bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase II study of RC48-ADC in HER2-negative patients with locally advanced or metastatic urothelial carcinoma.
Authors: Xu Huayan , Sheng Xinan , Yan Xieqiao , Chi Zhihong , Cui Chuanliang , Si Lu , Tang Bixia , Mao Lili , LIAN BIN , Wang Xuan , Li Siming , Zhou Li , Bai Xue , Guo Jun
Published: May 2020

e17113

Background: RC48-ADC is a novel humanized anti-HER2 antibody-drug conjugate (ADC). A phase II clinical study showed that RC48-ADC has a good effect on locally advanced or metastatic urothelial carcinoma with HER2-positive expression that failed standard chemotherapy. In the study, some patients with HER2-postive immunohistochemistry (IHC 2+) but negative FISH test still benefit from the treatment of RC48-ADC.The study was to evaluate the activity and safety of RC48-ADC in HER2-negative patients with locally advanced or metastatic urothelial carcinoma. Methods: This study is an open-label, single-center, one-arm, non-randomized phase II trial. Eligibility criteria include: histologically confirmed urothelial carcinoma, HER2-negasitive (IHC 0 or 1+), ECOG PS 0-1, treated with ≥1 prior systemic treatment. The patients received RC48-ADC treatment alone (2mg/kg IV infusion, q2w) until disease progression, unacceptable toxicity, withdrawal, or study termination. The primary objectives were activity (ORR) and safety. Progress-free survival, disease control rate and overall survival will also be assessed. Results: As of February 2020, 8 patients were enrolled in the study. The median age was 65 years old. At baseline, most patients (6/8) had visceral metastasis. 6 (75%) patients had received≥2 lines treatment and 4 (50%) patients had prior immune checkpoint inhibitor (CPI) therapy in second line treatment. The objective response rate was 25% (2/8) and the DCR was 75% (6/8). The ORR was 33.3% (2/6) in patients with visceral metastasis and was 50.0% (2/4) in liver metastasis patients. The ORR was 33.3% (2/6) in patients post to ≥ 2 lines of treatment and 25% (1/4) in patients post to immunotherapy. Common treatment-related AEs were AST increase (62.5%), ALT increase (50.0%), nausea (50.0%), leukopenia (37.5%), fatigue (37.5%), vomiting (37.5%), hypoesthesia (25.0%), alopecia (25.0%), and neutropenia (25.0%). Most of these AE were Grade 1 or 2. The AE of Grade 3 was neutropenia (12.5%). The SAE was CPK increased (12.5%). Conclusions: The study showed that RC48-ADC was safety and the ORR was 25% in HER-negative patients with locally advanced or metastatic urothelial carcinoma. Clinical trial information: NCT04073602.
Effect of androgen deprivation therapy combined with nivolumab on the systemic antitumor immune response in castration-sensitive prostate cancer.
Authors: Dallos Matthew , Chaimowitz Matthew , Stein Mark N. , Lim Emerson A. , Hawley Jessica , Tagawa Scott T. , Nanus David M. , Kelly William Kevin , Drake Charles G.
Published: May 2020

e17503

Background: To date, immunotherapy has limited efficacy in castration-resistant prostate cancer. However, we previously reported that androgen deprivation therapy (ADT) has significant immunomodulatory effects and can induce a complex immune cell infiltrate before castration-resistance develops. Therefore, we designed an ongoing clinical trial to assess the effects of immunotherapy plus ADT in men with recurrent castration-sensitive prostate cancer (CSPC) (NCT03689699). We hypothesized that PD-1 blockade given at the time of castration could induce systemic anti-tumor immune responses with epitope spreading and modulate key circulating cytokine networks. Methods: 15 patients with recurrent CSPC were treated with nivolumab (480mg) every 4 weeks for 8 weeks followed by nivolumab plus degarelix for an additional 16 weeks. Sera was collected at 3 time points: pre-treatment, after nivolumab alone (8 weeks) and at completion of therapy with nivolumab plus degarelix (24weeks). To assess the therapeutic effects on systemic humoral immune responses and to evaluate for induction of epitope spreading, we analyzed treatment-induced serum IgGs against an array of self-antigens over time. We also performed a 44-parameter electrochemiluminescence assay to measure the effects of therapy on innate cytokines and the Th1/Th2 and Th17 pathways. Results: ADT combined with PD-1 blockade led to significant changes in systemic immunity including induction of humoral antigen spread with IgG responses to secondary tumor antigens including PSA, KLK2, K-Ras and modulation of key circulating cytokines. We observed a significant increase in mean levels of IFN-gamma (8.68 +/- 10.74 pg/ml vs 9.53 +/- 7.36 pg/ml), an increase in IL-10 (0.37 +/- 0.29 pg/ml vs 0.66 +/- 0.53 pg/ml) and a decrease in IL-8 (106.7 +/- 275.47 pg/ml vs 25.49 +/- 23.09 pg/ml) when comparing cytokine levels before and after nivolumab plus degarelix respectively. Conclusions: ADT plus nivolumab led to significant changes in systemic immunity and overall appeared to promote a pro-inflammatory state. This immune response also appeared tumor specific with induction of humoral responses against secondary tumor antigens. However we also observed changes in targetable immunosuppresive cytokines like interleukin-8 and are currently testing whether ADT plus combined PD-1 and IL-8 blockade can further promote robust anti-tumor immune responses in prostate cancer. Clinical trial information: NCT03689699 .
A novel liquid biopsy aid for identifying clinically significant prostate cancer in at-risk men: Combining artificial intelligence with flow cytometry-based immunophenotyping.
Authors: Dominguez George , Campisi Anthony J , Roop John , Kumar Amit
Published: May 2020

e17508

Background: Current screening methods for prostate cancer (PCa) result in a large number of false positives making it difficult for clinicians to assess disease status thus warranting advancements in screening and early detection methods. The goal of this study was to design a liquid biopsy assay that uses flow cytometry-based immunophenotyping and artificial intelligence (AI) analysis to detect clinically significant PCa in at-risk men. Methods: Standard multiparametric flow cytometry techniques were used to immunophenotype 27 different MDSC, myeloid, and lymphocyte cell populations found in the peripheral blood of 114 biopsy-confirmed PCa (GS6 = 54; ≥ GS7 = 60) and 58 biopsy-confirmed benign prostatic hyperplasia (BPH) patients. Pattern recognition neural networks (PRNNs), a type of AI, were trained with flow cytometry data from two data sets: patients with confirmed clinically significant PCa (≥ GS7) versus patients with BPH or clinically insignificant PCa (GS6). Predictions were evaluated using the performance of the trained PRNNs on 37 known ≥ GS7 PCa patients and 40 known BPH/ < GS7 PCa patients not used in the PRNN training set (holdout samples). Results: In the holdout data set, 21 out of the 23 patients with clinically significant PCa were identified correctly (Sens = 91.3%, 95%CI = 72.0%-98.9%; PPV = 33.3%, 95%CI = 28.4%-38.7%) while 30 out of the 72 patients at low-risk or no-risk were identified correctly (Spec = 41.7%, 95%CI = 30.2%-53.9%; NPV = 93.8%, 95%CI = 79.5%-98.3%) for an accuracy of 53.7% (95%CI = 43.2%-64.0%). For all patients in this study, our data suggests that approximately 47 out of the 112 patients with BPH or GS6 PCa could have avoided an unnecessary prostate biopsy procedure. Conclusions: Pairing our PRNN with surface biomarker blood-based analyses of various leukocyte populations has enabled the ability to objectively identify patterns indicative for the existence of clinically significant PCa (≥ GS7). In a clinical setting, we believe that this technology, in use with other known clinical factors, would allow for clinicians to have a more informed decision when recommending their patients for a prostate biopsy procedure.
Comorbidity burden in prostate cancer patients by ESRD status.
Authors: Sarabu Nagaraju , Dong Weichuan , Fernstrum Austin , Ray Al , Ponsky Lee Evan , Koroukian Siran M.
Published: May 2020

e17510

Background: The co-occurrence of cancer and end-stage-renal disease (ESRD) may pose significant challenge in the management of both diseases. Further complicating clinical decisions is our limited understanding of the comorbidity burden (CB), which also affects their outcomes to a considerable extent. The purpose of this study is to characterize the CB in prostate cancer patients, with and without ESRD. Methods: Using SEER-Medicare database between years 2000-2016, we retrieved sociodemographic variables, including age (40-54, 55-64, 65-74, and 75+), race (African American vs. all others), marital status (married/partnered vs. all others), residence in a census tract with poverty rate > 20%, and dual Medicare-Medicaid enrollment status; chronic conditions identified in the year of cancer diagnosis; and ESRD status preceding prostate cancer diagnosis. We limited our study population to cancer patients enrolled in Medicare at the time of cancer diagnosis, and were receiving their care through the fee-for-service system. In this descriptive analysis, we compared the prevalence of these conditions between prostate cancer patients by ESRD status. Results: Our study population included 2,046 ESRD and 302,136 non-ESRD men diagnosed with incident prostate cancer during the study period. Compared to non-ESRD patients, a disproportionately higher percentage of ESRD patients were in the 40-54 and 55-64 age groups compared to non-ESRD (11.0 vs 0.95% and 32.2% vs. 8.51%, respectively). Similarly, the percentage of prostate cancer patients who were African American was 44.1% among ESRD patients, compared with 13.6% in their non-ESRD counterparts. With regard to comorbidities, several conditions were significantly higher in ESRD than non-ESRD patients, including: anemia (65.4% vs. 15.3%), congestive heart failure (31.1% vs. 8.9%), ischemic heart disease (38.9% vs. 25.2%), diabetes (40.7% vs. 17.0%), hypertension (68.0% vs. 42.6%), hypothyroidism (4.6% vs. 2.9%), hyperlipidemia (43.1% vs. 35.1%), and stroke (3.7% vs. 2.5%). Conclusions: Compared to their non-ESRD counterparts, ESRD patients present with high CB, severely compromising their physiologic reserve and tolerance for various cancer treatment modalities, and affecting outcomes. Future studies should compare the prevalence of specific combinations of conditions constituting multimorbidity between ESRD and non-ESRD patients, and identify multimorbidity profiles associated with a lower likelihood to receive standard treatment. Such detailed analysis will be foundational to clinical management and outcome studies.
Colina 111 PET results in a nonmetastatic castration-resistant cancer (nmCRPC) in population that is negative by conventional imaging: True incidence from real-world evidence data.
Authors: Pitzzu Martin , Gennari Luciana , Olguin Norberto , Jankilevich Gustavo
Published: May 2020

e17522

Background: Nonmetastatic Castration-Resistant Prostate Cancer (nmCRPC) is characterized by a rising prostate-specifing antigen (PSA) level, castrate testosterone levels,and no evidence of distant metastases by conventional bone scan and croos-sectional image of the chest,abdomen and pelvis. SPARTAN and PROSPER trials recently demonstrated metastasis free survival in patients with nmCPRC treated with apalutamide with androgen blockade therapy and enzalutamide respectively, Real incidence of nmCPRC in latinoamerican population is unknown. Therefore, patients with negative conventional imaging could be metastatic with PET use, fall the percentage of non metastatic setting PET Colina demonstrated improved sensitivity and specificity used for biochemically recurrent hormone – sensitive patients and staging advanced disease. Colina – PET performance in nmCPRC remain largely unknown and requires evaluation. In this study we examined the incidence of nmCPRC in an Argentinian population by conventional imaging studies and the impact of use of Colina Pet. Methods: Overall 300 patients from public and private insitutions were assessed. Real World Evidence Prostate cancer database were retrospectively screened for records of patients with nmCPRC. Results: Three hundred medical records of consecutive patients with prostate cancer were assessed. All patients were evaluated by multidisciplinary team Localized disease 214 patients and metastatic Prostate Cancer Castration Sensitive 86 patients. With a median a six years of median follow up, 43 patients developed Prostate Cancer Castration Resistant. Six patients showed nmCPRC criteria, in all of them Colina Pet was indicated. After PET colina 5 cases were positives and only one patient were negative. Conclusions: The incidence or nmCPRC is 0,02% in argentine cohort and drop out to 0,003% with PET use. Colina-PET detected loco-regional of M1 disease in nearly all patients with CPRC and no detectable metastasis by conventional imaging. Further epidemiologic with real world evidence data studies with cost-efective evaluations should be launched to put in context the rol of PET in this setting.
Prevalence and genetic features of TMPRSS2-ERG fusion in Chinese patients with prostate cancer.
Authors: He Wei , Sun Fukang , Zhao Juping , Jun Dai , Xu Le , Wang Chenghe , Fang Chen , Huang Xin , Chen Shiqing , Zhao Xiaochen , Bai Yuezong
Published: May 2020

e17529

Background: Prostate cancer (PCa) is one of the most common malignancies, with rising incidence rate in China. The Cancer Genome Atlas (TCGA) revealed 53% of patients with PCa had ETS family gene fusions. The most frequent fusion type of ETS fusions is TMPRSS2-ERG, which may predicts resistance to taxane and androgen-deprivation therapies. The prevalence of TMPRSS2-ERG fusion in Chinese PCa patients evaluated by fluorescence in situ hybridization (FISH) or immunohistochemistry (IHC) varied from 7.5% to 78.0%. However, the sample sizes were small. In the present study, we investigated the prevalence and genetic features of TMPRSS2-ERG fusion by next generation sequencing (NGS) in a larger Chinese PCa cohort. Methods: Genomic profiling was performed through NGS from Chinese patients with PCa between January, 2017 and November, 2019. Formalin fixed paraffin-embedded (FFPE) tumor specimens or blood samples from participants were collected for NGS. IHC staining for PD-L1 expression was performed using PD-L1 IHC 22C3 pharmDx assay or Ventana PD-L1 SP263 assay. Data analyses were performed using SPSS and R 3.6.1. Results: A total of 526 Chinese PCa patients were included in this study. The median age was 70 (range, 29-90) years old. We observed 13.1% patients with a positive PD-L1 expression, 3.0% patients with MSI-H, and a median TMB of 4.0 muts/Mb (range: 0-72.9). TMPRSS2 fusions were detected in 47 (8.9%) PCa patients, and 6.8% of patients had TMPRSS2-ERG fusion, which is significantly lower than that of Caucasian patients. The PD-L1 expression pattern and TMB distribution of the TMPRSS2-ERG fusion-positive patients were similar with TMPRSS2-ERG fusion-negative patients, however no fusion-positive patients were identified as MSI-H. Among these 36 TMPRSS2-ERG fusion-positive patients, the most frequently somatic mutations were detected in TP53 (38.9%), AR (11.1%), ATM (11.1%), and PTEN (11.1%). 9 (22.2%) patients harbored somatic mutations in PI3K/ AKT/mTOR pathway that has been previously demonstrated to collaborate with ERG to promote prostate cancer progression. Conclusions: This study revealed the prevalence and genetic features of TMPRSS2-ERG fusion in Chinese PCa patients by NGS in the first time. Our results provide a better understanding of molecular features in Chinese TMPRSS2-ERG fusion-positive PCa patients.
Defining diagnostic criteria for ductal prostate cancer on prostatic MRI.
Authors: Ranasinghe Weranja Kalana Bodhisiri , Troncoso Patricia , Kokorovic Andrea , Elsheshtawi Mohamed A , Zhang Miao , Aparicio Ana , Chapin Brian Francis , Bathala Tharakeswara
Published: May 2020

e17532

Background: Ductal prostate adenocarcinoma (DAC) is an aggressive histologic variant of prostate cancer (PCa) which often be missed due to their low PSA secretion. Further, a large proportion of DACs have extra-prostatic extension and nodal disease at presentation warranting accurate diagnosis and treatment planning. However studies have yet to differentiate DACs from high grade acinar PCas (PAC) on MRI. Therefore we aimed to develop MRI criteria to identify DACs and assess its diagnostic accuracy. Methods: Patients with histologically proven DAC who had MRIs prior to RP were identified from January 2011 to November 2018. Histology-based MRI diagnostic criteria were developed using RP specimens from nine patients with a pure dominant DAC focus and corresponding MRIs. Sixty-eight DAC patients were compared to a matched cohort of 70 patients with Gleason Score 8 or 9 PAC using the pre-defined MRI criteria. Chi-Squared, T tests, Mann Whitney U tests and sensitivity analyses were performed. Results: The following features of DAC were defined on MRI after correlation with histology: 1) intermediate T2 signal 2)well-circumscribed 3) lobulated tumor and 4) a dark peripheral rim. Majority of DACs were lobulated (79.4% vs 5.7%), with a dark peripheral rim on T2 weighted imaging (55.9% vs 4.3%) and had ≥3 MRI features compared to PAC (73.6% vs 7.2%) (all p < 0.001). Moreover, a higher proportion of pure DACs were lobulated (100% vs 5.7%), had a dark peripheral rim (94.7% vs 4.3%) and ≥3 MRI features (100% vs 7.2%) compared to PAC (all P < 0.001). There were no differences in median T2 contrast enhancement, ADC values or ADC ratios between the groups. Using our criteria MRI demonstrated sensitivity of 73.5%, specificity of 92.9 %, PPV of 90.9%, and NPV of 78.3% in diagnosing DACs if ≥3 features were present. In the diagnosis of pure DACs, MRI demonstrated sensitivity of 100%, specificity of 92.9%, PPV of 95.2%, and NPV of 100%. The area under the curve (AUC) for the diagnosis of all DACs was 0.81 and 0.98 for pure DACs. Conclusions: The presence of ≥3 features (well-circumscribed, lobulations and a dark peripheral rim and intermediate signal on the T2 phase) on prostatic MRI can help differentiate DAC from PAC. While this is the largest cohort of DACs to be analyzed, further studies are needed to validate these findings.
Racial disparities in utilization and effectiveness of first-line therapies in metastatic castrate-resistant prostate cancer.
Authors: Marar Mallika , Mamtani Ronac , Narayan Vivek , Vapiwala Neha , Parikh Ravi Bharat
Published: May 2020

e17541

Background: Prospective evidence suggests that abiraterone use is associated with improved progression-free survival in African-American (AA) men with metastatic castrate-resistant prostate cancer (mCRPC) compared to white men. It is unclear whether race-based differences in treatment utilization and effectiveness exist for men with newly diagnosed mCRPC treated in real-world clinical practice. Methods: In this retrospective cohort study, we used the Flatiron Health electronic health record-derived de-identified database to identify patients with mCRPC who received first-line (1L) systemic therapy between 2012 and 2018. We used multivariable logistic regression analysis to examine differences in utilization of abiraterone, enzalutamide, and docetaxel between AA and white men. We then used Fine-Gray models with death as a competing risk to assess treatment-specific associations between race and time to next therapy (TTNT) – a proxy for progression-free survival. Finally, we used multivariable Cox proportional hazards analyses to assess for treatment-specific racial disparities in all-cause mortality. All analyses were adjusted for age, Elixhauser comorbidity index, baseline steroid or opioid use (a proxy for disease aggressiveness), performance status, insurance status, and (if significant) an interaction term for race and age. Results: Of 3,808 mCRPC patients in the cohort, 2,165 (68.7%) were white and 404 (10.6%) were AA. At time of metastatic diagnosis, AA men were younger (69 vs. 75, p < 0.001) and more likely to have PSA value greater than 50 (57.9% vs. 42.6%, p < 0.001) compared to white men. Median follow up was 15 months. There were no significant racial differences in 1L utilization, TTNT, or all-cause mortality associated with abiraterone, enzalutamide, or docetaxel use (Table). Conclusions: In this large real-world analysis of men with mCRPC who received 1L therapy, we found no significant treatment-specific differences in utilization, TTNT, or all-cause mortality between AA and white men. Long-term prospective evidence is needed to justify differential treatment selection for AA men with mCRPC. [Table: see text]
Prostate cancer associated natural killer cells show a pro-angiogenic and pro-inflammatory phenotype.
Authors: Albini Adriana , Bruno Antonino , Gallazzi Matteo , Naselli Angelo , Mortara Lorenzo , Noonan Douglas M
Published: May 2020

e17544

Background: Prostate cancer (PCa) represents the second most common cancer worldwide in men. Angiogenesis has been shown to play a crucial role in PCa progression in several preclinical models. Production of pro-angiogenic factors can correlate with metastasis, Gleason score and prognosis in PCa and plasma levels of VEGF were shown to be higher in patients with metastatic PCa than those with localized disease. Natural killer (NK) cells, effector lymphocytes of the innate immunity, have been found to be immunosuppressed in solid cancers, including PCa. Methods: Here, we phenotypically and functionally characterize circulating NK cells from PCa patients and their interaction with endothelial cells and macrophages. NK cell subset distribution has been investigated by multicolor flow cytometry (FACS) for surface antigens on peripheral blood samples PCa patients (TANKs). Conditioned media (CM) from FACS-sorted TANKs were used for functional studies of angiogenesis, on human umbilical-vein endothelial cells (HUVEC), studies for macrophage recruitment (migration assay on Boyden chambers) and polarization. Molecular studies were performed by real time PCR (qPCR) on HUCECs and macrophages exposed to CM of TANKs. Protein arrays were performed to characterize the secretome on FACS-sorted TANKs. Results: We found that TANKs acquire a pro-angiogenic/ dNK-like CD56brightCD9+CD49a+CXCR4+ phenotype. The same phenotype was observed on cytolytic NK cells, from healthy donors, exposed to CMs of three different PCa cell lines (PC-3, DU-145, LNCaP), together with increased production of CXCL8, Angiogenin, Angiopoietin1 and reduced production of TNFa, IFNg and GranzymeA. CMs from TANKs support the formation on capillary-like structures on HUVEC, together with increased expression of VEGF, VEGR-2, CXCL8, ICAM-1 and VCAM-1. Secretome analysis revealed the ability of TANKs release pro-angiogenic pro-invasive factors (CLXL8, MMP-1, MMP-9; uPAR) and cytokines/chemokines involved in macrophage recruitment (CCL1, CCL2, CCL5, CCL7, CCL13, CXCL1, CXCL11) and M2-like polarization (IL-10). Finally, CMs from TANKs can recruit THP-1 monocyte and polarize THP-1 macrophage towards CD206, Arginase1, CXCL8-expressing M2-like/TAM phenotype. Conclusions: Our results place PCa TANKs as effector cells able in supporting angiogenesis in PCa by directly interaction with endothelial cells and via macrophage polarization.
Circulating tumor DNA-targeted sequencing to reveal germline and somatic alterations that can guide decision-making in metastatic castration-resistant prostate cancer.
Authors: Dong Baijun , Fan Liancheng , Yang Bin , Chen Wei , Li Yonghong , Wu Kaijie , Zhang Fengbo , Dong Haiying , Cheng Huihua , Yang Yining , Li Lei , Yao Xudong , Xue Wei
Published: May 2020

e17556

Background: The genomic landscape of metastatic castration-resistant prostate cancer (mCRPC) is dynamic with the application of multiple treatments. The circulating tumor DNA (ctDNA), which reveals germline and somatic alterations, provides a mini-invasive tool for monitoring tumor evolution. Methods: We performed an exploratory analysis of 299 ctDNA samples from 8 centers through application of multiple-gene deep targeted sequencing. Results: The most common recurrent genomic alterations were in AR(34.7%), TP53(18.9%), CDK12(15.4%), BRCA2(13.3%), and the majority of these clinically actionable gene alterations were identified in somatic level (CDK12 100% in somatic). The results showed the frequency of AR amplification and TP53 defect significantly increased in post-second and later line treatment group compared with treatment-naive group. AR amplification and TP53 or RB1 defect were associated with resistance to abiraterone or docetaxel. CDK12 was more frequently altered in our cohort than those in previous reports which mainly focused on Caucasian population. The patients with CDK12 defect showed rapid resistance to abiraterone and limited efficacy of Poly (ADP-ribose) polymerase inhibitors (PARPi). However, these patients seemed to benefit from chemotherapy, especially platinum-based chemotherapy. Conclusions: This multi-institutional real-world study explored the genomic landscape and captured the significant diversity of mCRPC at different treatment stages by liquid biopsy. These findings established genomic drivers associated with resistance to multiple treatments (including PARPi and platinum-based chemotherapy) in mCRPC. Hence, ctDNA targeted sequencing can help guide clinical decision making in mCRPC throughout the whole treatment process. CDK12 might be able to be a novel predictive biomarker to guide treatment selection in mCRPC.
The role of programmed death-ligand 1 and non-epithelial circulating tumor cells in locally advanced prostate cancer.
Authors: Li Ke , Mao Yunhua , Li Yiyuan , Wu Ruji , Wang Dejuan , Qiu Jianguang
Published: May 2020

e17557

Background: Circulating tumor cells (CTCs) is considered as an effective prognostic biomarker in malignancies. It is recently recognized that detections of programmed death-ligand 1 (PD-L1) and mesenchymal markers in CTCs may improve the predictive value. Therefore, we aimed to determine the cut-off values of these CTCs biomarkers in prostate cancer (PCa), assess the rates of PD-L1 positive and non-epithelial (NE) subgroup in CTCs among patients with high-risk (HRPC) and locally advanced PCa (LAPC) before surgery, and evaluate the clinical values of these markers. Methods: Four PCa cell lines selected from Cancer Cell Line Encyclopedia were applied in spiking experiments to establish the cut-offs of PD-L1 positive and NE CTCs. 182 HRPC and 89 LAPC patients were enrolled from June 2016 to December 2018. All patients underwent radical prostatectomy after blood sample collection. CTCs enumeration and biomarkers identification were conducted by Canpatrol CTC enrichment system and the RNA in situ hybridization technique. Lastly, using the cut-offs,we evaluated the association between CTCs markers and other variables in terms of clinical data, disease outcome, tumor tissues immunochemistry (IHC) staining, and the response of immunotherapy. Results: The cut-offs were determined as the lowest rates of NE and PD-L1+ CTCs among the cell lines, 45% and 25%, respectively. In HRPC patients, a higher PSA level and more advanced T stage were observed in the NE CTCs positive group (≥45%), compared with the negative group ( P= 0.041 and P= 0.004). Multivariate analysis showed that the NE CTCs rate, instead of total CTCs number, was an independent risk predictor for progression-free survival (PFS) (HR = 3.85, P= 0.013). In LAPC patients, the PD-L1+ CTCs positive group (≥25%) presented a higher PSA level and higher percentage of lymph node metastasis than negative group ( P= 0.027 and P= 0.028). The median PFSs between the two groups were 16.6 mouths vs. 21.8 mouths, respectively. (HR = 2.87, P= 0.002 ). No significant correlation was found between PD-L1 expression in CTCs and in tumor tissue IHC staining. However, we observed a significant correlation between PD-L1+ CTCs rate and ERG or PTEN expression in tissues ( P= 0.010 and P= 0.009). In addition, patients in PD-L1+ CTCs positive group presented a better PSA response to Durvalumab treatment than those in negative group. Conclusions: PD-L1+ and NE CTCs were an effective prognosis predictors for HRPC and LAPC patients with radical prostatectomy. LAPC patients with PD-L1+ CTCs might benefit from adjuvant immunotherapy
Genomic profiles and clinical outcomes to distinguish primary from secondary metastatic hormone-sensitive prostate cancer (mHSPC).
Authors: Nizialek Emily , Lim Su Jin , Wang Hao , Isaacsson Velho Pedro , Antonarakis Emmanuel S.
Published: May 2020

e17558

Background: Clinical outcomes may differ among pts with primary (de novo) mHSPC vs. secondary (relapsed) mHSPC occurring after previous local therapy. However, it is unknown what molecular features distinguish these potentially distinct presentations. Methods: A single-center retrospective study was performed using pts with mHSPC and available somatic genomic data. Clinicopathologic characteristics were collected, and pts were classified as primary mHSPC (n = 118) or secondary mHSPC (n = 104). A targeted set of genes suspected to influence disease severity and response to systemic therapy was analyzed: BRCA2, PTEN, RB1, TP53, SPOP, CDK12, combined PTEN/RB1/TP53 alterations (2 out of 3), and a composite of any homologous recombination deficiency (HRD) mutation. Hazard ratios for PFS and OS were compared between groups using the log-rank test. Differences in genomic features and baseline characteristics between groups were compared using Fischer exact and chi-squared tests. Results: Median PFS from initiation of first-line ADT was 16.0 mo and 28.9 mo for men with primary and secondary mHSPC, respectively (HR 0.59, 95% CI 0.43–0.83; P= 0.002). OS did not differ between groups (HR 0.92, 95% CI 0.56–1.52; P= 0.7) There were more men with Gleason 8-10 disease in the primary vs. secondary mHSPC groups (91% vs. 67%, P= < 0.01). In terms of molecular alterations, there were more PTEN and CDK12 mutations in the primary mHSPC group ( PTEN: 27% vs 19%, CDK12: 7% vs 3%), but more BRCA2 mutations in the secondary mHSPC group (5% vs 10%, respectively). In univariate analysis, PTEN mutations (HR 1.39, P= 0.08) and combined PTEN/RB1/TP53 mutations (HR 1.46, P= 0.09) predicted worse PFS; PTEN mutations (HR 1.63, P= 0.09) and combined PTEN/RB1/TP53 mutations (HR 2.38, P= 0.01) also predicted worse OS. In multivariable models adjusting for age at first metastasis and Gleason sum, only combined PTEN/RB1/TP53 mutations were predictive of worse OS (adjusted HR 2.32, 95% CI 1.14–4.71; P= 0.02). Conclusions: Compared to secondary mHSPC, primary mHSPC pts had higher Gleason scores, more frequent PTEN and CDK12 mutations, and less frequent BRCA2 mutations. In our study, such pts demonstrated worse PFS but not OS. While the strongest negative predictor of OS was the presence of combined PTEN/RB1/TP53 mutations, other contributors such as CDK12 and BRCA2 may also partially explain differences in outcomes. Thus, primary mHSPC appears to be clinically and genomically distinct from secondary mHSPC, and may require unique treatment paradigms.
Inflammatory and insulinemic dietary patterns: Influence on circulating biomarkers and prostate cancer risk in the prostate, lung, colorectal and ovarian cancer (PLCO) cohort.
Authors: Aroke Desmond , Folefac Edmund , Jin Qi , Shi Ni , Clinton Steven K. , Tabung Fred
Published: May 2020

e17561

Background: Prostate cancer (PCa) is common in countries with affluent dietary patterns and represents a heterogeneous collection of subtypes with varying behavior. Reductionist strategies focusing on individual nutrients or foods have not clearly defined risk factors. We have developed mechanisms-based dietary patterns focusing upon inflammation and chronic insulin hypersecretion, processes that are hypothesized to impact prostate carcinogenesis. Methods: First, we examined associations of the empirical dietary index for hyperinsulinemia (EDIH) and empirical dietary inflammatory pattern (EDIP) scores with circulating concentrations of relevant biomarkers, to assess the validity of these two dietary patterns. Secondly, we investigated associations of the EDIH and EDIP with risk of PCa (total, low-grade, high-grade, advanced and lethal). EDIH and EDIP dietary scores calculated from food frequency questionnaire data for 3,517 men and women who provided a blood sample at enrollment, were used to validate dietary patterns against known relevant biomarkers. A separate sample of 49,317 men was used to evaluate the associations of EDIH and EDIP with prostate cancer risk. We used multivariable-adjusted linear regression to compute the percent change and 95% confidence intervals (95%CI) in biomarker concentrations, and Cox regression to estimate hazard ratios (HR) and 95%CI for PCa risk; in dietary score quintiles, using the lowest quintile as reference. Results: Compared to the lowest quintile, participants in the highest EDIH quintile (most hyperinsulinemic diets) had significantly higher concentrations of C-peptide, insulin, CRP, and TNF-R2 and lower adiponectin. Those consuming the most pro-inflammatory diets (EDIP) had significantly higher concentrations of IL-6, TNF-R2, C-peptide and insulin with lower adiponectin. Men classified in EDIH quintile 5 compared to 1, were also at higher total PCa risk: HR, 1.11; 95%CI, 1.01, 1.23; P-trend = 0.03, especially high-grade cancer: HR, 1.18; 95%CI, 1.02, 1.37; P-trend = 0.06; whereas the EDIP was not associated with risk. Conclusions: EDIH and EDIP predicted concentrations of biomarkers relevant to the insulinemic and inflammatory potential of diet in PLCO. EDIH predicted future PCa risk and may suggest a dietary pattern for PCa prevention.
Phase Ib study assessing different sequencing regimens of atezolizumab (anti-PD-L1) and sipuleucel-T (SipT)in patients who have asymptomatic or minimally symptomatic metastatic castrate resistant prostate cancer.
Authors: Rosser Charles Joel , Hirasawa Yosuke , Acoba Jared David , Tamura David Jon , Pal Sumanta K. , Huang Jeffrey , Scholz Mark C. , Dorff Tanya B.
Published: May 2020

e17564

Background: Combining an immune checkpoint inhibitor with a tumor vaccine may leverage complementary mechanisms of action for treatment of mCRPC. Atezolizumab, a fully human anti–PD-L1 IgG1 antibody, is an approved treatment option in multiple indications; while SipT, an autologous cellular immunotherapeutic, is approved for treatment of metastatic castrate resistant prostate cancer (mCRPC). We present a phase Ib study evaluating safety, tolerability and objective response rate of atezolizumab + SipT in patients with mCRPC (NCT03024216). Methods: Eligible patients who had asymptomatic or minimally symptomatic progressive mCRPC and met standard criteria for sipuleucel-T were randomized to receive either atezolizumab 1200 mg IV every 3 weeks for 2 doses then SipT IV every 2 weeks for a total of three infusions (Arm 1) or SipT IV every 2 weeks for a total of three infusions followed by atezolizumab 1200 mg IV every 3 weeks for 2 doses (Arm 2). The primary endpoint was safety, while secondary endpoints included objective tumor response (PCWG2 and modified RECISTv1.1 criteria) and comparing systemic immune responses after induction between the arms. Results: As of February 6, 2020, 37 pts (median follow-up 7.4 months, median age 75 yrs [range 53.0–86.0]; median number of previous treatments 4 [range 1-8], 75.7% ECOG PS = 0) were enrolled. Three patients did not complete induction therapy (1 – withdrew consent, 1 developed toxicity, and 1 progressed). There were no grade 5 toxicities attributed to study drugs and grade 4 toxicities were noted in 2 patients, 1 in each arm (Arm 1 bronchitis and Arm 2 hypotension). Eight grade 3 toxicities were noted in arm 1 (hyponatremia, pulmonary embolus x3, bone pain, hypophosphatemia, shock, tooth fracture from a fall), while 4 grade 3 toxicities were noted in arm 2 (anemia, hypertension x 2, pneumonia). None of the grade 3 or 4 SAEs were noted to be irAEs. At 6 months, there were 11 SD (7 in Arm 1 and 4 in Arm 2), 18 PD and 7 unevaluable (3 withdrew from study and 4 have yet to reach 6 month evaluation). At this time, PFS was noted to be 8.2 months in Arm 1 and 5.8 months in Arm 2 (p = 0.054). Conclusions: The safety profile of the combination of atezolizumab with sipuleucel-T appears manageable in a heavily pre-treated population and consistent with those agents administered as monotherapy. Responses were seen but no CR. Immune activation studies may shed light on which sequence is optimal. Clinical trial information: NCT03024216 .
Effect of modulation of CD3 binding in a PSMAxCD3 T-cell engaging bispecific antibody on maintenance of efficient tumor cell kill and cytokine release.
Authors: Buelow Ben , Dang Kevin , Dalvi Pranjali , Li Yuping , Cheung Alexander , Rancan Chiara , Sankaran Preethi , Pham Duy , Harris Katherine , Davison Laura , Balasubramani Aarti , Clarke Starlynn , Starzinski Alec , Fong Lawrence , Iyer Suhasini
Published: May 2020

e17583

Background: Castration resistant prostate cancer (CRPC) is an incurable disease and represents a significant unmet need. Prostate specific membrane antigen (PSMA) is a protein highly expressed on the surface of prostate cancer cells; expression has been shown to increase with disease progression. Therapies targeting PSMA, such as anti-PSMA radioligand conjugates, have shown promise in clinical trials, validating this target for CRPC. T-cell recruiting bispecific antibodies (T-BsAbs) have demonstrated potent tumor killing activity against multiple tumor types, but immune-mediated toxicities have hampered T-cell redirecting therapies to date. Using Teneobio’s unique antibody discovery platform, we have developed a CD3xPSMA bispecific antibody (TNB-585) that retains the potent cytotoxicity of other T-BsAbs but with significantly reduced cytokine release. Methods: Antibodies targeting CD3 and PSMA were generated via immunization of our proprietary transgenic animals. Candidate antibodies were selected by repertoire deep sequencing of B-cells from draining lymph nodes, followed by high-throughput gene assembly and recombinant expression. Multiple bispecific antibodies targeting CD3 and PSMA were assembled and evaluated for their ability to selectively activate primary human T-cells and mediate killing of PSMA+ tumor cells in vitro, ex vivo, and in vivo. T-cell activation surface markers, cytokine production, and tumor cell cytotoxicity were measured. Results: In co-culture experiments, primary human T-cells were activated only in the presence of both the bispecifics and PSMA+ cells. These bispecifics mediated potent and selective cytotoxicity against PSMA-positive tumor cells, prostate tumor cell lines, or primary human prostate tumor cells isolated from patients. From among these we identified TNB-585, which showed attenuated binding to CD3. TNB-585 mediated comparable tumor cell cytotoxicity to CD3xPSMA T-BsAbs containing a high affinity anti-CD3 domain but with significantly reduced cytokine production. TNB-585 also showed tumor growth inhibition in xenograft models of prostate cancer in vivo. Conclusions: We have developed a novel CD3xPSMA T-BsAb that mediates T-cell killing of PSMA+ tumor cells with minimal production of cytokines. This molecule may improve safety, efficacy, and offer opportunities for combination therapy to treat CRPC. A Phase 1 clinical trial of this compound in CRPC is scheduled to begin in Q1 2021.
Sipuleucel-T (sip-T) and oral androgen axis inhibitors in black men being treated for metastatic castration-resistance prostate cancer (mCRPC): Observations from the Medicare Fee for Service (FFS) population.
Authors: Borno Hala , Moses Kelvin A. , Monk Paul , Fitch Kate , Harmon Matthew , Flanders Scott , McKay Rana R.
Published: May 2020

e17589

Background: Black men historically have been underrepresented in clinical trials, contributing to poor understanding of potential race-based differences in prostate cancer care and biology. This retrospective, real world analysis examines survival outcomes in black men who received sip-T or oral agents like abiraterone or enzalutamide for mCRPC. Methods: Using Medicare Fee for Service Identifiable Research data, we identified racially black men with a qualifying prostate cancer diagnosis (ICD-9 185, ICD-10 C-61) and an initial drug claim for treatment (abiraterone acetate, cabazitaxel, docetaxel, enzalutamide, radium-223, or sip-T) in 2014 or 2015. Continuous Part A, B, and D eligibility and no HMO enrollment were required for 24 months or until death per Social Security Death Index. We compared outcomes in black patients who received sip-T at any time vs those who received an oral agent in any line and no sip-T. Survival was estimated using the Kaplan-Meier method (unadjusted) and hazard ratios using Cox proportional hazards regression. Results: Of 14,456 patients identified in 2014 and 2015, 1603 were racially black. Among eligible men, 140 received sip-T and 1266 received an oral agent. At 24 months, 76% of men who received sip-T were still alive compared with 49% of those who received the oral agents (Table). Median OS was not estimable in men who received sip-T but was 23.1 months (95% CI: 21.6, NE) in those who received oral agents (Table). In a univariate model, use of sip-T resulted in a 63% reduction in risk of death compared to never receiving sip-T (HR, 0.37 [95% CI, 0.26, 0.52], P < 0.0001). Conclusions: In this real world analysis of black mCRPC patients, sip-T at any point was associated with longer OS over those receiving the oral agents without ever receiving sip-T. Development of a multivariate model is planned. [Table: see text]
Disease characteristics and outcome of patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) who received a beta emitter (177Lu-PSMA) after an alpha emitter (radium-223).
Authors: Sartor A. Oliver , la Fougère Christian , Essler Markus , Ezziddin Samer , Kramer Gero , Ellinger Jörg , Nordquist Luke T. , Sylvester John , Paganelli Giovanni , Peer Avivit , Boegemann Martin , Meltzer Jeffrey , Sandstrom Per , Song Danny
Published: May 2020

e17592

Background: Ra-223, a targeted alpha therapy, showed an overall survival (OS) benefit and favorable safety profile in mCRPC pts in a phase 3 trial. 177Lu-PSMA radioligand is an investigational agent for mCRPC. REASSURE (NCT02141438) is a global, prospective, observational study investigating Ra-223 safety in routine clinical practice over 7 years’ follow-up in mCRPC pts. Data from the second prespecified interim analysis (IA) were used to investigate safety and outcomes of pts who received 177Lu-PSMA after Ra-223 therapy. Methods: Data cut-off for the second prespecified IA was March 2019, and included pts who had subsequent 177Lu-PSMA after the last Ra-223 dose. Disease characteristics, adverse events (AEs) after last Ra-223 dose, and OS are described. Results: Of 1465 pts overall, 26 received 177Lu-PSMA subsequent to Ra-223. In this subgroup, pts received multiple anticancer therapies prior to 177Lu-PSMA. 13 pts (50%) received Ra-223 as combination therapy at second line (metastatic setting). Pts received a median of six Ra-223 doses. After Ra-223 treatment ended, 3 pts (12%) had drug-related serious AEs, 9 pts (35%) had grade 3/4 bone marrow suppression-relevant hematologic AEs. Median duration of 177Lu-PSMA treatment was 3.5 months. 19 pts (73%) received 177Lu-PSMA as fourth-line therapy or onwards. OS was 28.0 months from start of Ra-223 and 13.2 months from start of 177Lu-PSMA. Conclusions: In this select population receiving a sequence of multiple lines of therapy with different modes of action, grade 3/4 hematologic AEs after Ra-223 were low. Treatment with subsequent 177Lu-PSMA seems feasible, based on duration of 177Lu-PSMA and survival. Clinical trial information: NCT02141438 . [Table: see text]
Relative risk of HTN and major cardiovascular events associated with use of androgen receptor antagonists for nonmetastatic, castration-resistant prostate cancer.
Authors: Jahan Nusrat , Mogollon-Duffo Francis , Rehman Shabnam , Singal Sakshi , Hardwicke Fred L.
Published: May 2020

e17605

Background: Metastatic, castration-resistant prostate cancer (mCRPC) is a lethal disease, often preceded by nonmetastatic, castration-resistant phase. Recently, three androgen receptor (AR) antagonists — apalutamide, enzalutamide, and darolutamide — have been approved for nonmetastatic, castration-resistant prostate cancer (nmCRPC). AR-antagonists have been associated with increased risk of hypertension (HTN) and major cardiovascular (CV) events. We conducted a systematic review and meta-analysis of the published phase 3 randomized controlled trials (RCTs) to determine the relative risk of HTN and major CV events associated with use of AR-antagonists for nmCRPC. Methods: We conducted a systematic search at PUBMED, MEDLINE, EMBASE, and meeting abstracts from inception until November 2019. Published phase 3 RCTs using AR-antagonists in the study arm for nmCRPC and reporting the number of events of HTN and major CV events were included in the analyses. We used Mantel-Haenszel (MH) method and random effects model to calculate the estimated pooled risk ratio (RR) with 95% confidence interval (CI). Heterogeneity was tested with I2 value and Cochran’s Q-test. Results: Three phase 3 RCTs (ARAMIS, PROSPER, and SPARTAN) randomizing 2687 patients in the AR-antagonist arms and 1417 patients in the control arms were included in the final analysis for HTN. SPARTAN did not include data for major CV events; hence, other two studies comprising 2903 patients were analyzed for major CV events. Major CV events included myocardial infraction/coronary artery disease, ischemic/hemorrhagic cerebrovascular events, and heart failure. AR-antagonists used in the study arms were — ARAMIS: darolutamide, PROSPER: enzalutamide, and SPARTAN: apalutamide. Placebo was used in the control arms. All patients continued androgen deprivation therapy. Randomization was 2:1 in all studies. The pooled RR of any-grade HTN is 1.5 (95% CI: 1.03 – 2.18, p = 0.03, I2 = 70%); and, the pooled RR of grade ≥3 HTN is 1.39 (95% CI: 1.03 – 1.88, p = 0.03, I2 = 13%). The pooled RR of any-grade major CV events is 1.49 (95% CI: 1.05 – 2.13, p = 0.03, I2 = 0%); and, the pooled RR of grade ≥3 major CV events is 1.80 (95% CI: 1.11 – 2.92, p = 0.02, I2 = 0%). Conclusions: Our meta-analysis demonstrated use of AR-antagonists for nmCRPC is associated with increased risk of HTN and major CV events. A careful selection of patients and aggressive management of the CV risk factors are crucial to enhance safety and proper utilization of these promising drugs.