bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efficacy of abiraterone and enzalutamide in patients who had disease progression within twelve months of completing docetaxel for metastatic castration sensitive prostate cancer.
Authors: Chen Gang , VanderWeele David James , Karzai Fatima , Bilusic Marijo , Al Harthy Munjid , Arlen Philip M. , Rosner Inger L. , Chun Guinevere , Owens Helen , Couvillon Anna , Hankin Amy , Williams Monique , Cordes Lisa M. , Figg William Douglas , Gulley James L. , Dahut William L. , Madan Ravi Amrit 
Published: March 2019

241 Background: Docetaxel is a standard of care for mCSPC. Enzalutamide and abiraterone have been proven to improve survival in metastatic castration-resistant prostate cancer (mCRPC) patients. Little is known about patients who have been treated with docetaxel for mCSPC and subsequent therapeutic responses. This retrospective analysis is to evaluate the response duration of abiraterone and enzalutamide in patients who previously received docetaxel for mCSPC but developed mCRPC within 12 months. Methods: Clinical Trial NCT02649855 enrolled patients with newly diagnosed mCSPC who were treated with standard androgen deprivation therapy (ADT) and docetaxel (75 mg/m2 every 3 weeks for 6 cycles) sequenced with immunotherapy (PROSTVAC) from February 2016 to present. Patients who had progression (based on consecutive PSA rises or imaging) within 1 year of completing docetaxel and went on to subsequent abiraterone/enzalutamide were evaluated. (Note these are different PSA progression criteria than used in CHAARTED, Sweeney, NEJM, 2015). Results: Of the 46 patients evaluated regardless of immunotherapy sequence, 15 (33%) went on subsequent therapy after progression on docetaxel for mCSPC, with 12 patients starting abiraterone/enzalutamide (6 each with high and low volume disease). The median age was 62 (41-83) years. 7/12 patients (58.3%) initiated enzalutamide and 5/12 patients (41.7%) initiated abiraterone. The median duration of treatment for both was 7.12 (1.53–16.0) months, the median time to prostate-specific antigen (PSA) progression was 5.54 (0–15.83) months; 5/12 (41.7%) of patients did not have PSA response. Of note, patients with low volume disease had a median treatment duration of 5.88 months, 3 of them did not have PSA response. Conclusions: These data from a small cohort suggest that patients who have progression within 12 months of completing docetaxel for mCSPC have limited subsequent benefit from enzalutamide or abiraterone. Additional studies are required to determine optimal timing and treatment sequence for patients with mCSPC who rapidly develop mCRPC. Clinical trial information: NCT02649855.
Identification of bone involvement in patients with prostate cancer recurrence using 18F-fluciclovine PET/CT and impact on subsequent management.
Authors: Kipper Michael S , Dato Paul ,   LOCATE Study Group
Published: March 2019

248 Background: Bone is the most frequent site of metastasis in prostate cancer. Accurate localization of recurrence following primary treatment can help optimize salvage therapy. Positron emission tomography (PET) tracer, 18F-fluciclovine, is approved in Europe and the US for men with rising prostate specific antigen (PSA) after prior treatment. LOCATE was a prospective trial to study the impact of 18F-fluciclovine PET/computed tomography (PET/CT) on management of men with prostate cancer recurrence and negative standard imaging after curative intent treatment. Here, we explore changes in management (CIM) in men with 18F-fluciclovine-avid bone lesions. Methods: 18F-Fluciclovine PET/CT was performed and interpreted according to standard practice at 15 US centers. Eligible men (≥ 18 y; prior curative intent treatment of prostate cancer; recurrence based on rising PSA; negative/equivocal findings on standard bone and pelvic imaging) had their treatment plans recorded pre- and post-scan. Results: A total of 213 men (median pre-scan PSA, 1.0 ng/mL) were enrolled. Overall, 18F-fluciclovine detected lesions in 122 (57%) and 126 (59%) had CIM post-scan. 18F-Fluciclovine-avid bone lesions were found in 23 (11%) men. Prior to the fluciclovine scan, 21 (91%) had a 99mTc-MDP scan (20 negative, 1 equivocal results), 1 (4%) had an unspecified bone scan (negative result) and 1 (4%) did not receive a bone-specific scan. Of the 23 men with positive scans, 15 (65%) had post-scan CIM: ADT added to planned radiotherapy (RT; 4, 27%); ADT replaced with targeted treatment of fluciclovine-positive extrapelvic bony areas (4, 27%); RT modified to target fluciclovine-positive areas (4, 27%); modified ADT regime (2, 13%); and watchful waiting in favor of RT (1, 7%). The majority of men with no post-scan CIM were prescribed ADT (6/8, 75%). Conclusions: Despite negative standard bone imaging,18F-fluciclovine localized recurrence of prostate cancer to bone in 11% of patients; the majority of whom had a management change as a result, frequently in order to target fluciclovine-positive sites. Further study to investigate the clinical outcomes of such changes is warranted. Clinical trial information: NCT02680041.
The tumor immune microenvironment differs between metastatic castrate resistant prostate cancer (CRPC) and hormone sensitive prostate cancer (HSPC).
Authors: Yuen Kobe Chi Yung , Tran Ben , Gibbs Peter , Anton Angelyn , Mariathasan Sanjeev , Sandhu Shahneen Kaur , Kadel Edward Ernest 
Published: March 2019

251 Background: Immune checkpoint inhibitors (CPIs) (anti-CTLA4, anti-PD-1/PD-L1 mAbs) have had limited monotherapy activity in prostate cancer (PC) compared to urothelial cancer (UC). Recent biomarker studies revealed molecular features associated w/ better efficacy/resistance to CPIs in UC.1 Here we examined the tumor immune microenvironment (iTME) of hormone naïve/sensitive (HSPC) & castrate resistant prostate (CRPC) specimens from primary & metastatic sites, to determine if parallels to UC molecular correlates exist that will allow us to predict subsets of PC pts who are more likely to benefit from rational combination therapies w/ CPIs. Methods: Tumor FFPE archival tissues (HSPC, n = 98; CRPC, n = 46; Unk, n = 6) were sourced from a Royal Melbourne Hospital cohort of PC patients. Tissues were evaluated by H&E for TILs & IHC performed for PD-L1 (clones SP142 & SP263) & CD8. RNAseq was conducted & Lund bladder molecular subtyping performed during bioinformatics analyses. TCGA PRAD dataset was used for further validation. Results: We first applied Lund molecular subtyping to broadly categorize this cohort into luminal/basal subtypes. CRPC tumors were almost entirely luminal, whereas HSPC tumors were mainly basal. Luminal PC tumors enriched for Wnt gene sets (p = 0.026) & enriched for a genomically unstable (GU) subtype w/ higher expression of DNA damage repair (DDR) & cell cycle gene sets (p = 0.082). Compared to CRPC, HSPCs had higher numbers of infiltrating CD8s (p = 4.37e-004), increased expression of T-effector, MHC-I antigen presentation machinery, immune checkpoints, macrophages & activated stromal biology, including the fibroblast TGFβ response signature. PD-L1 on immune cells by SP142 & SP263 was 30% & 17% respectively & was enriched in HSPC samples (SP142: CRPC 18% vs. HSPC 34%, p = 0.08). Within patients w/ CRPC, differences were minimal between primary & metastatic samples. Conclusions: These analyses on the iTME contexture of PC reveal potentially actionable biological nodes for targeted therapies. These findings could inform future clinical strategies to improve CPI responses in CRPC & HSPC w/ rationale combinations.1. Mariathasan et al. Nature 2018.
Clinical outcome with concurrent or layered treatment with radium-223 and abiraterone: A retrospective study of real-world experience with patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).
Authors: George Daniel J. , Sternberg Cora N. , Sartor A. Oliver , Saad Fred , TOMBAL Bertrand F. , Miller Kurt , Kalinovsky Jan , Jiao XiaoLong , Tangirala Krishna , Higano Celestia S. 
Published: March 2019

253 Background: Limited data exist on Ra-223 use in combination with Abi in a real-world setting. This retrospective study evaluated clinical outcomes in pts with mCRPC who received concurrent or layered Ra-223 + Abi treatment. Methods: This study used the Flatiron prostate cancer registry of electronic health records of pts with mCRPC treated with Ra-223 in US cancer clinics between 1/01/2013 and 6/30/2017. Two sub-cohorts were defined: pts treated with Ra-223 + Abi in a concurrent (both started within 30 days) or layered fashion (one of the two started over 30 days later). Descriptive analysis was done for baseline (BL) characteristics (prior to start of Ra-223), prior therapies, and clinical outcomes including skeletal-related events (SREs) and overall survival (OS). Results: 625 pts were treated with Ra-223; 136 (21.8%) received Ra-223 + Abi. Most received layered therapy (n = 97, 71%); concurrent start was less common (n = 39, 29%) [Table]. Conclusions: Prior to the start of Ra-223 therapy, half of the pts had prior SREs; almost one-fifth had prior pathologic fractures. Pts treated with Ra-223 + Abi had also received prior chemo and/or enzalutamide. SRE occurrence seems higher for concurrent treatment, but results should be cautiously interpreted due to low concurrent cohort size. OS in both cohorts exceeded the OS in the Phase III ALSYMPCA study (14.9 mo).[Table: see text]
First-in-field small molecule inhibitors targeting BRN2 as a therapeutic strategy for small cell prostate cancer.
Authors: Thaper Daksh L. , Munuganti Ravi , Nouruzi Shaghayegh , Kumar Sahil , Kim Soojin , Vahid Sepideh , Sivak Olena , Aguda Adeleke , Puca Loredana , Beltran Himisha , Zoubeidi Amina 
Published: March 2019

260 Background: Resistance to newly developed androgen receptor pathway inhibitors (ARPIs), such as Enzalutamide (ENZ), rapidly emerges and patients generally die within two years. In particular, a subset of patients who relapse following ARPI therapy exhibit lineage switching whereby tumours shed their dependence on AR signaling and emerge with neuroendocrine features. These tumours, termed treatment induced neuroendocrine prostate cancer (t-NEPC), carry an extremely poor prognosis and, to date, treatment remains decades old cytotoxic chemotherapies; therefore, targeted therapies are desperately needed. Recently our group identified the neural transcription factor BRN2 as a major clinically relevant driver of NEPC and aggressive tumor growth, both in vitro and in vivo, suggesting targeting BRN2 is a promising strategy to prevent neuroendocrine differentiation or treat NEPC. Methods: Study the effects of BRN2 inhibition using siRNA, small molecule inhibitors (BRN2i) and CRISPR K/O models. The efficacy of the small molecules was examined using reporter assays, florescence polarization assays, Biolayer Interferometry, DARTS, chromatin fractionation, RNA-seq and ChIP-seq. Pharmacokinetic studies measured stability and bioavailability of the molecules and in-vivo efficacy is to be measured in NCI-H660 xenograft model. Results: Inhibition of BRN2 drastically reduced cell proliferation in NEPC cell lines 42DENZR and NCI-H660 cell lines. Targeting BRN2 with our first-in-field small molecule inhibitors lead to downregulation several known targets in NEPC like EZH2, ASCL1, SOX2 and PEG10. Treatment with BRN2i reduced recruitment of BRN2 to the chromatin by approximately 93% within 16 hours. Moreover, these BRN2 inhibitors displayed adequate pharmacokinetic properties and reduced NEPC proliferation in vivo. Conclusions: No therapies exist for highly lethal NEPC. Hence, the described work aims to lay the pre-clinical foundation for the integration of BRN2 targeted therapies into the treatment landscape to improve survival for patients suffering from small cell prostate cancer.
Apalutamide (APA) or enzalutamide (ENZA) in men with nonmetastatic castration-resistant prostate cancer (CRPC): A systematic review and network meta-analysis of randomized clinical trials (RCTs).
Authors: Riaz Irbaz Bin , Bhattacharjee Sandipan , Malik Saad , Ho Thanh P. , Sipra Qurat Ul Ain Riaz , Farooq Muhammad Zain , Khan Safi U. , Murad M. Hassan , Kohli Manish 
Published: March 2019

263 Background: In non-metastatic CRPC with short PSA doubling time, APA or ENZA with ADT have shown to slow development of metastasis. We performed an indirect comparison of APA and ENZA clinical effectiveness (efficacy and side effects) using network meta-analysis. Methods: A search of Medline, Embase, Cochrane Library, and Cochrane Central Register of Controlled Trials was performed to identify relevant RCTs. Collected data included hazard ratio (HR) and confidence interval (CI) for primary outcome of median time to metastasis free survival (MFS) and secondary outcomes of median time to overall survival (OS), PSA progression, initiation of cytotoxic therapy and number of adverse events (AE) in each study arm. Risk for bias was assessed using the Cochrane Collaboration’s tool. We used a fixed effects model using Bayesian approach to generate pooled estimates. Results: Two randomized trials (n=2608) were analyzed. SPARTAN trial compared APA plus ADT to ADT alone and PROSPER compared ENZA plus ADT to ADT alone. Risk of bias was low. There were no statistically significant differences between APA and ENZA in MFS, OS, median time to PSA progression and initiation of cytotoxic therapy. The MFS endpoint hazard ratio (HR) was 0.97 (95% CI 0.73-1.28) for comparing the two drugs. APA had fewer reports of hypertension (HR 0.54, 95% CI 0.31–0.91) compared to enzalutamide. However, no significant differences were observed in other AEs including grade 3 or higher AE, serious AE, AE leading to death or trial discontinuation. Common AEs (nausea, diarrhea, fall, dizziness, arthralgia, weight loss) and AEs of special interests (mental impairment disorders, seizures) were also comparable between APA and ENZA. Conclusions: In non-metastatic CRPC with short PSA doubling time, APA and ENZA showed similar time to metastasis free survival. APA was associated with lower incidence of hypertension than ENZA; otherwise, side effect profile was similar. Given similar efficacy and risk profile demonstrated in this study, clinical decision making should depend on other factors such as cost and availability.
Impact of treatment sequence in metastatic castration-resistant prostate cancer (mCRPC) on outcome in a prospective cohort study.
Authors: Lozano Rebeca , Castro Elena , Piulats Josep M. , Medina Ana , Guzman Jose Carlos Villa , Garcia Carbonero Iciar , Villatoro Rosa , Arranz Jose Angel , Perez-Gracia Jose Luis , Garde Javier , Gonzalez del Alba Aranzazu , Montesa A. , Luque Raquel , Borrega Pablo , Vázquez Sergio , Martinez Esther , Gonzalez Gragera Belen , Romero-Laorden Nuria , Olmos David , Lorente David 
Published: March 2019

264 Background: Abiraterone (Abi), enzalutamide (Enza) and docetaxel (Doc) are all valid first-line (1L) mCRPC treatment options. Evidence suggests a degree of cross-resistance between agents, which may impact the efficacy of subsequent lines of therapy. Evidence on the optimal treatment sequence is lacking. Methods: We evaluated the outcome of patients (pts) treated with 1L Doc, Abi or Enza in the prospective PROREPAIR-B cohort study. We assessed the impact of 1L treatment option (Doc vs Abi/Enza) on overall survival (OS), progression-free survival (PFS) to 1L-therapy (PCWG2) and PFS2 (time from initiation of 1L-therapy to progression on second-line [2L] therapy). Uni- (UV) and multivariable (MV) cox-regression models were used. MV model covariates included age (≥75 years), local therapy, Gleason Score, metastases at diagnosis, visceral metastases, ALP (≥ULN), LDH (≥ULN), haemoglobin (≤LNL), albumin (≤LNL) and ECOG PS. Results: 406 pts received 1L-Doce (N=188) or Abi/Enza (N=218). Pts receiving Doc were younger (p=0.002), had higher rates of visceral metastases (17.6 vs 8.7%; p=0.008), ALP (52.1% vs 40.4%; p=0.018), LDH (48.1% vs 31.2%; p<0.001) and lower Hb (7.4 vs 2.8%; p=0.029) and albumin (11.3 vs 4.6%). PFS was higher in pts receiving 1L-Abi/Enza (10.8 vs 8.3 months; HR:0.5; p<0.001). Pts receiving 1L Abi/Enza had higher rates of radiographic progression (88.4 vs 80%; p=0.032). 123/188 pts treated with 1L-Doc received 2L-Abi/Enza: 30 received other 2L and 35 had not started 2L. 111/216 pts treated with 1L-Abi/Enza received 2L-Doc, 26 were started on other 2L and 79 had not initiated 2L. A significant difference between pts treated with initial Abi/Enza vs Doc was observed in PFS2 (20.6 vs 16.6m; HR:0.78; p=0.006) but not OS (31.3 vs 29.9 m; HR:1.05; p=0.725). Choice of first-line agent was not associated with OS in the MV model. Conclusions: Despite longer PFS to 1L and PFS2 in pts treated with initial Abi/Enza, no differences in OS were observed between treatment sequences starting with Doc vs Abi/Enza. Pts treated with 1L-Doc had worse baseline prognostic features. Molecular stratification may enable biomarker-driven patient selection to optimize benefit in pts. (NCT03075735).
Correlation between time to PSA progression (TTPP), radiographic progression-free survival (rPFS) and overall survival (OS) in first-line abiraterone/enzalutamide (Abi/Enza) and docetaxel (Doc) treated patients in a prospective cohort study.
Authors: Lorente David , Castro Elena , Lozano Rebeca , Puente Javier , Romero-Laorden Nuria , Morales-Barrera Rafael , Rodriguez Vida Alejo , Sáez M Isabel , Mendez-Vidal Maria Jose , Fernandez Eva , Almagro Elena , Hernandez Amaia , Hernando Polo Susana , Pérez-Valderrama Begoña , López-Campos Fernando , Llacer Perez Casilda , Montesa A. , Lainez Nuria , Piulats Josep M. , Olmos David 
Published: March 2019

267 Background: Abiraterone, enzalutamide and docetaxel represent first-line (1L) treatment options in mCRPC. A significant correlation between rPFS and OS has been reported for patients treated with 1L abi and enza in mCRPC. It is however unclear whether TTPP or rPFS present a similar magnitude of correlation with OS in Doc-treated pts. Methods: We evaluated the association of TTPP and rPFS with OS in pts treated with 1L Abi/Enza or Doc in a prospective multicenter observational cohort study. TTPP and rPFS were defined as per PCWG2. Correlation between TTPP and rPFS with OS was evaluated with Spearman rho coefficients (r), and by calculating the concordance index (c-index) in Cox-regression models. Results: 406 out of 419 pts received 1L Abi/Enza or Doc. After a median follow-up of 40 months (m), 253 mCRPC-related deaths were observed, with a median OS of 31.3 m (95% CI: 27.6-35). Median rPFS and TTPP were 10.8 m (95% CI:9.7-11.9) and 7.2 m (95% CI:6.7-7.7), respectively. Significant correlations between rPFS/TTPP and OS were observed in all pts treated at 1L, as well as in Abi/Enza and Doc treated pts (Table). R and c-index were consistently higher in Abi/Enza treated pts than in Doc treated pts, with a higher difference in predictive accuracy of the Cox regression model observed when comparing the association between TTPP and OS (c-index 0.788 in Abi/Enza treated pts vs 0.627 in Doc treated pts). Conclusions: Differences in r and c-index were observed when evaluating the association between TTPP/rPFS and OS in Abi/Enza and Doc treated pts, suggesting rPFS and TTPP may better predict OS in Abi/Enza than in Doc-treated pts. Indirect comparisons of TTPP in Abi/Enza vs Doc pts may therefore not reflect their true impact on OS. Further insight on the exact significance of TTPP is needed. Clinical trial information: NCT03075735. [Table: see text]
Stereotactic body radiotherapy (SBRT) versus conventional fractionated intensity-modulated radiotherapy (CF-IMRT) for patients with early-stage localized prostate cancer: One-year late toxicity results from a prospective randomized phase II study.
Authors: Poon Darren M.C. , Lam Daisy , Wong Kenneth C.W. , Chu C.M , Mo Frankie , Suen Joyce , Ng Chi-Fai , Chan Anthony T. C. 
Published: March 2019

27 Background: It remains uncertain whether stereotactic body radiotherapy (SBRT) is superior to conventional fractionated intensity-modulated radiotherapy (CF-IMRT) in the treatment of early-stage prostate cancer. Here we report the 1-year late toxicity results from this randomized phase II study comparing SBRT and CF-IMRT. Methods: The primary endpoint of this single centre randomized phase II study is the health-related quality of life (HRQOL), as measured by the bowel and urinary domains of the Expanded Prostate Cancer Index Composite (EPIC) instrument. The secondary endpoints include toxicities, biochemical control and overall survival. We enrolled low and intermediate risk localized prostate cancer patients (T1-T2, Gleason score ≤7 and PSA <20). Patients were randomly assigned in a 1:1 ratio to receive either CF-IMRT with 38 fractions of 2 Gy in 7.5 weeks (five fractions per week) or SBRT with 5 fractions of 7.25 Gy in 2 weeks (three fractions per week). Neoadjuvant androgen-deprivation treatment is optional for the intermediate risk patients. A 1-year late adverse event is defined as the first occurrence of worst severity of the adverse event within 1 year after the completion of RT, and it was evaluated with the Common Terminology Criteria for Adverse Events (version 4.0). Patient recruitment was completed in May 2017. Results: Between Jan 2015 and May 2017, 68 patients were recruited and 4 patients were not eligible. 64 patients were randomized to treatments with SBRT (n=31) or CF-IMRT (n=33). At 1- year follow-up, two grade 3 genitourinary (GU) late toxicities, one in each arm (3%), were reported. SBRT patients experienced significantly less ≥ grade 1 late gastrointestinal (GI) toxicities (SBRT vs IMRT: 64% vs 84%, p=0.041) and similar ≥grade 1 late GU toxicities (SBRT vs IMRT: 93% vs 100%, p=0.2307) to IMRT patients. Conclusions: SBRT results in significantly less 1-year late GI toxicities than CF-IMRT in with low and intermediate risk prostate cancer. The study is registered at ClinicalTrials.gov (NCT02339701). Clinical trial information: NCT02339701.
Value of serum neuroendocrine markers in evaluation of neuroendocrine prostate cancer: A validation study using metastatic biopsies.
Authors: Vlachostergios Panagiotis J. , Peruzzo Nicolas , Nauseef Jones , Oromendia Clara , Manohar Jyothi , Molina Ana M. , Nanus David M. , Beltran Himisha , Tagawa Scott T. 
Published: March 2019

278 Background: NEPC, de novo or treatment-related in late stage CRPC, is a distinct entity with poor prognosis. Developing non-invasive methods for detection of NEPC is important for clinical practice and trial enrollment. We previously reported on the clinical and genomic characterization of NEPC (Conteduca et al ESMO 2018). A separate study (Aggarwal et al JCO 2018) suggested that low levels of NSE and CgA were associated with a strong NPV for NEPC on biopsy (bx). This study aimed to validate the utility of NSE and CgA in evaluation of NEPC by comparison with met bx. Methods: Our IRB-approved NEPC database was screened for pts who underwent met bx and had concurrent serum NSE, CgA. Clinical data, serum PSA, LDH, ALP, Hb were recorded at time of bx. Comparison of continuous variables between CRPC adeno and NEPC was assessed by nonparametric Kruskal-Wallis test. ROC curve analysis was performed for evaluation of predictive models with serum NE markers. Results: 152 men were identified, median age 71 yrs (49-97). 35 pts had pure/mixed NEPC, while the rest (N=117) had typical adenoca on bx. Half of pts (80/152, 52.6%) received abiraterone or/and enzalutamide. Liver mets were more common in NEPC pts (P=0.001). Median serum NSE (11.2 vs 8.6 ng/mL, P=0.008) and CgA (211 vs 135 ng/mL, P=0.035) were higher in pts with NEPC vs CRPC adeno (Table). Using ROC curve analysis for NSE (normal 3.7-8.9 ng/mL) and CgA (normal 0-95 ng/mL) as independent diagnostic tests, the following cut-offs were identified: NSE 30.1 (Sn: 37%, Sp: 94%, PPV: 34%, NPV: 82%), CgA 170 (Sn: 63%, Sp: 59%, PPV: 23%, NPV: 83%). Conclusions: Our study confirms the potential utility of serum NSE and CgA in excluding a morphological dx of NEPC when below certain thresholds. However, our findings cannot support deferring a met bx in such cases. Larger studies are needed to evaluate for a more robust predictive ability of serum NE markers. [Table: see text]