bluuebunny/crossref_metadata_2025_split huggingface dataset:
Retrospective review of 250 gallium-68 PSMA scans in prostate cancer patients in Health Canada Special Access Program.
Authors: Cohen Philip Frank , Tarzwell Robert , Leong Jason 
Published: June 2023

e17035 Background: Prostate Cancer is the most common malignancy in men, and until recently has been staged using standard imaging tests, such as ultrasound, CT, bone scan, and MRI. A novel imaging test targeting the membrane receptor, Prostate Specific Membrane Antigen (PSMA) using the PET tracer Ga-68 PSMA-11 has recently been approved in several countries for staging and assessing potential for radionuclide therapy. This agent was only recently approved in Canada, but has been available through the Health Canada Special Access (SA) Program for over a year, until it was approved (Illuccix, Telix Pharmaceuticals). Methods: In the past year, 275 prostate cancer patients were scanned at our facility (INITIO Medical Imaging, Burnaby BC) through Health Canada SA. All patients were required to have positive prostate cancer biopsies, with negative or indeterminate CT and bone scan, and rising PSA (prostate specific antigen) blood test in order to qualify for SA, or high risk Gleason Score prostate cancer. Results: Of the 275 patients, 71 had high risk cancers and 28/71 had positive PSMA studies (39%). 185 of the patients had biochemical evidence of recurrence and negative /indeterminate conventional imaging tests, and 101/185 or 55% had positive PSMA scans. All other patients were scanned for metastatic castrate resistant prostate cancer (MCRPC). Conclusions: Ga-68 PSMA scans are highly sensitive for upstaging patients at high risk of prostate cancer metastasis or recurrence, even with negative conventional imaging studies.
Therapy with metronomic cyclophosphamide (mCyc) in metastatic castrate resistant prostate cancer (mCRPC) and genomic correlates.
Authors: Mar Nataliya , Dwabe Sami , Zarrabi Kevin Kayvan , Eturi Aditya , Kelly William Kevin , Rezazadeh Arash 
Published: June 2023

e17041 Background: Multiple historic studies demonstrated activity of mCyc in various solid tumors, including mCRPC. Low doses of oral mCyc can lead to enhanced immune stimulation by depleting regulatory T-cells. Its adverse effect profile is well established, with grade 3 and 4 toxicities being rare. In recent years, use of mCyc in mCRPC has fallen out of favor with development of novel therapies. Methods: We conducted a retrospective study of all patients with mCRPC, who received therapy with mCyc for at least 4 weeks at the University of California Irvine and Thomas Jefferson University between 6/1/17 and 1/31/23. Different oral mCyc regimens were included - 50 mg daily continuously, 50 mg daily on days 1 to 14 out of a 28-day cycle, and 250 mg daily on days 1 to 14 out of a 28-day cycle. Results: A total of 20 patients were included, from 62 to 92 years in age. At prostate cancer (PCa) diagnosis, 60.0% (12/20) had de novo metastatic disease. Duration of mCyc therapy was 4 to 41 weeks. Median number of unique PCa therapies received prior to mCyc was 4 [range: 1 to 9], with 75.0% (15/20) pretreated with taxane-based chemotherapy. 25.0% (5/20) of patients achieved a 50% drop in PSA (PSA50), while 30.0% (6/20) achieved PSA reduction but less than PSA50. 10.0% (2/20) had PSA stability without reduction, but experienced improvement in cancer-related symptoms. In those with PSA50, median duration of therapy was 16.3 weeks [range: 14 to 41]. In PSA responders, median time to PSA nadir was 7.2 weeks [range: 1 to 28]. After starting mCyc, 38.5% (5/13) of patients with any PSA or clinical response (i.e. responders) had a transient PSA rise followed by PSA decline, which is suggestive of tumor flare. In responders, 15.4% (2/13) had liver metastasis and 7.7% (1/13) had bone marrow involvement with associated cytopenias. In responders with previous prostate biopsies, 66.6% (6/9) had Gleason 9 or 10 disease. 53.8% (7/13) of responders had genomic data available with a liquid biopsy or tissue sequencing, revealing 3 patients with TP53 mutations and 1 patient with BRCA2 and RB1 co-mutations. 15.0% (3/20) of patients required dose reduction and 20.0% (4/20) dose interruption due to toxicity, with no treatment discontinuations observed. Adverse reactions leading to dose modifications included cytopenias, anorexia, fatigue, nausea, and diarrhea. Conclusions: Despite availability of novel therapeutics for mCRPC, treatment options remain limited. Recognizing the small sample size of this retrospective dataset, oral mCyc showed promising activity with a quick onset of action and a tolerable toxicity profile in heavily pretreated mCRPC patients with aggressive disease features. Given its unique mechanism of action, this provides rationale for future clinical trials, including combining mCyc with other immunomodulating agents such as PD1/PD-L1 inhibitors.
Clonal hematopoiesis of indeterminate potential (CHIP) and association with response to bipolar androgen therapy (BAT).
Authors: Holler Albert E , Gondek Lukasz , Tsai Hua-Ling , Markowski Mark Christopher , Paller Channing Judith , Carducci Michael Anthony , Denmeade Samuel R. , Antonarakis Emmanuel S. , Luo Jun , Marshall Catherine Handy 
Published: June 2023

e17048 Background: CHIP, the expansion of hematopoietic cells carrying acquired somatic alterations associated with hematologic malignancies, is associated with increased inflammation, risk of heart disease, and poor outcomes. BAT, where testosterone levels are therapeutically manipulated between castrate levels to supraphysiologic levels, has been shown to be an effective therapy for some men with castration resistant prostate cancer. Clinical predictors of response are not established. We hypothesized that CHIP, would be negatively associated with clinical outcomes. Methods: Baseline peripheral blood from participants on the RESTORE Cohort C (NCT02090114) were analyzed for the presence of CHIP. Patients in this cohort had castration resistant prostate cancer with progressive disease after treatment with ADT alone. All participants were treated with 400mg of intramuscular testosterone cypionate every 28 days. Peripheral blood mononuclear cells were analyzed for the presence of CHIP using targeted next generation sequencing focused on 49 genes most commonly mutated in CHIP and myeloid malignancies. Given patients had metastatic and non-metastatic CRPC, progression free survival was determined based on the time to the start of the next therapy. Results: CHIP was present in 6 of 29 patients at baseline (21%) with one patient having 2 clones (Table). Median age of patients CHIP+ was 73 compared to age of 68 in the CHIP- group (p = 0.16). Median PSA was higher in the CHIP+ group (median 15, IQR 1-56) compared to the CHIP- group (median 3.5, IQR 1-57). 67% of the CHIP+ group and 57% of the CHIP- group had baseline Gleason scores of > = 8. The CHIP+ group had a median PFS of 8.8 months compared to 13.3 months in the CHIP- group (HR 3.3 95%CI 1.2, 9.1; p = 0.02). This remained significant after adjusting for age. There was no difference in overall survival (HR = 2.5 95% CI 0.5,2.9; p = 0.3). Conclusions: Among men treated with BAT as first line treatment for CRPC after ADT alone, CHIP was associated with a decreased progression free survival. Larger studies are needed to understand the impact of CHIP in larger cohorts of men treated with BAT and other therapies for prostate cancer.[Table: see text]
Castration-resistant prostate cancer (CRPC) on PSMA-PET: Imaging features, disease distribution, and a comparison to castration-sensitive prostate cancer (CSPC).
Authors: Hsu Miles , Shan Xinhe , Zhang Rebecca , Pantel Austin , Takvorian Samuel U , Narayan Vivek , Vaughn David J. , Vapiwala Neha , Haas Naomi B. 
Published: June 2023

e17062 Background: 18F-DCFPyL PET/CT is increasingly used in the staging and response assessment of patients (pts) with prostate cancer. Recent studies suggest that short-term ADT increases prostate-specific membrane antigen (PSMA) expression, whereas long-term ADT suppresses PSMA. Changes in PSMA expression after the development of CRPC are uncertain. We described 18F-DCFPyL PET findings in pts with CRPC and compared them to findings in CSPC. Methods: We analyzed 538 18F-DCFPyL scans performed at our large academic center. CRPC was defined as rising PSA w/ testosterone < 50 ng/dL on ADT. M0 CRPC was defined as absence of extra-pelvic disease (dz) and oligometastatic CRPC (oCRPC) was defined as ≤ 5 LN + osseous lesions and absence of visceral dz. Highest SUV max (hSUVmax) was abstracted from radiologist impression. Means between groups were compared using two-tailed t-tests; undetectable PSA levels were scored as “0”. Logistic regression was used to compare dz distribution between castrate states. Significance was defined as p < 0.05. Results: There were 81 pts with CRPC, 72 pts with metastatic CRPC (mCRPC) and 123 pts with mCSPC. The median ages of pts with mCRPC (74.5 years) and mCSPC (71) were similar. The mean PSAs of mCSPC (20.2 ng/mL) and mCRPC (69.4) were significantly different. hSUVmax was higher in mCRPC (mean 40.3, 95% CI 32.7 – 47.8) than in mHSPC (22.6, 18.4 – 26.9), p < 0.001. Distribution of mCRPC lesions was as follows: prostate bed (26.4%), local pelvic LN (25%), distant LN (M1a, 41.7%), osseous (M1b, 16.7%), and visceral (M1c, 16.7%). In a multivariate analysis mCRPC pts had lower rates of pelvic LN dz and higher rates of M1c, with a trend toward increased M1b (p < 0.10), compared to mCSPC pts. ADT and androgen pathway inhibition did not affect hSUVmax in CRPC. Within CRPC, there were 9 pts with M0 dz, 24 pts with oCRPC, and 48 pts with polymetastatic dz (pmCRPC). The ages (Table) of pmCRPC and oCRPC pts were similar. The mean PSA of pmCRPC (100.9) was higher than that of oCRPC (8.8) and M0 CRPC (5.7). hSUVmax between oCRPC (40.3) and pmCRPC (40.3) was similar. Conclusions: The greater hSUVmax in mCRPC may implicate the effect of ADT on PSMA expression or may describe differing tumor biology. mCRPC pts had less local dz and more frequent distant metastases, likely reflecting more advanced disease. These findings will help inform detection of developing castrate resistance on PSMA-PET. More data are needed on the classification of oligometastatic dz on PSMA-PET and the impact of hormone therapy on PSMA in CRPC. [Table: see text]
Impact of pre-treatment hemoglobin (Hgb) on outcomes in metastatic castration resistant prostate cancer (mCRPC) with lutetium-177-PSMA-617 (Lu-177).
Authors: Nelson Ariel Ann , Riemersma Kristin , Bylow Kathryn A. , Holt Michael , Kilari Deepak 
Published: June 2023

e17065 Background: The Phase 3 VISION and TheraP trials excluded men with Hgb≤ 9 g/dL or blood transfusion within 30 days of Lu-177. Patients (pts) with mCRPC who are eligible for Lu-177 are often pancytopenic due to marrow infiltration and previous cytotoxic therapy. Clinicians are often faced with the dilemma of packed red blood cell (RBC) transfusion (Tx) to meet “eligibility requirements" of Lu-177. The impact of low Hgb levels on treatment (trt) outcomes is unclear. Methods: We retrospectively identified pts with mCRPC who received at least one cycle of Lu-177 between July 2022 and January 2023 at a single institution. Demographic, disease, laboratory and trt characteristics were recorded. Pts with Hgb level ≤10 g/dL or who received RBC Tx up to 14 days prior to the first Lu-177 dose were compared to pts with a pre-trt Hgb level ≥10 g/dL and no prior PRBC Tx. Data were summarized using descriptive statistics. Time to trt discontinuation was defined as the time from the first Lu-177 cycle until progressive disease per treating physician (clinical, radiographic, PSA progression) or adverse effect necessitating cessation and compared using the Kaplan Meier method. Cox proportional hazard regression analysis were utilized to assess the association of Hgb ≤ or ≥ 10 g/dL on the risk of trt discontinuation. Results: 51 pts were included, median follow up was 5.75 months, median age 70 years, 90% Caucasian. 49% (n = 25) had Gleason 9 /10 disease. Median number of prior trt was 4. 94% (n = 48), received prior docetaxel and 39% (n = 20) received prior cabazitaxel. 27% (n = 14) of pts had either Hgb≤10 or received a RBC Tx prior to trt. Of these, 50% of pts (n = 7) had stopped Lu-177 prior to completion of 6 cycles. Median number of cycles was 3. Reasons for trt cessation included clinical decline (n = 4), PSA or radiographic disease progression (n = 2), cytopenia (n = 1). Of pts who had Hgb ≥10 (n = 37), most (86%) are in ongoing trt, 11% (n = 4) have stopped trt due to progressive disease, 1 pt died. Pts with Hgb≤10 had a shorter time to trt discontinuation, 4.5 months (95% CI: 4.43- NA) vs not reached for those with Hgb≥10, p = 0.004 and an increased risk of trt discontinuation HR = 1.65 (95% CI: 1.53-18.09, p = 0.009). Conclusions: Pre-trt Hgb≤10 g/dL may be associated with worse outcomes in pts with mCRPC undergoing trt with Lu-177 and caution should be exercised. A larger data set and longer follow up is needed to further investigate outcomes in this pt population. Multivariable analysis is planned. [Table: see text]
Androgen receptor inhibitors and anti-NKG2A checkpoint inhibitor to enhance NK cell–mediated killing of prostate cancer cell lines in vitro.
Authors: Schwermann Maximilian , Tajiknia Vida , Zhou Lanlan , George Andrew , Srinivasan Praveen , De Souza Andre , Mega Anthony E. , Safran Howard , Carneiro Benedito A. , El-Deiry Wafik S. 
Published: June 2023

e17066 Background: The blockade of the androgen receptor (AR) pathway is essential for the treatment of prostate cancer (PC). Checkpoint inhibitors have limited activity in immunologically cold prostate tumors. Emerging results suggest that AR signaling modulates CD8+ T cells and modifies its cytotoxic function, but the therapeutic role of NK cells in anti-tumor immune response in PC remains unknown. We investigated the mechanisms of AR inhibitors (ARi) enzalutamide (Enza) and darolutamide (Daro) on the antitumor function of NK cells and their enhancement when combined with NKG2A inhibitor. Methods: We performed co-culture assays with PC cell lines (LNCap, 22Rv1 [ARv7 mutation], DU145, PC3 [AR-]) and NK-92 cells, in a 1:1 ratio, in the presence of ARi and in combination with the anti-NKG2A mAb monalizumab and analyzed immune cell-mediated tumor cell killing (ImageXpress Confocal HT). NK cells expression of NKG2A and PD-1 receptors and PC cell lines expression of HLA-E and PD-L1 were investigated after treatment with Enza and Daro by flow cytometry. Results: ARi significantly increased immune-mediated NK-92 cell killing of PC cell lines at 24hrs (control[C]: 15.8%±3.9; Enza: 40%±4.3; Daro: 36%±3.72, p < 0.0001). This immune enhancement effect was increased by NKG2A blockade with monalizumab ([C]: 31.2%±3.1, [T]: 43.92%±4.52, p = 0.0045). Treatment of the LNCaP cell line (AR+) with ARi increased HLA-E ([MFI values x10³] control[C]: 28.57±2.9; [T]: 37.38 ±1.2 p = 0.0046) and PD-L1 expression ([MFI values x10³] control[C]: 163.1±8.1; [T]: 202.5±11.2 p = 0.003). No significant difference was observed in the surface expression of these markers in the AR- cell lines. NKG2A surface expression on NK cells was also upregulated upon treatment with ARi ([MFI values x10³] control[C]: 52.42±2.9; [T]: 61.4 ±2.2 p = 0.008). Conclusions: Enza and Daro enhance NK cell killing of PC cell lines, and the combination of ARi with checkpoint inhibitor monalizumab promotes NK cell activation. Blockade of AR signaling modulates PC cells' expression of HLA-E and PD-L1 and NK cell expression of NKG2A. These results describe a novel modulatory effect of androgen on NK cell function and provide insights for future NK-cell-based therapeutic approaches for treating PC. Experiments validating these results in patient samples are ongoing.
Development of BLX-3030, a potent and selective inhibitor of CDK9 for the treatment of NMYC-driven NEPCS.
Authors: Medley Kyle , Li Zhaoliang , Lin Chenyu , Bearss David J , Vankayalapati Hariprasad 
Published: June 2023

e17067 Background: Cell lineage reprogramming in cancer cells is a major mechanism for cancers to develop drug resistance and escape targeted therapy. The use of new potent targeted therapies in prostate cancers has led to the development of highly aggressive cancers, including neuroendocrine prostate cancer (NEPC).Gene amplification of N-MYC and C-MYC oncogenes leads to its overexpression in NEPC and mCRPC patients. This overexpression is highly prevalent in these lethal subtypes of cancers, detected in 2% of all Prostate Cancers (PCa) and over 10-17% of mCRPC patients. N-MYC is a transcriptional target of CDK9, which acts as an oncogenic driver, sufficient to transform human-derived prostate cancer cells to take on NEPC phenotypic changes. This results in a more aggressive disease identified in late-stage human PCa patients. Additionally, N-MYC and C-MYC are required for tumor drug resistance and its downregulation, through CDK9 inhibition, lowers tumor growth. Our efforts have demonstrated that targeting both N-MYC and C-MYC as a driver of NEPC and mCRPC with a highly selective CDK9 inhibitor (BLX-3030) is a viable approach for therapeutic intervention of mCRPC and NEPC. Methods: We employed our AI/ML driven FIELDS fragment-based design strategies, in vitro including FACS/apoptosis, cell migration, live cell imaging, immunofluorescent and in vivo tumor models, 7-day tox, PK, selectivity, and ADME-Tox and in vitro safety and secondary pharmacological assays. Results: We discovered and synthesized a series of novel small molecule CDK9 agents that reversibly bind to CDK9, competitively block the ATP site with an IC50 of < 5 nM, and elicit pharmacological responses in N-MYC, C-MYC, and other prostate cancer cells in vitro and in vivo. We detected the expression of CDK9 and N-MYC in PC-3, DU-145, LNCaP, LASCPC-01, NCI-H660, and 22RV1 cell lines. BLX-3030 exhibited potent cellular efficacy in PC cells (IC50 of 22 to 590 nM) and in N-MYC expressed cells (IC50 of 76, 470, and 132 nM), respectively. BLX-3030 reduced pCDK9, C-MYC, Mcl-1, N-MYC and its downstream RNA Pol II (Ser-2) and pAR (Ser-81) in a dose dependent manner. Additionally, we performed FACS/apoptosis, cell migration, and live cell imaging, including immunofluorescence. We also conducted three separate in vivo efficacy mouse models (LASCPC-01, 22RV1, and C4-2) which demonstrated > 70% TGI. Several in vitro ADME-Tox, hERG, P450, safety panel screen, in vivo MTD and dose range finding experiments in SD rats and beagle dogs will also be presented. Conclusions: In summary, a series of BLX-3030 and its analogs display a potency in MYC-driven PCa, with ideal PK properties in rodent, canine species ranging 28-82 % F, with low clearance, and > 3.0 hr half-life. Within this profile, BLX-3030 was selected as a candidate that had the appropriate developable properties. Our plans for IND enabling studies and future clinical trials will also be discussed.
Efficacy and safety of darolutamide in Chinese patients with metastatic hormone-sensitive prostate cancer (mHSPC): A subpopulation analysis of the phase 3 ARASENS study.
Authors: Wang Shanshan , Fu Cheng , Zou Qing , Li Youyuan , He Dalin , Wang Shaogang , Wang Hongkai , Smith Matthew Raymond , Tombal Bertrand F. , Hussain Maha H. A. , Niu Yi , Cai Ling , Hu Nan , Huang Shiyun , Kapur Shivani , Li Rui , Kuss Iris , Ye Dingwei 
Published: June 2023

e17076 Background: Darolutamide (DARO) is an androgen receptor inhibitor approved in China for the treatment of nonmetastatic castration-resistant prostate cancer (CRPC). In the global ARASENS trial, DARO significantly increased overall survival (OS) vs placebo (PBO) in patients (pts) with mHSPC. The efficacy and safety of DARO in the Chinese subpopulation of ARASENS are reported here. Methods: In this randomized, double-blind phase 3 trial, 1305 pts with mHSPC were randomized 1:1 to receive DARO 600 mg orally twice daily or PBO, in combination with androgen-deprivation therapy (ADT) and docetaxel. The primary endpoint was OS. Results: In mainland China, 202 pts were randomized to the DARO group (n = 104) or the PBO group (n = 98). Demographics and baseline characteristics were well balanced between treatment groups and comparable to the overall ARASENS population, except for a slightly higher proportion of pts with Gleason score ≥8, higher proportion with metastatic disease at diagnosis, and higher median baseline prostate-specific antigen (PSA) in Chinese pts vs the overall population. The risk of death was reduced by 36% (HR 0.64, 95% CI 0.41–0.99) with DARO vs PBO in Chinese pts (Table). The key secondary endpoint time to CRPC (HR 0.32, 95% CI 0.20–0.50) and the exploratory endpoint time to PSA progression (HR 0.22, 95% CI 0.13–0.37) also favored DARO. In the DARO group, 81% of pts had a maximum PSA decline of ≥90% from baseline (PSA90) at week 12, while 88% had PSA90 and 71% reached PSA < 0.2 ng/mL at any time. Incidences of treatment-emergent adverse events (TEAEs) in Chinese pts were similar between treatment groups and comparable to the overall population. The most common grade 3/4 TEAE in Chinese pts was neutropenia (DARO 64%, PBO 62%), a known toxicity of docetaxel; grade 3/4 febrile neutropenia occurred in 4.0% of Chinese pts compared with 7.6% in the overall population. Conclusions: In the ARASENS subpopulation of Chinese pts with mHSPC, DARO + ADT + docetaxel showed favorable efficacy and safety vs PBO + ADT + docetaxel: OS and clinically relevant secondary endpoints favored DARO vs PBO, and the incidences of TEAEs were similar in the two treatment groups. These results are consistent with the findings reported for the overall population in ARASENS. Clinical trial information: NCT02799602 . [Table: see text]