cytotoxic chemotherapy and targeted agents, and efficacy analysis included the objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Results: The median age at diagnosis was 49 years (range, 15–74), 17 patients were male (52%), and 22 patients were pheochromocytomas (67%). Disease status was recurrent (73%), initially metastatic (21%), and locally advanced (6%). Of 23 patients who underwent germline tests, 14 (61%) were identified with germline mutations, and the most frequent mutation was SDHB germline mutation (n=8, 57%). Of the 33 patients, 18 received chemotherapy with cyclophosphamide, vincristine, and dacarbazine (CVD). The ORR was 22% (4/18; all PR), and the disease control rate (DCR) was 67% (n=12). The median PFS was 7.9 months [95% confidence interval (CI), 1.6-not available (NA)], and the median OS was 36.2 months (95% CI, 5.7-NA). Six patients were treated with sunitinib, and the ORR was 33% (2/6; all PR), and the DCR was 83% (n=5). The median PFS was 14.6 months (95% CI, 3.6-NA), and the median OS was 14.6 months (95% CI, 3.6-NA). In CVD treatment, patients with SDHB/SDHD mutation (either germline or somatic) were significantly associated with superior OS & PFS compared with the non-SDHB/SDHD mutation group, with a median OS of 94.0 months vs. 5.7 months (P = 0.01) and a median PFS of 20.1 months vs. 1.6 months (P = 0.03), respectively. In the SDHB/SDHD mutation group, the ORR was 50% (3/6, all PR), and the DCR was 100% (n=6), but in a non-SDHB/SDHD mutation group, the ORR was 11% (1/9, PR) and the DCR was 44% (n=4). Conclusions: Systemic treatment with CVD and sunitinib provided meaningful disease control, and outcomes were comparable with previous data. Especially, CVD treatment was effective in patients with SDHB/SDHD mutation, and further validation is needed in future studies.
Effects of docetaxel on circulating immune cell subsets and association with outcomes in metastatic castration-sensitive prostate cancer.
Authors: Chandran Elias , Goswami Meghali , Donahue Renee Nicole , Atiq Mohammad O. , Karzai Fatima , Bilusic Marijo , Marte Jennifer L. , Arlen Philip M. , Cordes Lisa M. , Owens Helen , Hausler Megan , Hankin Amy , Williams Monique , Dahut William L. , Figg William Douglas , Schlom Jeffrey , Gulley James L. , Madan Ravi Amrit 
Published: March 2023

207 Background: Docetaxel with androgen deprivation therapy (ADT) has been shown to improve survival in metastatic castration-sensitive prostate cancer (mCSPC). There is limited data on the immunologic effects of docetaxel in mCSPC. Greater knowledge of the immune impact of docetaxel could inform future trials in prostate cancer. Methods: A clinical trial in mCSPC evaluated sequencing docetaxel and ADT with Prostvac, a poxviral vaccine targeting prostate-specific antigen (PSA). Eligibility criteria included mCSPC within 4 months of ADT and ECOG performance status 0-2. Patients given 6 cycles of docetaxel 75mg/m2 with ADT alone for mCSPC were included in this analysis. Peripheral blood mononuclear cells (PBMCs) were sampled at baseline and at 3 weeks after commencing docetaxel. Immune cell subsets analyzed included CD4+ and CD8+ T-cells, T regulatory cells (Tregs), natural killer (NK) cells, dendritic cells (DCs) and myeloid-derived suppressor cells (MDSCs). Analyses were performed to determine if the baseline immune status or immune changes induced by therapy associate with PSA at 2 years. Results: Fifteen patients were evaluated for peripheral immune responses in this study. Median age was 63 years (range 50-73). Fourteen were white and 1 was black. ECOG performance status was 0 in 11 patients, 1 in 4 patients. Disease volume was high in 7 and low in 8 patients. Among 158 immune cell subsets assessed, only changes in Tregs and activated NK cells with a lytic and cytokine producing phenotype (CD16+ CD56br) were noted after initiation of docetaxel in addition to ADT. Patients with PSA ≤0.2 at 2 years had higher baseline frequencies of total CD4+ T cells, several activated CD4+ T-cell subsets, plasmacytoid DCs, and CD49d- Tregs. They also had lower baseline frequencies of total CD8+ T cells, naïve CD8+ T cells, and CD73+CD8+ T-cells. Patients with PSA ≤0.2 at 2 years also had greater percent increases in CD8+ effector memory (EM) PD-1+ T-cells after treatment. Conclusions: This is the first study to demonstrate increases in activated NK cells with lytic and cytokine producing potential after treatment with docetaxel. Given that NK cells are associated with clinical outcomes in prostate cancer (Zhao SG, JNCI, 2019) and that increased NK cells were seen after treatment with enzalutamide as well (Madan, JITC, 2021), developing immunotherapy combinations to capitalize on NK cell activity may be a path forward for developing immunotherapy in prostate cancer. Clinical trial information: NCT02649855 . [Table: see text]
Evaluating p53 nuclear expression and prostate cancer progression in a predominantly African American cohort.
Authors: Gesztes William , Lap Coen , Dalivand Maryam , Hamilton Colleen , Martha Antonio , Byrne Morgan , Diao Guoqing , Jain Maneesh Rajiv , Nava Victor 
Published: March 2023

217 Background: Increased utilization of next-generation sequencing has revealed evidence of early TP53 alterations in localized prostate cancer (PCa), suggesting a growing clinical potential for p53 immunohistochemistry (IHC). Prior research by Harmon and Gesztes et al. (Radiology, 2021 & Scientific Reports, 2022) support the clinical utility of detecting p53 overexpression in core biopsies and radical prostatectomies (RP) to predict underlying TP53 alterations, biochemical recurrence (BCR), and metastasis. However, to date, no established consensus exists evaluating p53 “overexpression” in PCa. This study aimed to compare two fundamental approaches to assess p53 expression across various specimens with regard to PCa progression. A secondary study aim explored whether ethnic differences in p53 expression exist. Methods: This retrospective cohort study comprised 84 randomly selected PCa patients (46 metastatic; 38 non-metastatic) enrolled between 1996 – 2021 at the DC VA Medical Center. Representative sections of core biopsies (60%), RP (17%), prostate chips (7%), and metastatic deposits (16%) were examined, where (%) equals a share of the total cohort. IHC was performed on selected sections with a p53 monoclonal antibody (Biocare Medical; p53 Tumor Suppressor Protein; clone DO-7). p53 nuclear expression was manually scored according to the highest intensity (0 absent, 1+ weak, 2+ moderate, or 3+ marked) and percentage (0%, <1%, 1-5%, and >5%) of tumor cell nuclei observed in one index block per patient. All slides were reviewed by two pathologists who were blinded to clinical data. Fisher’s exact test was used to test the association between p53 positivity and categorical variables. Results: Of 84 men included, 63 (75%) self-identified as African American (AA). The median follow-up time was 6.2 years. Thirty-four patients (40%) exhibited p53 nuclear expression, of which 18 patients (21%) showed marked (3+) nuclear intensity. Notably, 11 of 18 (61%) 3+ patients displayed <5% p53 expression. All patients with >5% p53 positivity showed marked (3+) p53 staining. The presence of marked p53 staining, regardless of percentage, was found to be significantly associated with a higher Gleason score ( p=0.0002), higher PSA at the time of biopsy ( p<0.0001), BCR ( p=0.0007) and metastasis ( p<0.0001). Importantly, marked p53 staining was identified only in patients who developed metastatic disease. No significant differences were observed in marked p53 expression between AA and Caucasian men. Conclusions: In prostate cancer, marked (3+) p53 nuclear intensity (regardless of the percentage) is associated with disease progression with no observable ethnic predilection. Therefore, careful assessment of intensity is essential to avoid under-detection (when percent criteria are applied) and maximize the number of patients who may benefit from enhanced clinical interventions.