bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impact of olaparib vs physician’s choice of new hormonal agent (pcNHA) on burden of pain in metastatic castration-resistant prostate cancer (mCRPC): PROfound.
Authors: Saad Fred , Roubaud Guilhem , Procopio Giuseppe , Shore Neal D. , Fizazi Karim , Thiery-Vuillemin Antoine , Anjos Gabriel dos , Gravis Gwenaelle , Joung Jae Young , Matsubara Nobuaki , Castellano Daniel , Hussain Maha H. A. , Degboe Arnold , Gresty Christopher , Kang Jinyu , Burgents Joseph E , De Bono Johann S. 
Published: May 2020

5538 Background: In the Phase III PROfound study (NCT02987543) olaparib significantly improved radiographic progression-free survival (primary endpoint) vs pcNHA (enzalutamide or abiraterone) in patients (pts) with mCRPC and homologous recombination repair (HRR) gene alterations. In pts with alterations in BRCA1, BRCA2 and/or ATM (cohort A), time to pain progression was also significantly improved by olaparib vs pcNHA. We report additional pain analyses evaluated in the overall study population (cohort A and B). Methods: Pts were randomized to olaparib tablets (300 mg bid; n=256) or pcNHA (n=131). Pts completed the Brief Pain Inventory-Short Form (BPI–SF) questionnaire (electronic administration) every 4 weeks up to 6 months after progression or treatment crossover. Responses were analysed to determine time to progression to worst pain, pain severity and first opiate use for cancer-related pain (Kaplan-Meier), and also pain interference in daily activity (mixed model for repeated measures). Results: 85% and 76% of olaparib pts were free of pain progression (worst pain item) compared with 75% and 51% in the pcNHA arm, respectively at 6 and 12 months. The proportion of pts without pain progression (overall pain severity) also favoured olaparib (Table). Median time to first opiate use was significantly prolonged in olaparib arm compared with pcNHA arm; 18 months for olaparib vs 9 months for pcNHA (Table). BPI-SF pain interference scores were also more favourable for olaparib than pcNHA; difference in overall adjusted mean change from baseline score −0.75 (95% CI: −1.14, −0.36) P=0.0002. Further pain burden results for cohort A will also be presented. Conclusions: Olaparib reduced the burden of pain and time to first opiate use in pts with mCRPC and HRR gene alterations vs pcNHA, demonstrating a clinical and symptomatic patient benefit. Clinical trial information: NCT02987543 . [Table: see text]
Overall survival after 177Lu-PSMA-617 molecular radiotherapy in patients with metastatic castrate-resistant prostate cancer: Post-hoc analysis of a prospective phase II trial.
Authors: Calais Jeremie , Gartmann Jeannine , Armstrong Wesley R , Thin Pan , Nguyen Kathleen , Lok Vincent , Gosa Laura , Slavik Roger , Dahlbom Magnus , Herrmann Ken , Eiber Matthias , Fendler Wolfgang Peter , Czernin Johannes 
Published: May 2020

5549 Background: This was an open-label randomized prospective bi-centric single-arm phase II clinical trial of 177Lu-PSMA-617 molecular radiotherapy in patients with progressive metastatic castrate-resistant prostate cancer (mCRPC) conducted at University of California Los Angeles (USA) and Excel Diagnostics & Nuclear Oncology Center (Houston, TX, USA) (NCT03042312). The study was investigator-initiated under an investigational new drug approval protocol (IND#133661) with authorization of charging for investigational drug (cost-recovery, Title 21 CFR 312.8). We report here the post-hoc analysis of overall survival (OS) in a single-study site cohort (UCLA). Methods: Patients with progressive mCRPC (biochemical, radiographic, or clinical) after ≥1 novel androgen axis drug (NAAD), either chemotherapy (CTX) naïve or post-CTX, with sufficient bone marrow reserve, normal kidney function, and sufficient PSMA-target expression by PET were eligible. Patients received up to 4 cycles of 177Lu-PSMA-617 every 8±1 weeks and were randomized into 2 treatment activities groups (6.0 or 7.4 GBq). Efficacy was defined as serum PSA decline of ≥50% from baseline and served as primary endpoint (hypothesis: ≥40% of responders after 2 cycles). Results: 43 patients were randomized to the 6.0 GBq (n= 14) and 7.4 GBq (n=29) treatment arms. 11/43 (26%) were CTX naïve while 10/43 (23%), 12/43 (28%), 5/43 (12%) and 5/43 (12%) had received 1, 2, 3 or 4 CTX regimens. Median baseline PSA was 29.2 ng/ml (mean 228.8, range 0.5-2082.6). 21/43 (49%) completed 4 cycles of 177Lu-PSMA-617 whereas 4/43 (9%), 13/43 (30%) and 5/43 (12%) underwent 1, 2 and 3 cycles. PSA decline of ≥50% was observed in 11/43 of patients (26%) after 2 cycles and in 16/43 (37%) at any time (best PSA response). 9/43 (21%) had a PSA decline of ≥90% and 23/43 (53%) had any PSA decline (>0%). After a median follow-up of 19.5 months the median OS was 14.8, 15.7 and 13.5 months in the whole cohort, the 6.0 GBq and 7.4 GBq treatment arms, respectively (p=0.68). Patients showing a PSA decline of ≥50% after 2 cycles and at any time had a longer OS: median 20.1 months vs. 13.6 (p=0.091) and 20.1 vs. 11.6 (p=0.002), respectively. Conclusions: In this post-hoc analysis of a single-site cohort of 43 patients included in a prospective phase II trial the median OS after 177Lu-PSMA-617 molecular radiotherapy in patients with progressive mCRPC was 14.8 months. There was no difference of efficacy between the 6.0 GBq and 7.4 GBq treatment arms. Clinical trial information: NCT03042312 .
First-in-human phase I study of HPN424, a tri-specific half-life extended PSMA-targeting T-cell engager in patients with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Bendell Johanna C. , Fong Lawrence , Stein Mark N. , Beer Tomasz M. , Ross Ashley , Gao Xin , Weitzman Aaron , Austin Richard , Ganti Vaishnavi , Law Che-Leung , Lemon Bryan , Wesche Holger , De Bono Johann S. 
Published: May 2020

5552 Background: HPN424 is a first-in-class, prostate-specific membrane antigen (PSMA)-targeting T-cell engager designed as a small, globular protein to enable efficient solid-tumor penetration with prolonged half-life. HPN424 is derived from the TriTAC platform (Tri-specific T-Cell-Activating Construct) and engineered with three binding domains: anti-PSMA for tumor cell engagement, anti-albumin for half-life extension and anti-CD3 for T-cell engagement. Methods: This Ph I study is evaluating HPN424 in progressing mCRPC patients (pts) who have received >2 prior systemic therapies. Primary endpoints are safety, tolerability and determination of MTD/RP2D. Secondary objectives are pharmacokinetics (PK), pharmacodynamics, immunogenicity, and preliminary anti-tumor activity. HPN424 is administered IV once weekly. Tumor assessments include PSA, CT, and bone scans every 9 weeks. Results: As of 1/17/20, 27 pts were dosed in 8 cohorts ranging from 1.3 to 72ng/kg. Pts received a median of 6 prior systemic regimens, including >1 novel AR therapy, and 59% received prior chemotherapy for mCRPC. Median PSA at baseline was 251 ng/mL (range: 0.05 – 5000). No DLTs have been observed. The most common grade >3 TRAEs were cytokine release syndrome (CRS) (3 pts) and transient elevated liver transaminases (2 pts) that occurred concurrently with CRS. All CRS events resolved and pts were successfully re-treated. Short-term steroid premedication was effective in limiting CRS and allowing long-term weekly treatment. HPN424 demonstrated dose proportional increase in Cmax and AUC with a geometric mean T1/2 of 30.5 hours. Dose-dependent, transient increases in peripheral cytokine and chemokine levels were observed. Reduction in circulating tumor cells (CTCs) was seen in 11 of 19 pts with measurable CTC at baseline. Six pts had PSA decreases from baseline ranging from -3.8% to -76%, including 2 pts with PSA decline ≥50%. Ten of 20 pts (50%) with > 18 weeks follow-up remained on study beyond week 18 and includes 8 pts on study > 24 weeks. Conclusions: HPN424 represents a novel half-life extended PSMA-targeting T-cell engager that can be safely administered once weekly. AEs have been transient and manageable. Cytokine increases indicate T-cell activation. CTC reductions in subset of pts suggest target engagement. Early signs of clinical activity include PSA reductions and time on study, including 8 pts on study > 24 weeks. Dose escalation is ongoing, including exploration of step dosing. Clinical trial information: NCT03577028 .
TALAPRO-1: Phase II study of talazoparib (TALA) in patients (pts) with DNA damage repair alterations (DDRm) and metastatic castration-resistant prostate cancer (mCRPC) – updated interim analysis (IA).
Authors: De Bono Johann S. , Mehra Niven , Higano Celestia S. , Saad Fred , Buttigliero Consuelo , van Oort Inge M. , Mata Marielena , Chen Hsiang-Chun , Healy Cynthia G. , Paccagnella M. Luisa , Czibere Akos , Fizazi Karim 
Published: May 2020

5566 Background: PARP inhibitors (PARPi) show antitumor activity in mCRPC/DDRm pts treated with novel hormonal therapy (NHT). TALAPRO-1 is an open-label study evaluating TALA (potent PARP inhibitor/trapper) in men with mCRPC/DDRm. We report a planned IA (Dec 2019). Methods: TALAPRO-1 (NCT03148795) is enrolling pts (N ≈ 100) with measurable soft tissue disease, progressive mCRPC, and DDRm likely to sensitize to PARPi ( ATM, ATR, BRCA1/2, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, RAD51C), who received 1–2 chemotherapy regimens (≥1 taxane-based) for metastatic disease and progressed on ≥1 NHT (enzalutamide/abiraterone acetate) given for mCRPC. DDRm are defined as known/likely pathogenic variants or homozygous deletions. Pts receive oral TALA 1 mg/day (moderate renal impairment 0.75 mg/day) until radiographic progression, unacceptable toxicity, consent withdrawal or death. Primary endpoint is objective response rate (ORR). Secondary endpoints: time to OR; response duration; PSA decrease ≥50%; circulating tumor cell (CTC) count conversion (to CTC = 0 and <5 per 7.5 mL blood); time to PSA progression; radiographic PFS (rPFS); overall survival; safety. A planned efficacy/safety IA was done when 60 pts with DDRm and measurable disease completed ≥6 months of TALA/no longer followed (DDR population [DDRp]). Radiographic responses are based on investigator assessments. Results: 113 pts received TALA (cutoff Dec 12, 2019); 75 pts were DDRp, had measurable disease, received ≥16 wk treatment, and were evaluable for ORR (54.7% BRCA1/2, 4.0% PALB2, 22.7% ATM; 18.7% other DDRm).All DDRp pts had prior docetaxel; 45.3% cabazitaxel. Confirmed ORR, rPFS, and composite response (investigator-assessed) in pts who received TALA for ≥16 weeks are in the table. Most common treatment-emergent adverse events: anemia (42.5%); nausea (32.7%). Conclusions: TALA monotherapy has encouraging antitumor activity in docetaxel-pretreated mCRPC pts with BRCA1/2 alterations and was generally well tolerated. Clinical trial information: NCT03148795 . [Table: see text]
Clinical significance of CTC enumeration on the Epic Sciences platform in metastatic castration-resistant prostate cancer (mCRPC) patients treated with AR signaling inhibitors (ARSi).
Authors: Schonhoft Joseph , Gill Audrey , Graf Ryon P , Jendrisak Adam , Barnett Ethan , Benoliel Hannah , Carbone Emily , Tubbs Alisa , Orr Sarah , Byun Jiyun , Wenstrup Rick , Scher Howard I. 
Published: May 2020

5571 Background: Circulating Tumor Cell (CTC) number, enumerated using the analytically valid FDA cleared Cell Search (Menarini Silicon Biosystems) platform has been shown to be prognostic for survival pre- and post-therapy, and used as an aid to monitoring breast, colorectal and prostate cancers. The assay uses antibody-based capture and defines a CTC as an EpCAM+ and CD45- intact cell. In contrast, with the Epic sciences CTC detection platform red blood cells are first lysed and all nucleated cells deposited on pathology slides, fixed, and imaged. There is no affinity selection and CTCs for this analysis were defined in silico as any cytokeratin (CK)+, CD45- cell with an intact DAPI+ nucleus. Here we report the prognostic significance of the CK+ CTCs detected on the EPIC Sciences platform in mCRPC patients prior to treatment with an AR signaling inhibitor. Methods: A pre-treatment blood sample was collected from 181 unique patients with progressing mCRPC about to start an ARSI as 1st, 2nd or 3rd line therapy at MSKCC. CTCs were enumerated on the Epic Sciences platform and verified by a trained human technician. Results: At least 1 CTC was detected (median = 1, 0-711 CTCs/ml) in 134 (74%) of cases, with higher counts observed in patients with visceral or multiple osseous sites relative to those with lymph node only disease. Counts increased by line of therapy. The table shows the associated risk of death for CTCs modeled as a continuous variable. Conclusions: The results support the clinical validity of CTC number determined on the Epic Sciences platform as a significant baseline prognostic factor. In multivariate modeling CTC number was found to be the most significant blood-based predictor of poor OS with each doubling representing a 20% greater risk of death observed with adjustment for therapy line, LDH, PSA, and ALK. [Table: see text]
Circulating tumor cells (CTCs) with small-cell like pathology are prevalent in metastatic castration-resistant prostate cancer (mCRPC) and show selective pharmacodynamic reductions in patients treated with platinum but not ARSI or taxane.
Authors: Scher Howard I. , Jendrisak Adam , Gill Audrey , Barnett Ethan , Gopalan Anuradha , Zaidi Samir , Benoliel Hannah , Carbone Emily , Byun Jiyun , Schonhoft Joseph , Wenstrup Rick 
Published: May 2020

5572 Background: The increasing availability and earlier use of life prolonging drugs targeting the androgen receptor signaling axis (ARSI) has resulted in an increase in the frequency of late state tumors with “small cell/neuroendocrine (NESC) phenotypes” similar to small-cell lung cancer (SCLC). Definitive pathologic criteria to diagnose the “entity” are lacking, and the eligibility criteria across trials are inconsistent, limiting the ability to relate outcomes between studies. We hypothesized that an analytically valid assay for a rigorously defined “small-cell CTC” phenotype might serve as a unifying biomarker for the presence of NESC-like tumors in an individual for use in clinical trials. Methods: Using the WHO guidelines for small-cell diagnosis in tissue as reference, we defined an equivalent set of single-cell CTC criteria for defining a CTC with small-cell histology: a small and circular CD45-, CK+ cell with high N/C ratio lacking detectable nucleoli. Small-cell subtype pharmacodynamic changes were studied in 233 patients with progressing mCRPC about to start an AR signaling inhibitor ARSi (N=111), taxane (N=89), or platinum (N=33). Results: CTCs with small-cell morphology had lower AR protein expression compared with non-small-cell CTCs (P<0.0001) and increased with therapy line. The small-cell CTC subtype decreased in number from baseline to on-therapy in patients treated with platinum but not in those treated with ARSi or taxane (Table). Conclusions: Digital pathology analysis of CTCs defined a CTC subtype consistent with that of small-cell carcinoma that were only reduced in number with platinum-based therapy. The tracking of CTC subtypes after treatment with different drug classes may help assess drug activity in heavily treated patients that often have heterogeneous disease that of which may not be captured using standard measures of response. [Table: see text]
Clinical outcomes and markers of treatment response in a randomized phase II study of androgen deprivation therapy with or without palbociclib in RB-intact metastatic hormone-sensitive prostate cancer (mHSPC).
Authors: Palmbos Phillip Lee , Tomlins Scott A. , Daignault Stephanie , Agarwal Neeraj , Twardowski Przemyslaw , Morgans Alicia K. , Kelly William Kevin , Arora Vivek , Antonarakis Emmanuel S. , Siddiqui Javed , Robinson Dan , Knudsen Karen E. , Chinnaiyan Arul , Hussain Maha H. A. 
Published: May 2020

5573 Background: Targeted therapies based on tumor molecular markers are not currently used in mHSPC. Palbociclib, a CDK4/6 inhibitor, blocked proliferation and promoted G1 arrest in a Rb-and Cyclin D-dependent manner in preclinical models of HSPC. We hypothesized that co-targeting AR (ADT) and cell cycle (palbociclib) would improve outcomes in mHSPC pts. Methods: mHSPC pts with Rb intact tumors based on IHC of metastatic tumor biopsy were stratified and randomized (1:2) to Arm A: ADT or Arm B: ADT+ palbociclib (125mg 3 weeks on, 1 week off). Primary endpoint was confirmed PSA RR (≤ 4 ng/mL) after 28 weeks of therapy. Secondary endpoints included safety/tolerability, PFS, PSA and radiographic RR. Metastatic biopsy and primary tumors were subjected to whole exome and transcriptomic sequencing where available. CTC’s were enumerated at various time points. Results: 72 eligible pts (median age 67 years, PSA 73ng/mL) with newly diagnosed mHSPC were registered and underwent biopsy. 97% retained RB expression (IHC). 62 pts were stratified by disease extent and early initiation of ADT, and randomized. 60 pts initiated therapy (Arm A: 20; Arm B: 40). Adverse events were reported previously. 80% of pts (Arm A: 16/20, Arm B: 32/40; p = 0.87) on both arms met primary PSA endpoint (≤4ng/mL at 28 weeks). PSA undetectable rate at 28 weeks was Arm A: 50% (10/20) and Arm B: 43% (17/40; p = 0.5). Measurable disease RR: Arm A: 89% and Arm B: 89%. 12-month biochemical PFS was Arm A 69% (95%CI: 44-85%), Arm B 74% (95%CI: 57-85%). 41 patients on trial underwent sequencing of metastatic biopsy and 10 patients had matched primary prostate tumor sequencing results. CCND1 amp, 8q gain, PTEN and KMT2C mutations were each observed in metastatic, but not paired prostate primary tumors. TP53, PIK3 pathway (PIK3CA, AKT1, PTEN) mutations and 8q gains were associated with reduced PSA PFS [HR (95%CI): 3.0 (1.2-7.2), p = 0.018; 3.2(1.03-10),p = 0.044; 4.96 (1.8-12), p = 0.001, respectively]. Pretreatment CTCs were associated with lower PSA CR (p = 0.04) and shorter PFS (12-month PFS: 58% vs. 86%, p = 0.031). Conclusions: A tissue based biomarker preselected trial is feasible in mHSPC. ADT + palbociclib did not impact outcomes. Pretreatment CTC counts, TP53 and PIK3 pathway mutations, and 8q gain may offer prognostic value in mHSPC. Support: Movember-PCF Challenge Award, Pfizer. Clinical trial information: NCT02059213 .
A blood-based multi-mRNA liquid biopsy with >90% accuracy for diagnosis and assessment of prostate cancers.
Authors: Rahbar Kambiz , Kidd Mark S. , Drozdov Ignat A. , Kitz Alexandra , Malczewska Anna , Rajwa Pawel , Boegemann Martin , Bernemann Christof , Bodei Lisa , Modlin Irvin Mark 
Published: May 2020

5574 Background: There are a paucity of blood-based biomarkers with clinical utility for prostate cancer (PCa). We developed a circulating mRNA (27-gene) prostate cancer signature to diagnose and manage PCa. Methods: Gene identification: Publicly available PCa transcriptome sets ( n= 1,159 samples) were evaluated and compared with normal blood-based transcriptomes using gene co-expression network enrichment, differential expression and functional enrichment analyses to identify candidate markers. Gene expression evaluation: Seven PCA cell lines and two normal prostate epithelial lines were used to assess candidate genes. Marker genes were determined in PCa tumor tissue ( n= 50) and validated in the TCGA-PRAD ( n= 500) dataset. Blood gene expression: Set #I: PCA: n= 132, BPH: n= 44, controls n= 55. Set #II: n= 50 (biochemical recurrence [BCR]). We constructed an artificial intelligence PCa model using classification algorithm analyses. Scoring: normalized algorithmically analyzed gene expression (0 to 100), positive score >20. PSA: BPH ( n= 44) and PCa ( n= 132). Clinical score assessment: Surgical cohort: ( n= 47), samples: pre-surgical and post: 1 week - 14 months. Statistics: Kruskal-Wallis, Pearson-correlation, Fisher’s and AUROC analyses (Mean±SEM). Results: Transcriptomic analysis identified 27 candidates. Cell lines/tissue: Expression levels were significantly elevated ( p< 0.001, 2.1-35.8-fold) in cell lines and PCa surgical samples. All 27 markers were confirmed in TCGA-PRAD samples (average TPM: 58 to 10,366). Blood: In Set#I, levels in PCa were 47±2 ( p< 0.0001) compared to BPH (19±1) and controls (18±0.5); AUROC: 0.92 (BPH) and 0.94 (controls), with an accuracy of 85-88%, a sensitivity of 86% and specificities 82 and 93%. For PSA, the AUROC (PCa vs. BPH) was 0.51 ( p= 0.88). PSA was positive in 86% of BPH and was > 10ng/ml in 30%. PSA was positive in 83% of PCa and > 10ng/ml in 40% (Fisher’s p= 0.28). PSA accuracy ( > 10ng/ml) was 48%. Levels in Set#II (BCR) were 44±3. ProstaTest-was positive in 48 (96%). Surgical cohort ( n= 47): Prostatest accuracy 100% pre-surgery. Resection decreased levels (KW-statistic: 57.4, p< 0.0001) from 52±1 to 23.5±2. Conclusions: A 27-gene blood signature was developed for PCa that exhibited a diagnostic accuracy of 92%; significantly better than PSA (48%, p< 0.0001). Surgical resection significantly ( p< 0.0001) decreased levels. Biochemical recurrence was accurately detected (96%). A multi-gene prostate cancer liquid biopsy is likely to have clinical utility in both diagnosis and monitoring of PCa.
Osteonecrosis of the jaw (ONJ) in radium 223 (Ra223)-treated metastatic castration-resistant prostate cancer (mCRPC) patients (pts) with exposure to zoledronic acid and/or denosumab.
Authors: Cao Yen Thi Kim Hong , Trieu Janson , Rojas Vanessa , Elias Michael , Anderson Michael J. , Vogelzang Nicholas J. 
Published: May 2020

5575 Background: Bone health agents (BHA) including denosumab, a monoclonal antibody, and Zoledronic acid (ZA), a bisphosphonate, are recommended for men with CRPC and bone metastases to prevent skeletal-related complications. ONJ occurs in about 5% of patients (pts) on BHA. The incidence of ONJ in pts treated with Ra223 and BHA remains unknown, particularly in those who receive sequential treatment of BHAs. Here we describe the rate of ONJ in a real-world setting in mCRPC pts treated with Ra223 in 3 groups: 1) denosumab alone, 2) ZA alone, and 3) sequential ZA /denosumab or vice versa. Methods: A retrospective analysis of a cohort of mCRPC pts with bone metastases who received Ra223. Follow-up was until date of death or last data entry. Chart inclusion criteria included patients who received Ra223 between November 2010 to August 2018 with documentations of data points. Results: A total of 177 pts received Ra223 between 11/2010 and 8/2018. Median age 73 at 1st Ra223 (range 40-93); Median PSA 15.8- at 1st Ra223 (range 0.1-1952); Demographics-AA-10, C-130, Asian-9, unspecified-28; Median Alk Phos 95 at 1st Ra233 (range 25-1515). 93 % (164/177) received BHA. Of the 164 who received BHA, 45% (73/164) received denosumab only, 37% (61/164) received ZA only, and 18% (30/164) received sequential treatment. ONJ developed in 9.7% (16/164) of all patients on BHA. Denosumab alone caused ONJ in 7 of 73 pts (9.6%). ZA alone caused ONJ in 6 of 61 pts (9.8%). ONJ occurred in 3 of 30 pts (10%) in the sequential group. The median number of doses of BHA before development of ONJ was 10 with denosumab, 20 with ZA, and 19.5 (denosumab) and 22 (ZA) in the sequential group. Conclusions: In patients treated with Ra223 and a BHA, the rate of ONJ is 9.7%. The rate of ONJ was similar in groups treated with denosumab alone, ZA alone, and sequential treatment of ZA and denosumab However, ONJ developed more quickly in patients on denosumab. We conclude that the risk of ONJ is increased in patients treated with Ra223 and BHA. ZA or sequential therapy appears to delay time to onset of ONJ compared to denosumab. Clinicians should be mindful of the toxic synergy between Ra223 and BHA. ZA may be the preferred BHA partner with Ra223.