bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase II study of the efficacy of abirateron acetate with dutasteride for castration-resistant prostate cancer.
Authors: Matsuyama Hideyasu , Shiota Masaki , Tashiro Kojiro , Kanji Hiromi , Horiyama Shizuyo , Eto Masatoshi , Egawa Shin , Haginaka Jun , Inoue Ryo ,   Pharmacy and Pharmaceutical Sciences, Mukogawa Women's University, Nishinomiya, Japan
Published: March 2021

112 Background: Abiraterone (Abi) has been becoming a pivotal drug not only for metastatic castration resistant prostate cancer (mCRPC), but also for metastatic hormone sensitive prostate cancer (mHSPC). Abi is metabolized to delta-4 Abi (D4A), the strongest antitumor metabolite, by 3βHSD, and D4A is metabolized to 3-keto-5-α Abi, which acts as agonist to AR, by 5 α reductase. Reduction of 3-keto-5-α Abi by 5 α reductase inhibitor may increase the antitumor activity of Abi. Purpose of this study is to evaluate the efficacy and safety of the combination therapy of Abi and dutasteride (Duta), a 5 α reductase inhibitor, for the patients with CRPC. Methods: This is a non-randomized single-arm prospective phase II study. Patients with CRPC without any prior AR-targeting agent or docetaxel were recruited in this study with estimated enrollment of 20. Patients were treated with Abi (1,000 mg daily) and prednisone (5 mg daily) for 4 weeks, followed by the add-on of Duta (0.5 mg daily) for 12weeks. If PSA decline continued, combination treatment was allowed until progression. Abi and its metabolites including D4A and 3-keto-5-α Abi were measured by ESI-TOF-MS at baseline, 4, 6, 8, 12, 16, and 20 weeks, and the sample was collected at 2-4 hours after Abi administration. Primary endpoint was PSA decline >50%, and secondary endpoints were Time-to-treatment failure (TTF), and safety. Results: Totally 17 cases with CRPC (mean age: 78.4, initial PSA:92.6ng/ml, median Gleason score: 9) were recruited, and 14 were eligible for starting the combination therapy. Efficacy could be evaluated in 11 cases except 3 on-protocol treatment. Mean PSA decline of Abi/Duta combination therapy was significantly higher than that of monotherapy (p = 0.0143, 73 vs. 35 %). PSA decline>50% was noted in 36.4% for monotherapy, and 72.7% for combination therapy, respectively. Surprisingly, PSA decline>50% was significantly associated with lower Abi, D4A, and 3-keto 5 α Abi at 2 and 4 weeks after combination. Median TTF and progression (radiographic and/or PSA) was noted in 10.4 months (0.9-32), and 5 (45,4%), respectively with a median follow-up of 13.8 months. Progression was significantly associated with lower D4A, and 3-keto 5 a Abi at 4 and 8 weeks after combination therapy. Concerning safety, Grade 2 vertigo occurred in a case during Abi monotherapy period, while no adverse effect was found in combination therapy. Conclusions: Abi/Duta combination therapy seems to be theoretical to decrease AR-agonistic metabolite (3-keto 5 α Abi), and feasible for patients with first-line treatment of CRPC with lesser toxicity. Clinical trial information: UMIN000027795.
Evaluating the role of stereotactic body radiation therapy with respect to androgen receptor signaling inhibitors for metastatic prostate cancer.
Authors: Brennan Victoria , Spektor Alexander , Sweeney Christopher , Choudhury Atish Dipankar , Rathkopf Dana E. , Pomerantz Mark , Hertan Lauren Michelle , Martin Neil E. , Nguyen Paul L. , Balboni Tracy A. , Huynh Mai Anh , King Martin T. 
Published: March 2021

121 Background: Outcomes of stereotactic body radiation therapy (SBRT) with respect to androgen receptor signaling inhibitors (ARSI) have not been characterized for metastatic prostate cancer. Our purpose is to characterize prostate specific antigen (PSA) response and progression free survival (PFS) following SBRT among men who have received ARSI in castration sensitive and resistant settings. Methods: A single institution retrospective analysis was performed for men treated with SBRT and ARSI and categorized into 4 groups: 1) oligometastatic castration-sensitive prostate cancer (omCSPC), 2) ARSI-sensitive (ARSI-s) oligometastatic castration-resistant prostate cancer (omCRPC), 3) ARSI-resistant (ARSI-r) omCRPC, and 4) polymetastatic CRPC (pmCRPC). We calculated the PSA reduction greater than 50% (PSA50) and median PFS (PSA or radiographic progression) as determined by routine care. We also used Cox regression analysis to determine factors influencing PFS for ARSI-r disease. Results: 73 men with 126 lesions were treated with SBRT and followed for a median of 14.4 months. The percentages of men who achieved a PSA50 for omCSPC, ARSI-s omCRPC, ARSI-r omCRPC and pmCRPC were 100%, 90%, 62.9%, and 16.7%, respectively. Respective median PFS values were: not reached, 17.3, 9.0, and 1.6 months. For the 35 men with ARSI-r omCRPC, incomplete ablation (defined as the presence of untreated lesions after SBRT or prior palliative external beam radiation therapy (EBRT)) (HR 3.51 [1.36, 9.06]; p = 0.01) was associated with worse PFS on multivariable analysis. For the subgroup of 22 men with ARSI-r omCRPC without prior palliative EBRT or untreated metastases, the median PFS was 13.1 months. Conclusions: SBRT may augment the efficacy of ARSI, particularly among men with ARSI-r omCRPC, provided that all lesions received ablative radiation doses. Future prospective study of SBRT for men receiving ARSI is warranted.
Salvage chemotherapy with cisplatin, ifosfamide, and paclitaxel in metastatic castration-resistant prostate cancer.
Authors: Von Amsberg Gunhild , Zilles Mirjam , Gild Philipp , Alsdorf Winfried , Boeckelmann Lukas , Langebrake Claudia , Oh-Hohenhorst Su Jung , Tilki Derya , Graefen Markus , Dyshlovoy Sergey , Bokemeyer Carsten 
Published: March 2021

123 Background: Recent developments in the treatment of metastatic castration resistant prostate cancer (mCRPC) lead to a revival of platinum-based chemotherapy demonstrating increased activity in patients with aggressive variants of disease. Here, we report on the results of a combinational salvage therapy with cisplatin, ifosfamide and paclitaxel (TIP) in mCRPC. Methods: We retrospectively analyzed patients with mCRPC treated with TIP at the University Hospital Hamburg-Eppendorf between November 2013 and September 2020. Accompanying in vitro analyses were performed using human prostate carcinoma cell lines harboring different levels of drug resistance including the docetaxel-resistant sublines PC3-DR and DU45-DR. Results: In total, 17 mCRPC patients treated with TIP were eligible for efficacy analyses with a median age of 65 yrs. At baseline, liver metastases were present in 88%, metastases of other visceral sides (lung, adrenal gland, brain) in 47% and bone metastases in 76% of the patients. Median hemoglobin was 9.8mg/dl, LDH 903 U/l and AP 205 U/l. Median PSA value was 77 ng/ml covering a wide range including three patients with a PSA-value below 1ng/ml. NSE was evaluated in 83% of the patients (median 38,5 U/l). Patients were extensively pretreated with a median of three treatment lines before TIP (100% docetaxel, 82% abirateron and/or enzalutamide, 47% cabazitaxel, 41% others). A median of 3,5 cycles of TIP were applied with 29% of the patients receiving the maximum of 6 cycles. Four patients discontinued treatment due to side effects (PNP, infection, ifosfamide induced psychosis). At interim analyses, 59 % of the patients showed a radiological response or stable disease with only one patient progressing till the end of treatment. Median PFS was 2.5 months, median OS 6 months. A decrease of PSA > 30% and LDH > 50% was observed in 41% and 35% of the patients, respectively. In vitro experiments revealed additive effects of TIP in 22Rv1, LNCaP and DU45 cells and synergistic effects in neuroendocrine LASCPC-01 cells. In PC3 cells, TIP induced antagonistic effects at lower doses, whereas dose-independent additive effects were observed in docetaxel-resistant PC3-DR. Surprisingly, preliminary data of combined therapies with different drug pairs suggest an antagonistic effect of paclitaxel in the combination with both, cisplatin and ifosfamide. Conclusions: Combinational therapy with cisplatin, ifosfamide and paclitaxel showed promising activity in some patients with aggressive mCRPC. Preclinical data suggest that the drug combination of cisplatin and ifosfamide rule the efficacy of TIP in mCRPC.
Exploratory gene-by-gene analysis of olaparib in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC): PROfound.
Authors: De Bono Johann S. , Matsubara Nobuaki , Penel Nicolas , Mehra Niven , Kolinsky Michael Paul , Bompas Emmanuelle , Feyerabend Susan , Gravis Gwenaelle , Joung Jae Young , Nishimura Kazuo , Gedye Craig , Mateo Joaquin , Saad Fred , Fizazi Karim , Shore Neal , Kang Jinyu , Desai Chintu , Burgents Joseph E. , Harrington Elizabeth , Hussain Maha H. A. 
Published: March 2021

126 Background: The Phase 3 PROfound trial (NCT02987543) met its primary endpoint and key secondary endpoints, including improved overall survival (OS) for olaparib in men with mCRPC with alterations in BRCA1, BRCA2, or ATM (Cohort A). We report gene-by-gene analysis of olaparib antitumor activity among the 15 prespecified homologous recombination repair (HRR) genes. Methods: Pts were randomized to olaparib (300 mg bid; n=256) or physician’s choice of enzalutamide or abiraterone (control; n=131). Exploratory analyses in pts with alterations in BRCA1 and/or BRCA2 (BRCA, regardless of co-occurring alterations with other HRR genes) or in single genes were conducted. Results: Evidence of olaparib antitumor activity was observed in subgroups with >10 pts (table). Data for pts with alterations in only BRCA1, BRCA2, PPP2R2A, RAD51B, RAD54L, PALB2, BRIP1, CHEK1, BARD1, and RAD51D will be reported (no FANCL or RAD51C enrolled). Conclusions: Small subgroups limit interpretation for some genes. Olaparib antitumor activity is greatest in pts with BRCA alterations, with a spectrum of clinical sensitivity to olaparib as defined by rPFS and OS across the broader population with alterations in other HRR genes. Clinical trial information: NCT02987543. [Table: see text]
Real-world comparison of abiraterone (A) versus enzalutamide (E) for first-line therapy of metastatic castration-resistant prostate cancer (mCRPC).
Authors: Briones Carvajal Juan Rodrigo , Naimi Mahdi Farzad , Zhang Liying , Emmenegger Urban 
Published: March 2021

133 Background: Second generation androgen receptor signaling inhibitors such as A and E are commonly used first-line treatment options for mCRPC. While differences in the side effect profile of these agents are well documented, there are no predictive markers of response to A versus E, and there is a paucity of comparative outcome data. Methods: We conducted a retrospective exploratory analysis of 100 mCRPC patients (pts) treated at Odette Cancer Centre (Toronto, ON, Canada) between August 2012 and June 2020 with either A (n = 50) or E (n = 50). Pts undergoing first-line mCRPC therapy were randomly selected from a list of 327 A and 254 E patients. Following extraction of disease and pt characteristics, as well as outcome data, we applied the Wilcoxon rank-sum nonparametric test or the Fisher exact test for continuous or categorical variables, respectively, for between group comparisons. For time to event analyses, we created Kaplan-Meier (KM) curves with log-rank testing. Two-sided p-values < 0.05 were considered significant. Results: The A and E cohorts were comparable regarding diagnostic PSA, Gleason score categories, and treatments prior to presentation with mCRPC. The median time to CRPC in the A cohort was 23.3 (95%CI 15.6-29.9) months, compared to 24.1 (19.4-37.4) months in the E cohort (p = 0.942). At initiation of A or E therapy both the median (Q1,Q3) age (77(70,82) vs 76(69,81) years) and median Charlson Comorbidity Index (10(9,11) vs 10(9,11)) were similar (p = 0.469 and p = 0.736, respectively). The rate of diabetes was significantly lower in the A group (8% vs 38%; p < 0.001), but there were no significant differences in cardiovascular comorbidities. Pts starting A therapy had a higher rate of bone metastasis (92% vs 68%; p = 0.005); otherwise, the metastatic pattern did not differ. The median PSA at start of A was 46.75 (13.77,176.80), compared to 27.07 (8.64,136.20) in the E group (p = 0.218). Baseline ALP, hemoglobin and albumin were all comparable. Median follow-up was 13.7 (8.3,26.3) and 19.5 (9.8,34.0) months in the A and E groups (p = 0.091). 38% of A pts and 44% of E pts went on to further lines of systemic therapy upon progression (p = 0.685). The median time to next line of systemic therapy was 11.3 (95%CI 8.3-15.9) months for the A cohort and 12.7 (9.7-16.6) for the E cohort (p = 0.844). The actuarial median overall survival from KM estimations was 35.7 (20.4-52.5) months for the A group, and 34.0 (25.7-38.0) months for the E group. Conclusions: In men undergoing first-line A or E therapy for mCRPC, time to next line of systemic therapy and overall survival did not differ significantly, while baseline pt and disease characteristics were largely similar. A substantial number of pts do not receive ≥2 lines of therapy for mCRPC under real-world circumstances.
p2PSA-associated parameters are significant predictors of reclassification of first-year protocol biopsy on active surveillance for early-stage prostate cancer patients: From the PRIAS-JAPAN study.
Authors: Kato Takuma , Sugimoto Mikio , Kakehi Yoshiyuki , Shinohara Nobuo , Egawa Shin , Sasaki Hiroshi , Saito Toshihiro , Tanikawa Toshiki , Matsumura Masafumi , Hashine Katsuyoshi , Akamatsu Shusuke , Ogawa Osamu , Hara Isao 
Published: March 2021

153 Background: 44 Japanese institutions have joined the Prostate Cancer Research International: Active Surveillance (PRIAS) study as PRIAS-JAPAN. As an side study, PRIAS-JAPAN investigates the usefulness of [-2] proPSA (p2PSA), a precursor of PSA, as a predictive marker for the reclassification during active surveillance patients. In this study, we aimed to evaluate the usefulness of p2PSA related parameters to predict the reclassification of first year protocol biopsy (1yr PBx). Methods: 19 institutions participated in this side study which started in January 2013. All participants were eligible for PRAIS inclusion criteria. These patients were required to receive blood sampling on every visit and protocol biopsy after inclusion. PSA and PSA isoforms (free-PSA, p2PSA) were measured in serum samples and parameters (%free-PSA, %p2PSA, phi) were also calculated. Mann-Whitney U test was used to compare continuous variables between reclassification and non-reclassification groups. Fisher's exact test and Chi-squared test with yates' continuity correction were used for categorical variables. Multivariable logistic regression models were used to predict the risk of reclassification. To assess the predictive power for reclassification, we plotted ROC curves and calculated the AUC. Decision curve analysis (DCA) was used to evaluate whether adding variables to the baseline (age, PSA, prostate volume) model would yield net clinical benefit. Results: From January 2013 to July 2017, this study enrolled 237patients. 99 patients were excluded for the reason of discontinuation of AS, non-adherence of protocol blood sampling and rejection of biopsy. 138patients were able to analyzed PSA, PSA isoforms and its parameters at the time of inclusion and 1yr PBx. Patients who showed reclassification were significantly higher level of %p2PSA at inclusion and %p2PSA and phi just before 1yr PBx. Multivariate analyses showed %p2PSA at inclusion (p= 0.04), %p2PSA (p= 0.01) and Phi (p= 0.008) before 1yr PBx were statistically significant predictors of reclassification at 1yr PBx. ROC analysis revealed that %p2PSA before 1yr PBx (AUC 0.674) and phi before 1yr PBx (AUC 0.669) were a significant discriminant factor in predicting reclassification. DCA analysis showed that phi before 1yr PBx had a highest net benefit in the range of clinically plausible risk threshold (10–40%). Conclusions: %p2PSA and Phi before 1yr PBx have good prediction power and phi is a most useful indicator of clinical decision making about active surveillance. Clinical trial information: UMIN 000009876.
Landscape of circulating tumor DNA (ctDNA) abnormalities in advanced prostate cancer (aPCa): Distinctions in African American (AA) versus Caucasian (Ca) patients.
Authors: Barata Pedro C. , Swami Umang , Kessel Adam , Jaeger Ellen , Wesolowski Sergiusz , Chipman Jonathan , Bilen Mehmet Asim , Heath Elisabeth I. , Nandagopal Lakshminarayanan , Vaena Daniel A. , Maughan Benjamin Louis , Nussenzveig Roberto , Yandell Mark , Kohli Manish , Agarwal Neeraj , Sartor Oliver A. 
Published: March 2021

156 Background: AA have substantially higher prostate cancer incidence rates, are diagnosed at a younger age and with a more advanced stage as compared to Ca. However, after adjusting for known prognostic factors, AA have an increased overall survival. We hypothesized that these differences might be due to the underlying changes in the genomic landscape which can be revealed by liquid biopsy. Methods: Real world comprehensive genomic profiling of ctDNA from aPCa patients from two institutions. The first ctDNA results as reported by Guardant 360 panel (Redwood City, CA) were included. Association between genetic mutation and gene were tested using Barnard’s test. To account for multiple testing, we used Benjamini-Hochberg’s False Discovery Rate adjustment across all tests to determine thresholds for false discovery rates. Same analysis was performed using a Bayesian Network Machine learning approach. Results: Overall, 361 patients with aPCa (81 AA and 280 Ca) were included in the analysis. Pathogenic genomic alterations were found in 87.0% of the cases, more frequently TP53 (42.4%), AR (34.1%), PIK3CA (13.9%), BRAF (12.7%), NF1 (10.8%) and MYC (10.0%). Targetable alterations of interest included DNA repair genes [BRCA 2 (7.8%), BRCA 1 (4.4%), ATM (6.4%), CDK12 (2.2%)], PIK3CA/mTOR/AKT (19.1%), PTEN (3.3%) and NTRK (1.9%). MSI-high was found in 4 patients. AA as compared to Ca had a significantly higher prevalence of CDK12 (20.7% vs. 3.8%, p=0.016) and GNA11 mutations (3.7% vs. 0.4%, p=0.0225). BayesNet analysis also supported these results (table). Conclusions: In this dataset, liquid biopsy of ctDNA was useful for genetic characterization of aPCa and reveal differences in the molecular phenotype of AA and Ca in aPCa with potential clinical implications. These findings support ongoing research on the clinical utility of non-invasive genotyping and therapeutic response monitoring with a focus on AA population. [Table: see text]
Development and validation of circulating tumor cell (Epic Sciences) enumeration as a prognostic biomarker in men with metastatic castration-resistant prostate cancer.
Authors: Scher Howard I. , Armstrong Andrew J. , Schonhoft Joseph D. , Gill Audrey , Zhao Jimmy , Barnett Ethan , Carbone Emily , Lu James , Antonarakis Emmanuel S. , Luo Jun , Tagawa Scott T. , Yang Qian , George Daniel J. , Szmulewitz Russell Zelig , Danila Daniel Costin , Wenstrup Rick , Gonen Mithat , Halabi Susan 
Published: March 2021

157 Background: We evaluated the prognostic significance of circulating tumor cell (CTC) number as determined on the Epic Sciences platform in men with metastatic castration resistant prostate cancer (mCRPC) treated with an androgen receptor signaling inhibitor (ARSI). Methods: A pre-treatment blood sample was collected from men with progressing mCRPC starting either abiraterone or enzalutamide as a 1st, 2nd or 3rd line systemic therapy at Memorial Sloan Kettering Cancer Center (Discovery cohort, N=175) or as a 1st and 2nd line therapy as part of the multi-center PROPHECY trial (NCT02269982) (Validation cohort, N=107). Enumeration was performed on the Epic Sciences platform and associated with overall survival (OS) in the Discovery cohort, and progression-free survival (PFS) and OS in the Validation cohort. Matched blood samples from the Validation cohort were to CTC counts measured on the CellSearch Circulating Tumor Cell kit. Results: In the MSKCC Discovery cohort, CTC count was a statistically significant prognostic factor of OS as a dichotomous (< 3 CTCs/mL versus ≥ 3 CTCs/mL; HR = 1.8, (1.3-3.0, 95% CI)) and as a continuous variable when adjusting for line of therapy, presence of visceral metastases, PSA, lactate-dehydrogenase, and alkaline-phosphatase. The findings were validated in an independent dataset (PROPHECY trial) - (HR (95% CI) = 1.8, (1.1-3.0) for OS and 1.7 (1.1-2.9), for PFS). A strong correlation was observed between CTC counts determined in matched samples on the CellSearch and Epic platforms (r = 0.84). Conclusions: The findings validate the prognostic significance of pretreatment CTC number determined on the Epic Sciences platform for predicting OS in men with progressing mCRPC starting an ARSI.
Differences in the genomic landscape of advanced prostate cancer (aPC) patients (pts) with BRCA1 versus BRCA2 mutations as detected by machine learning analysis of the comprehensive genomic profile (CGP) of cell-free DNA (cfDNA).
Authors: Reisinger Raquel , Wesolowski Sergiusz , Swami Umang , Barata Pedro C. , Hernandez Edgar Javier , Nussenzveig Roberto , Lemmon Gordon , Peterson Bennet , Hensel Chuck , Bilen Mehmet Asim , Heath Elisabeth I. , Nandagopal Lakshminarayanan , Saylor Philip James , Babiker Hani M. , Kohli Manish , Pal Sumanta K. , Lilly Michael B. , Yandell Mark , Sartor A. Oliver , Agarwal Neeraj 
Published: March 2021

162 Background: PARP inhibitors (PARPi) provide significant clinical benefit for men with aPC with BRCA 1 and BRCA 2 mutations. However, in clinical trials, pts with BRCA1 mutations appeared to derive less benefit than pts with BRCA2 (De Bono et al., 2020). Probabilistic Graphical Models (PGMs) are artificial intelligence (AI) algorithms that capture multivariate, multi-level dependencies in complex patterns in large datasets while retaining human interpretability. We hypothesize that PGMs can reveal variants in BRCA1 and 2 that co-segregate with other known pathogenic variants and may explain the difference in response to PARPi therapy. Methods: Multilevel gene interdependencies between BRCA1 or BRCA2 were assessed using a Bayesian Network (BN) machine learning approach and Fisher’s exact test. CGP was performed by a validated cfDNA NGS panel that sequenced 74 clinically relevant cancer genes (Guardant360, Redwood City, CA). Only variants of known significance and those of unknown significance with a pathogenic REVEL score were included in the analysis. Results: Of 4671 men with aPC undergoing cfDNA CGP, 1248 men with somatic mutations in BRCA1, BRCA2, ATM, or combinations of the three were included in the analysis. The Bayesian network analysis demonstrated positive interdependencies between pathogenic variants in BRCA1 and 7 other genes. A positive interdependency between BRCA2 and 2 genes was present (table). ATM displayed negative interdependency with both BRCA 1 and 2. Conclusions: Our results demonstrate a decreased association of BRCA2 versus BRCA1 with known or predicted pathogenic variants at other loci. This may explain increased sensitivity of aPC with BRCA2 mutations to PARPi due to fewer concurrent resistance pathways. For example, alteration of ERBB2, which segregates strongly with BRCA1, is known to induce tumor progression and invasion in aPC and is associated with castration-resistance. These hypothesis-generating data reveal differential genomic signatures associated with BRCA1 as compared to BRCA2 and may inform development of future combinatorial treatment regimens for these pts. [Table: see text]