bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinicopathologic and genomic characterization of parenchymal brain metastases (BM) in prostate cancer (PCa).
Authors: Mota Jose Mauricio S. C. , Teo Min Yuen , Knezevic Andrea , Bambury Richard Martin , Hatzoglou Vaios , Autio Karen A. , Abida Wassim , Gopalan Anuradha , Fine Samson , Danila Daniel Costin , Rathkopf Dana E. , Slovin Susan F. , Young Robert J. , Reuter Victor E. , Heller Glenn , Scher Howard I. , Morris Michael J.
Published: March 2019

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Background: BM are rarely seen with PCa, but the incidence may be increasing with contemporary therapies. We sought to evaluate the clinical phenotypes associated with BM and their outcomes. Methods: The MSKCC institutional clinical database from 01/2001 through 06/2018 was reviewed to identify pts with PCa and (1) secondary malignant neoplasm of the brain / spinal cord per ICD-9 (198.3), (2) radiation treatment plan targeting the brain, (3) craniotomy, or (3) notes containing the terms “brain metastasis”. Medical charts were reviewed to confirm diagnosis (dx) and extract data. The logrank statistic and the Cox proportional hazards model were used to determine correlations with overall survival (OS). Results: Of 575 pts who met search criteria, 43 had BM and prostate adenocarcinoma. At PCa dx, median age was 60 years (range: 44 –77 years) and 51% had metastasis (mets). Median time from PCa dx to BM was 4.2 years. At the time of BM dx, 36 had metastatic castration-resistant PCa (mCRPC), 55% had liver mets and 66% had lung mets. 45% had ≥3 lines of therapy for mCRPC prior to BM dx (abiraterone/enzalutamide: 47%, chemotherapy: 91%). The median OS from BM dx was 5.8 months (Table). 4/10 pts with sequencing data had germline mutations ( ATM, BRCA1, BRIP1, MUTYH). To date, 4 BM were sequenced, and 3 showed PTEN loss. Conclusions: BM associated with a poor prognosis and occurred after prolonged treatment. Presence of liver/lung mets, 3 or more BM, and surgical resection (SR) prognosticate for OS in univariate analysis; SR in multivariate analysis. Further analysis is needed to determine if germline mutations and/or PTEN loss associate with BM. [Table: see text]
Early 18F-FDHT PET/CT as a predictor of treatment response in mCRPC treated with enzalutamide.
Authors: Hoving Hilde , Palthe Selma , Vallinga Marleen , Dost Rutger , Gietema Jourik A. , Antunes Inez , De Vries Erik F. J. , Glaudemans Andor , de Jong Igle Jan
Published: March 2019

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Background: Androgen deprivation is the mainstay in the treatment of metastatic prostate cancer. During treatment, the majority of patients will develop progressive disease despite castrate levels of testosterone; castration-resistant prostate cancer (CRPC). In vivo determination of androgen receptor status by 18F-FDHT PET/CT could be of use to predict treatment response timely and objectively. The objective of this study is to assess the value of early 18F-FDHT PET/CT to predict treatment response of enzalutamide in mCRPC. Methods: This pilot study was performed in 18 chemotherapy naïve men with mCRPC. 18F-FDHT PET/CT was performed at baseline and after 4 weeks of treatment with enzalutamide. Standard Uptake Value (SUV)max and SUVpeak of the 5 most intense and/or all bone, pleura and lymph node metastases were determined per patient. Area under the curve (AUC), sensitivity (Se) and specificity (Sp) of different characteristics of 18F-FDHT PET/CT were performed by ROC analysis. Response was determined at 12 weeks of treatment according to PCCTWG. Results: A total of 477 lesions (411 bone, 3 pleura and 63 lymph node) were found. At 12 weeks, response was seen in 16 patients, whereas 2 patients showed no response. The characteristics of 18F-FDHT PET/CT are shown in table 1. Baseline median SUVpeak of all metastatic lesions showed an AUC of 0.79 to predict response. AUC values using the 5 most intense lesions only or using the delta between baseline and 5 weeks were less accurate. Clinical trial information: NTR4086. Conclusions: Baseline 18F-FDHT PET/CT using SUVpeak of all metastatic lesions predicts treatment response in mCRPC treated with enzalutamide with an AUC of 0.79.[Table: see text]
Association between urinary, bowel, and hormonal treatment-related symptoms and clinical outcomes in nonmetastatic castration-resistant prostate cancer (nmCRPC): PROSPER study.
Authors: Saad Fred , Morlock Robert , Ivanescu Cristina , Sugg Jennifer , TOMBAL Bertrand F.
Published: March 2019

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Background: PROSPER data were analyzed to assess the relationship between time to worsening of urinary, bowel, and hormonal treatment-related symptoms and prostate-specific antigen (PSA) response, and the longitudinal association between symptom changes and metastasis-free survival (MFS). Methods: 1401 patients (pts) with nmCRPC at high metastasis risk were randomized 2:1 to enzalutamide (ENZA) or placebo. Urinary, bowel, and hormonal treatment-related symptoms were assessed with the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-PR25) at baseline (BL) and every 16 weeks. The association between time to first clinically meaningful symptom worsening and PSA response (≥50% decline from BL) was analyzed with stratified Cox regression using treatment as a covariate. Longitudinal symptom changes and MFS were evaluated in joint models using symptom scores as covariates, adjusted for treatment and clinical/demographic variables. The proportion of pts with improvement, no change, or deterioration at metastasis were analyzed by treatment group. Results: 723/1401 (52%) pts were PSA responders, including >90% of ENZA pts. PSA responders were significantly less likely to develop urinary, bowel, and hormone treatment-related symptoms vs. non-responders (hazard ratio [HR] 0.58 [95% confidence interval 0.41, 0.81]; 0.59 [0.43, 0.80]; and 0.70 [0.51, 0.97], respectively). Every 9-point increase in urinary symptom score was associated with a 10% increased metastasis risk (HR 1.1 [1.05, 1.15]). Bowel and hormonal symptoms did not predict metastasis. Most pts reported no EORTC score changes at metastasis and maintained stable urinary/bowel symptoms, with no major observed symptom differences between treatment groups. Conclusions: ENZA delays metastasis and extends time to symptom worsening. A ≥50% PSA reduction from BL is associated with a reduction in risk for urinary, bowel, and hormonal treatment-related symptom worsening; changes in urinary symptoms from BL also predict metastases. Clinical trial information: NCT02003924 (PROSPER).
Health-related quality of life (HRQoL) in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with olaparib in combination with abiraterone.
Authors: Clarke Noel W. , Thiery-Vuillemin Antoine , Wiechno Pawel J. , Alekseev Boris , Sala Nuria , Jones Robert , Kocak Ivo , Chiuri Vincenzo Emanuele , Jassem Jacek , Flechon Aude , Redfern Charles , Goessl Carsten Dietrich , Burgents Joseph , Gresty Christopher , Degboe Arnold , Saad Fred
Published: March 2019

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Background: A Phase II trial showed that addition of olaparib (O) to abiraterone (A) led to significant radiographic progression-free survival benefit for patients (pts) with mCRPC vs placebo (P) + A (hazard ratio [HR] 0.65, 95% confidence interval [CI] 0.44–0.97). We report predefined exploratory HRQoL analyses. Methods: This randomized, double-blind trial enrolled pts with mCRPC, post-docetaxel. Pts were randomized (71 per arm) to receive either O (300 mg bd, tablets) + A (1000 mg od) or P + A; all received prednisone (5 mg bd). Pts completed Functional Assessment of Cancer Therapy-Prostate (FACT-P total score [TS]; range 0–156, higher score = better HRQoL), Brief Pain Inventory–Short Form (BPI-SF) and worst bone pain (wbp) questionnaires (both range 0–10, higher score = more severe pain). Adjusted mean change from baseline was analysed using a mixed model for repeated measures, improvement by logistic regression and deterioration by log-rank test. Results: Overall compliance rates (O + A vs P + A) were 97% vs 96%, 92% vs 85%, and 96% vs 92% for FACT-P, BPI-SF and wbp, respectively. Best FACT-P TS response of ‘improved’ (increase ≥6 points from baseline at two consecutive visits) was reported by 22/67 (33%) evaluable pts in the O + A vs 18/64 (28%) pts in the P + A arm; the odds ratio (1.32; 95% CI 0.64–2.78) favored the O + A arm. Best FACT-P TS response of ‘worsened’ (decrease ≥6 points from baseline) was reported by 15 (22%) vs 22 (34%) pts. Adjusted mean change from baseline in FACT-P TS across all visits was -0.60 vs -2.09 in the O + A and P + A arms, respectively (difference 1.48; 95% CI -3.96–6.92). Time to deterioration (TTD) results are shown in the table. Clinical trial information: NCT01972217. Conclusions: Whilst not statistically significant, in this study a higher percentage of pts treated with O + A vs P + A had improved HRQoL, with fewer pts negatively affected. Ongoing phase III studies will help elucidate the impact of O on HRQoL in pts with mCRPC. (NCT01972217)[Table: see text]
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

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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

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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

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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.
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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

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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

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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

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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

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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

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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

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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]
AUCtox: A new method to evaluate the safety of anticancer drugs in metastatic prostate cancer.
Authors: Launay-Vacher Vincent , Helissey Carole , Laguerre Brigitte , Spaeth Dominique , Lloret Thomas , Stevens Jerome , Bossi Paolo , Scotte Florian ,   OptiSoins Prostate Study Group
Published: March 2019

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Background: The evaluation of anticancer drugs safety currently relies on the NCI-CTCAE classification. Most often in clinical trials, attention is focused on severe adverse events (AE) i.e.grade 3 or more. However, AE of lower grades can have a significant deleterious impact, especially when recurrent or permanent. We aimed at defining a new method to better describe the impact of treatment on quality of life (QoL). Methods: The oncology patient monitoring program OptiSoins prospectively records treatment, number of cycles, and toxicities (NCI-CTCAE). Patients with metastatic prostate cancer treated with either docetaxel (DOC) or cabazitaxel (CABA) were identified in the database. For each patient, toxicities and their grade reported in medical records were plotted against time under treatment, to calculate the area under the curve of toxicities (AUCtox) that takes into account both the intensity and duration of toxicities, and the number of events. AUCtox was calculated for any toxicity reported at least once. The association with QoL, evaluated by EQ-5D-3L. Results: In total, 146 patients were evaluable [DOC 85 (58%), CABA 61 (42%)]. Median age was 70.5 years (Q1-Q3: 64.7; 76.0). Median follow-up was 4.0 months. Patients underwent a median number of 6 cycles, with a median number of 15.0 evaluations (monitoring calls). At least one grade ≥3 AE was reported by 45.2% of patients, most frequently fatigue (20.6%) and pain (12.3%). A negative impact on global health status, assessed by the VAS of EQ-5D-3L, was identified for 3 AEs based on grade alone vs. 8 when considering AUCtox. Conclusions: Current evaluation of toxicity based on grade alone underestimates the impact of anticancer drugs on QoL. Our method, using AUCtox, can better detect this impact, allowing a more patient-oriented evaluation of drug safety. [Table: see text]
German health service research with the focus on effectiveness of secondary-antiandrogen deprivation therapy (s-ADT) in prostate cancer patients with buserelin in daily practice.
Authors: Luedecke Gerson , Geiges Goetz , Schulze Matthias , Lange Monica ,   Interessenverband zur Qualitätssicherung der Arbeit niedergelassener Uro-Onkologen in Deutschland e.V.
Published: March 2019

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Background: Aim of the health service research was to answer the questions: 1.) Is the s-ADT with buserelin a successful therapy perspective in biochemical progressive PCA patients after any ADT therapy performed prior? 2.) What is the response rate over all and with a PSA decline more than 50% from the starting level? Methods: In a time period of 2.5 years (2013-2016) a study collective of 1233 PCA patients was treated with buserelin of which 355 got a s-ADT therapy after biochemical progress. In follow-up controls the effectiveness was proven in respect to PSA decline after 6 and 12 months. Results: The cohort of 355 men had an age of 77.3 years with a risk distribution of 26.2% low risk, 33% intermediate and 40.8% high risk PCA. The initial PSA level before ADT change ranged from < 0.4 up to > 1000 ng/ml. Therapy effects over 12 month: 17.7% stayed unchanged, 49.7% progressed, 32.7% remitted and 23.8% declined in PSA more than 50% (effective). During the 12 month of follow-up 7.5% showed an initial PSA flair with a following remission, 15.6% an initial remission switching to progression. The PSA progression varied from 10 to 5229% increase and 40% had a PSA increase of more than 100% over 12 month. Conclusions: The s-ADT manipulation by buserelin after any prior ADT therapy induced in 33% over 1 year a positive PSA response and over all in 24% an effective PSA remission ( > 50% PSA decline) over 1 year. On the other hand 50% of the patients will progress with buserelin in s-ADT. The decision if s-ADT will succeed can be maid after 6 month of therapy with buserelin until a treatment change must be decided. Today, in respect to the early onset of abiraterone and docetaxcel in PCA management since 2017 the value of s-ADT must be discussed critically and again re-evaluated.
Integration of radium-223 dichloride (Xofigo) into clinical practice for the treatment of castration-resistant prostate cancer.
Authors: Doyle Catherine Mary , Mills Matthew , Damgaci Sultan , Smith Johnna , Zhang Jingsong , Fishman Mayer N. , El-Haddad Ghassan
Published: March 2019

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Background: Radium-223 dichloride (Xofigo) is an FDA-approved radionuclide used to treat symptomatic bone metastases in patients with castration-resistant prostate cancer (CRPC) with no known visceral metastases. Outside of clinical trial, the benefits of Radium-223 dichloride (Ra-223) in the treatment of CRPC have not yet been fully delineated in real life setting. Therefore, the purpose of this study was to evaluate the outcome of patients with CRPC who were treated with Ra-223, especially studying the variables associated with completion of 6 cycles of therapy. Methods: A total of 114 patients with CRPC and bone metastases referred for treatment with Ra-223 between March 2010 and February 2018 were identified for retrospective analysis. A chart review was conducted to analyze clinical characteristics, treatments, and outcomes including radiologic bone scans. Categorical variables were compared using Chi-square and independent student t test, and survival rates were generated using Kaplan-Meier analysis. Multivariate analysis (MVA) Cox proportional hazard ratios (HR) model was used in the assessment of OS and PFS. Results: Of the 114 patients referred for treatment, the overall median OS was 12.6 months. In MVA, improved OS was most strongly associated with completion of all six doses (p < 0.001). Median OS for the 56 patients who received full treatment was 24 months, while median OS for the 107 patients who did not complete treatment was 5.9 months. In univariate analysis, treatment completion was significantly associated with prior Sipuleucel-T (p = 0.002), concurrent Denosumab (p = 0.027), and baseline PSA < 30 ng/mL (p = 0.004). Conclusions: Completion of treatment with Ra-223 is a significant factor associated with improved OS. Therefore it is clinically important to delineate which patients are to the most appropriate candidates to complete treatment. Factors notable for treatment completion suggest patients might benefit from initiating Ra-223 treatment after receiving Sipuleucel-T and while their PSA remains low. Further consideration should be given to the sequence of Ra-223 in clinical practice, including use of concurrent Abiraterone and Enzalutamide.
A novel CD3xPSMA bispecific antibody for efficient T cell mediated killing of prostate tumor cells with minimal cytokine release.
Authors: Clarke Starlynn , Dang Kevin , Li Yuping , Sankaran Preethi , Pham Duy , Balasubramani Aarti , Davison Laura , Harris Katherine , Jorgensen Brett , Schellenberger Ute , Trinklein Nathan , Ugamraj Harshad , Buelow Roland , Van Schooten Wim , Force Aldred Shelley , Buelow Ben
Published: March 2019

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Background: Castration resistant prostate cancer (CRPC) remains an incurable disease and new therapeutics are urgently needed. Prostate specific membrane antigen (PSMA) is expressed on the surface of prostate cancer cells and expression increases with disease progression. Therapies directed against PSMA such as radiolabeled antibodies and T cell redirecting therapies including chimeric antigen receptor T cells (CAR-Ts) and T-cell engaging bispecific antibodies (T-BsAbs) have shown promising efficacy in clinical trials but also induce significant toxicity. In particular CAR-Ts and T-BsAbs potently kill tumor cells but induce cytokine release-related toxicities. Novel anti-CD3 engaging domains may be required to create T-BsAbs with a broader therapeutic window. We have developed fully human CD3xPSMA bispecific antibodies that efficiently eliminate prostate tumor cells while minimizing cytokine release. Methods: Antibodies targeting CD3 and PSMA were generated in transgenic rats that produce human antibodies (UniRat, OmniFlic) followed by repertoire deep sequencing of lymph nodes isolated from immunized animals and high-throughput gene assembly/expression. CD3xPSMA T-BsAbs were assembled and evaluated for T cell activation and ability to eliminate PSMA+ tumor cells in vitro. Results: Primary human T cells were activated only in the presence of both bispecific CD3xPSMA antibodies and PSMA (either plate-bound or on the surface of tumor cells). Potent and selective cytotoxicity against PSMA+ prostate tumor cells was observed in co-cultures of primary human T cells and tumor cells treated with CD3xPSMA bispecific antibodies. Strikingly, CD3xPSMA bispecifics containing a novel low affinity anti-CD3 domain produced similar levels of tumor cell cytotoxicity compared to CD3xPSMA bispecifics containing a traditional high affinity anti-CD3 domain, but with reduced cytokine production. Conclusions: We have created novel CD3xPSMA bispecific antibodies that mediate T-cell killing of PSMA+ tumor cells with minimal production of cytokines. Such T-BsAbs may improve safety, efficacy, and opportunities for combination therapy to treat CRPC.
A study into the pharmacodynamic biomarker effects of olaparib (PARP Inhibitor) ± degarelix (GnRH antagonist) given prior to radical prostatectomy (RP) CANCAP03.
Authors: Pacey Simon , Linch Mark David , Kynaston Howard , Warren Anne , Freeman Alex , Tysoe Ruth , Shaw Greg , Narahari Krishna , Kumar Satish , Martin Henno , Kularatne Bihani , Gnanapragasam Vincent , Davies Barry , Khan Josephine , Bratt Ola , Dev Harveer , Massie Charles , Shah Nimish
Published: March 2019

35

Background: Novel agents given prior to RP allows the study of drug effect(s) in primary human prostate cancer (PC), supporting future clinical study development. Pre-clinical and clinical data (mostly in setting of castration resistant PC) support PARP ± androgen inhibition as therapy for some patients (pt). We undertook a study of olaparib (O) ± degarelix (D) prior to RP. Methods: 20 evaluable (pre and post RP tissue available with 86% dose compliance) pt randomised 1:1 to O or O+D. Primary endpoint: measure PARP inhibition by IHC. Secondary endpoints were feasibility, safety, tolerability. Exploratory objectives: changes PSA, circulating tumour DNA & intra-tumoral immune cells. Men, due for RP, with high volume or aggressive PC, consented and were treated with O (300mg bd) 15 days ± D (240mg once), prior to RP. Diagnostic biopsy and RP tissue were collected. Adverse events (AE) were graded according to CTCAE v4 and followed up to resolution or 6-weeks post RP. Results: 24 men recruited, 4 not evaluable (opted radiotherapy, surgery date altered, not by AE). Interim results are presented of available data. Conclusions: 2 weeks of O (± D) can be given prior to RP with acceptable safety profile. Exploratory analyses of tumour tissue are ongoing however, preliminary data confirm PSA drop noted for pt on both regimens. While expected for O+D this is the first report of PSA changes following a short course of single agent PARPi (O) in pt with local/ hormone sensitive PC. Clinical trial information: NCT02324998. [Table: see text]
Ramucirumab (RAM) exposure-response (ER) relationship in RANGE: A randomized phase III trial of RAM plus docetaxel (DOC) versus placebo (P) plus DOC in advanced platinum-refractory urothelial carcinoma (UC) patients (pts).
Authors: De Wit Ronald , Powles Thomas , Castellano Daniel E. , Necchi Andrea , Lee Jae-Lyun , Van Der Heijden Michiel Simon , Matsubara Nobuaki , Bamias Aristotelis , Flechon Aude , Sternberg Cora N. , Drakaki Alexandra , Yu Evan Y. , Hamid Oday , Zimmermann Annamaria H. , Gao Ling , Long Amanda , Walgren Richard A. , Bell-McGuinn Katherine M , Petrylak Daniel Peter
Published: March 2019

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Background: Recent RANGE results showed significant improvement in PFS, a non-significant positive trend in OS, increased ORR and acceptable safety with RAM+DOC vs P+DOC in UC pts (Petrylak et al. Lancet 2017; Petrylak et al. ESMO 2018, abstr 865PD). RAM ER-OS relationships in RANGE are reported here. Methods: Pts received RAM (10 mg/kg) + DOC or P + DOC (Day 1 of a 21 day cycle) until discontinuation criteria were met. Population pharmacokinetic analysis predicted RAM minimum concentrations after first dose (RAM Cmin, 1). Multivariate Cox regression & matched case control (MCC) analyses using exposure treated as a continuous covariate, or grouped as quartiles, evaluated the ER-OS relationship. Results: Several poor prognostic factors, including Bellmunt risk factors, appeared to be more frequent in the lower exposure quartiles, suggesting a possible disease-PK interaction. Increasing RAM exposure as a continuous covariate in an ER population of n=246 pts significantly ( p=0.01) associated with improvements in OS. Higher exposure quartiles trended toward longer survival & smaller HRs compared to P (Table, Q1=lowest). Conclusions: OS and ORR benefits favored Q4, a group which was associated with more favorable prognostic features and higher exposure. The observed disease-PK interaction may confound the interpretation of the ER results and warrants further exploration. Clinical trial information: NCT02426125. [Table: see text]